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5th edition

Pharmacokinetic and
Pharmacodynamic
Data Analysis
Concepts and Applications

Johan Gabrielsson
Dan Weiner
5th edition
Pharmacokinetic and Pharmacodynamic
Data Analysis - Concepts and Applications
Features
• Teaches Pharmacokinetic and Pharmacodynamic concepts to undergraduate and
graduate scientists
• Meets the requirements for courses in Quantitative Pharmacology (Pharmacometrics)
• Uses over 100 real-life Case Studies
• Encourages students to apply the methods outside of the classroom
• Requires very little calculus or statistical methods

Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications

teaches everyday biological data analysis to the undergraduate and graduate levels.
Through numerous examples and over 100 tutorials, scientists learn how to use PKPD
seamlessly in a variety of practical areas, from simple plasma kinetics, multi-compartment
models, nonlinear kinetics, plasma protein binding, pharmacodynamic models, turnover
concepts, receptor binding, functional adaptation and rebound, dose-response-time data
analysis, inter-species scaling, target mediated drug disposition, and a lot more. The text
develops a logical, real-world approach to data and reasoning, showing the reader how to:

• Think both analytically and visually about data

• Use graphics to make a point
• Improve your pattern recognition ability
• Make sound decisions
• Strategize your data analyses
• Appreciate more fully the exciting field of Quantitative Pharmacology

Going beyond mere numerics and calculations, this textbook helps the reader become
life-long learners exceeding the confines of a course. They will find that with little more
PK/PD concepts, their daily professional lives will be more productive, understandable,
and creative.

Johan Gabrielsson, PhD Dan Weiner, PhD

He is professor of integrative He is a consultant and trainer on
Pharmacology at the SLU, PK/PD modeling and an adjunct
Uppsala, Sweden. He has professor with two universities.
conducted numerous workshops He was the original developer of
(6000 participants) on biological WinNonlin.
PK/PD data analysis.
Pharmacokinetic and Pharmacodynamic Data Analysis

II
Pharmacokinetic and
Pharmacodynamic
Data Analysis
Concepts and Applications

5th edition
Revised and expanded

Johan Gabrielsson
Dan Weiner

III
Pharmacokinetic and Pharmacodynamic Data Analysis

This book is dedicated to Barbro and Jenny Gabrielsson for boundless patience
and understanding during preparation of this and earlier editions.
Johan Gabrielsson

They were “so intent on making everything numerical” that they frequently
missed seeing what was there to be seen.
Barbara McClintock
Nobel Prize Laureate

Pharmacokinetic and Pharmacodynamic Data Analysis:

Concepts and Applications, 5th edition, revised and expanded
by Johan Gabrielsson and Dan Weiner

Cover picture: Painting by J. Gabrielsson

©2016 Johan Gabrielsson and Apotekarsocieteten,

Swedish Pharmaceutical Society,
P.O. Box 1136, S-111 81 Stockholm, Sweden

All rights reserved.

No parts of this book may be reproduced by any means, not transmitted, not translated
into a machine language without the written permission of the publisher.

E-book version
Webshop: gabrielsson.dipublish.com
ISBN: 978-91-984078-0-8
diPublish c/o Wapp Media, Sweden 2017

IV
Foreword

Pharmacokinetics is that branch of science, which deals with the time course of drug in the body.
Specifically it is the study of drug absorption, distribution and elimination. The companion subject of
pharmacodynamics deals with the time course of drug action and is intimately linked to pharmacokinetics.
As Lord Kelvin said:

“When you can measure what you are speaking about, and express it in numbers, you know something
about it: but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a
meager and unsatisfactory kind: it may be the beginning of knowledge, but you have scarcely, in your thoughts,
advanced to the stage of science.”

This is especially true of pharmacokinetics/pharmacodynamics (PK/PD) and modern PK/PD has

developed into a relatively sophisticated mathematical discipline.
The importance of PK/PD in drug development is becoming increasingly recognized and now
permeates the program from preclinical development through to Phase IV clinical trials. Specifically in
preclinical studies, PK/PD is used to support drug discovery, interpret toxicokinetic experiments and
via physiological modeling to extrapolate from animal to man. In the clinical program PK/PD is used
to support dose-finding and dose-escalation studies and there is at least one instance where it has been
used to recommend a dose which was not originally studied in the efficacy-safety studies. More recent
applications include the concentration-controlled clinical trial and population PK/PD.
However like all biological experiments, PK/PD data is noisy and one has to use sophisticated data
analysis techniques to estimate parameters of interest. Therefore a scientist working with PK/PD data
has frequently to fit a model to experimental data. One has to be careful about the term model as
applied in PK/PD. There are a number of so-called model independent methods that have become
popular recently. However in a PK/PD context model independent implies fewer assumptions about
the structural PK/PD model. Even with these methods one is often faced with fitting some empirical
expression to the data, for example a sum of exponentials, and when I talk about fitting models to data,
it is meant in this sense.
Most models used in PK/PD are nonlinear functions of the parameters of interest and consequently
severe data analysis problems arise. Therefore nonlinear regression and maximum likelihood techniques
have to be used which are much more computer intensive than their linear counterparts. In addition
there are several theoretical problems specific to nonlinear models, such as nonuniqueness of the solution
and the estimation of confidence intervals. Weighting schemes are a particular problem for PK/PD data
as it is generally impossible to get replicate measurements.
Professional scientists but amateur statisticians often carry out PK/PD data analysis. Consequently
the scientist working in the PK/PD area is dependent on the availability of good software packages.
Despite the lack of a complete understanding of the methodology the user of such packages needs to
be convinced of their reliability and accuracy. Although it is extremely difficult to completely validate
a nonlinear regression program some, perhaps even extensive, testing is required. As a final caveat I
would note that it is incumbent on the PK/PD scientist to obtain a reasonable understanding of the
methodology behind a software package if he or she is going to be able to correctly interpret the output
and diagnostics. It is also desirable that the software producer should provide adequate user support.
The current book is an evolution of the original text, which appeared in 1994, 1997, 2000 and 2010.
It has been expanded to over 1000 pages, an expansion which mirrors the growth of the subject over

V
Pharmacokinetic and Pharmacodynamic Data Analysis

the last decade. It is also testament to the increasing sophistication of PK/PD analyses being undertaken
by scientists working in the drug discovery/development arena. We are seeing a growth in mechanistic
rather than empirical modelling and the current text contains an extensive library of mechanistic models,
particularly in the area of pharmaco­dynamics. In the foreword to the second edition I concluded that the
book would provide a valuable introductory text to new researchers and a useful reference for established
scientists. In addition the book will be a useful reference for a variety of undergraduate courses and could
be used to support a graduate course in PK/PD.

Leon Aarons
Manchester, 2015

VI
Preface to the 5th edition

The 5th edition of Pharmacokinetic & Pharmacodynamic Data Analysis: Concepts and Applications
continues the central thesis of the first four editions: How do we go from data to insight in the most
effective way? That can probably be done by exposing ourselves to a large number of real life datasets
and situations, and solve these problems by pen, paper, and computer. The previous editions of the
book have served as course material during a number of basic and advanced courses within academia,
and at numerous pharmaceutical companies and regulatory agencies all over the globe. Therefore, a
substantial effort has been invested into the new pharmaco­kinetics and pharmaco­dynamics sections,
including many new and updated Case Studies.
The five most common dysfunctions of a kineticist/modeler are lack of experience with exploratory
data analysis; too much trust in the modeling software; weighting away data; slavery under formulas;
and, lack of holistic view of the analysis-modeling process. The book serves to remedy parts of these
dysfunctions, and besides being a repository of kinetic and dynamic datasets and modeling situations,
it is meant to serve as a text on points to consider in biological data analysis in general. The audience is
still industrial pharmacokineticists, pharmacologists, clinical pharmacologists, bioanalytical scientists,
toxicologists and scientists within academia and regulatory bodies.
The basic concepts presented here are fundamental to the pharmacokinetic and pharmaco­dynamic
field. Most are common knowledge among professionals and have been learned through education,
experience, observation and reading. Other ideas have evolved in my own practice and through the
experience of teaching students and observing and evaluating their work. Some of these thoughts have
been formulated in attempting to help students and colleagues overcoming common mistakes and
misconceptions typical among kineticists and junior modelers. A related aim is to build knowledge of
points to consider when analyzing and communicating data. The text addresses ‘What kind of data
does one need to collect in order to answer a specific question?’ The text is a compilation of different
viewpoints worth considering in biological data analyses. Over the years this book has evolved from
focusing on the technicalities of nonlinear regression to dissecting and exploring the biology behind a
concentration-time or response-time course. Having taught pattern recognition since the mid 80s, with
an increasing interest of this topic among students, this subject is further developed within Chapter
6. A new Case Study on target mediated drug disposition is also included as a tutorial that covers
different aspects of antibody kinetics and the use and abuse of the Michaelis-Menten constant Km as an
affinity parameter.
This book is envisioned as a beginning. The reader is encouraged to seek out additional sources and
knowledge on all the subjects offered here. Pharmacokinetics is an exciting and challenging science,
particularly when you couple it to a pharmacological response. Recommended complementary texts
are Clinical Pharmacokinetics by Rowland and Tozer, and Pharmacometrics by Ette and Williams.
I would like to acknowledge colleagues in academia and pharmaceutical industry for their generosity
and support towards kinetic and dynamic reasoning. The vast knowledge of professors Stephan Hjorth
(pharmacology) and Bert A. Peletier (mathematics) have been invaluable throughout the work on this
and earlier texts. Appreciation also goes to Björn Tillman Printografen AB for the professional book
design, and to the Swedish Pharmaceutical Press for agreeing to publish the 5th edition.

Johan Gabrielsson
Gothenburg and Uppsala, November 2015

VII
Pharmacokinetic and Pharmacodynamic Data Analysis

VIII
Table of Contents

1. Chapter 1 1 – General Principles............................................................................................................1

1.1 Introduction..........................................................................................................................................1
1.2 Basic Concepts....................................................................................................................................1
1.3 Why Model the Data?...........................................................................................................................2
1.4 The Art of Successful Modeling............................................................................................................4
1.5 How to Use This Book.........................................................................................................................7

2. CHAPTER 2 – Pharmacokinetic Concepts...........................................................................................13

2.1 Background.......................................................................................................................................13
2.2 One-Compartment Models................................................................................................................14
2.2.1 Intravenous bolus administration..............................................................................................14
2.2.2 Constant rate infusion...................................................................................................................22
2.2.3 Integration of clearance and volume..............................................................................................25
2.2.4 Extravascular administration .........................................................................................................28
2.2.5 Estimation of absorption parameters from first-order input............................................................32
2.2.6 Estimation of absorption parameters from zero-order input...........................................................38
2.2.7 What lies behind the apparent absorption rate constant? .............................................................40
2.2.8 Estimation of bioavailability............................................................................................................41
2.2.9 How does input to the plasma compartment vary?.......................................................................43
2.2.10 Multiple dosing..............................................................................................................................43
2.2.11 Absorption from multiples sites.....................................................................................................46
2.2.12 Conclusions for extravascular dosing ...........................................................................................47
2.3 Plasma and Urine Data.......................................................................................................................48
2.3.1 Basic renal physiology ..................................................................................................................48
2.3.2 Derivation of equations .................................................................................................................48
2.3.3 Analysis of urinary excretion data .................................................................................................50
2.3.4 Estimation of bioavailability from urinary data ...............................................................................56
2.4 Multi-Compartment Models................................................................................................................57
2.4.1 Catenary and mammillary models.................................................................................................57
2.4.2 Intravenous bolus administration...................................................................................................59
2.4.3 Reparameterization of the two-compartment model......................................................................66
2.4.4 Constant rate infusion..............................................................................................................72
2.4.5 Extravascular administration...............................................................................................................74
2.4.6 Plasma and urine data..................................................................................................................76
2.5 Clearance Concepts..........................................................................................................................77
2.5.1 Derivation of clearance..................................................................................................................77
2.5.2 Extraction......................................................................................................................................79
2.5.3 Impact of route of administration...................................................................................................83
2.5.4 In vitro/in vivo comparisons of clearance.......................................................................................85
2.5.5 Hepatic clearance models.............................................................................................................90
2.5.6 Additional readings........................................................................................................................94
2.6 Turnover ............................................................................................................................................94
2.6.1 Background..................................................................................................................................94

IX
Pharmacokinetic and Pharmacodynamic Data Analysis

2.6.2 Introduction to turnover of proteins, peptides and antibodies........................................................97

2.6.3 Turnover of immunoglobulins.......................................................................................................100
2.6.4 Turnover of hormones - Estradiol................................................................................................102
2.6.5 Comparison of models................................................................................................................104
2.6.6 Turnover of body temperature.....................................................................................................106
2.6.7 Feedback....................................................................................................................................110
2.7 Nonlinear Systems – Capacity, Time, Flow and Binding....................................................................112
2.7.1 What causes nonlinearity and how is it assessed?......................................................................112
2.7.2 Nonlinear kinetics – Capacity......................................................................................................114
2.7.2.1 Bolus input - Capacity limited elimination...............................................................................117
2.7.2.2 Constant rate input - Capacity limited elimination...................................................................118
2.7.2.3 First order input - Capacity limited elimination........................................................................118
2.7.2.4 Conclusions for capacity limited elimination............................................................................118
2.7.3 Nonlinear kinetics - Time.............................................................................................................119
2.7.3.1 Background...........................................................................................................................119
2.7.3.2 Turnover of induction.............................................................................................................120
2.7.3.3 Heteroinduction – Pentobarbital induction of nortriptyline.......................................................123
2.7.3.4 Autoinduction.........................................................................................................................126
2.7.4 Nonlinear kinetics - Flow.............................................................................................................129
2.7.5 Nonlinear kinetics - Binding.........................................................................................................129
2.7.6 Nonlinear drug and metabolite models........................................................................................135
2.7.7 Ethanol combines capacity, time and flow dependencies............................................................139
2.8 Non-Compartmental Analysis...........................................................................................................141
2.8.1 Non-compartmental versus regression analysis...........................................................................141
2.8.2 Computational methods – Linear trapezoidal rule........................................................................142
2.8.3 Computational methods – Log-linear trapezoidal rule..................................................................144
2.8.4 Strategies for estimation of lz......................................................................................................146
2.8.5 Pertinent pharmacokinetic estimates...........................................................................................148
2.8.6 Issues related to steady state......................................................................................................152
2.8.7 Metabolite kinetics......................................................................................................................155
2.8.8 When half-life is short relative to input time..................................................................................157
2.9 How to Assess Exposure ................................................................................................................158
2.9.1 What do we mean by exposure?.................................................................................................158
2.9.2 The case(s) for abandoning dose................................................................................................158
2.9.3 Exposure based on total concentrations.....................................................................................163
2.9.4 Exposure based on unbound concentrations..............................................................................167
2.9.5 Conclusions about exposure.......................................................................................................169
2.10 Inter-Species Scaling........................................................................................................................170
2.10.1 When and why do we extrapolate data across species?.............................................................170
2.10.2 What is allometry?.......................................................................................................................172
2.10.3 Allometric equations....................................................................................................................173
2.10.4 Time scales differ between different species................................................................................181
2.10.5 Estimation of parameters............................................................................................................183
2.10.6 The elementary Dedrick plot........................................................................................................184
2.10.7 The complex Dedrick plot...........................................................................................................186
2.10.8 Integration of concepts...............................................................................................................189

X
2.10.9 Physiological variables of 11 animal species and man.................................................................191
2.10.10 Allometric scaling of turnover parameters....................................................................................194
2.10.11 General conclusions about exposure and scaling........................................................................196
2.11 Additional Reading...........................................................................................................................198

3. CHAPTER 3 – Pharmacodynamic Concepts.....................................................................................199

3.1 Background ....................................................................................................................................199
3.2 Definitions........................................................................................................................................200
3.3 Law of Mass Action..........................................................................................................................202
3.4 Receptor Binding Models.................................................................................................................206
3.4.1 Saturation studies.......................................................................................................................206
3.4.2 Displacement studies..................................................................................................................207
3.5 Pharmacodynamic Models...............................................................................................................210
3.5.1 Background................................................................................................................................210
3.5.2 Linear effect-concentration model...............................................................................................210
3.5.3 Log-linear effect-concentration model.........................................................................................211
3.5.4 Ordinary Emax model....................................................................................................................213
3.5.5 Sigmoid Emax model....................................................................................................................216
3.5.6 Composite Emax model used to capture mixture dynamics ..........................................................221
3.5.7 Multiple binding site model..........................................................................................................224
3.6 Interaction Models............................................................................................................................224
3.6.1 Competitive antagonism..............................................................................................................224
3.6.2 Noncompetitive antagonism........................................................................................................225
3.6.3 General empirical dynamic model for two drugs..........................................................................226
3.6.4 Enantiomer interaction models....................................................................................................227
3.6.5 Additional sigmoidal models........................................................................................................228
3.6.6 Kinetics of pharmacological responses........................................................................................229
3.6.7 Area under the response-time curve............................................................................................233
3.7 Turnover Models – Reversible Drug Effects.......................................................................................235
3.7.1 Background................................................................................................................................235
3.7.2 Turnover model taxonomy ..........................................................................................................236
3.7.3 Model characteristics .................................................................................................................246
3.7.4 Initial parameter estimates...........................................................................................................247
3.7.5 Model behavior...........................................................................................................................252
3.7.6 Model extensions........................................................................................................................254
3.8 Turnover Models – Irreversible Drug Effects......................................................................................256
3.8.1 Simple irreversible action – Cell killing..........................................................................................257
3.8.2 Cell growth coupled with cell killing.............................................................................................258
3.8.3 Minimum inhibitory concentration................................................................................................260
3.9 Effect Compartment (Link) Models ..................................................................................................261
3.9.1 Background................................................................................................................................261
3.9.2 One-compartment models..........................................................................................................264
3.9.3 Two-compartment models..........................................................................................................266
3.9.4 Integration of time into the Hill equation.......................................................................................268
3.9.5 Alternative parameterizations......................................................................................................268
3.9.6 Some literature examples and simulations...................................................................................269

XI
Pharmacokinetic and Pharmacodynamic Data Analysis

3.9.7 Problems and pitfalls...................................................................................................................271

3.10 Dose-Response-Time Models..........................................................................................................272
3.10.1 Background................................................................................................................................272
3.10.2 Miotic data..................................................................................................................................273
3.10.3 Locomotor activity......................................................................................................................275
3.10.4 Antinociception...........................................................................................................................278
3.10.5 Body temperature.......................................................................................................................280
3.10.6 Turnover of antipsychotic effects ................................................................................................282
3.10.7 Conclusions about dose-response-time data modeling...............................................................283
3.11 Tolerance and Rebound Models.......................................................................................................284
3.11.1 Background................................................................................................................................284
3.11.2 Systems analysis.........................................................................................................................288
3.11.3 Time dependent attenuation of parameters.................................................................................288
3.11.4 Antagonistic metabolite model....................................................................................................291
3.11.5 Tolerance compartment model....................................................................................................292
3.11.6 Counteracting mechanisms.........................................................................................................293
3.11.7 Feedback and rebound...............................................................................................................294
3.11.8 Simple negative feedback on turnover rate..................................................................................296
3.11.9 Negative feedback via a moderator ............................................................................................297
3.11.10 Negative feedback via a moderator and level of response...........................................................301
3.11.11 Simulation of negative feedback via a moderator ........................................................................302
3.11.12 Pool model – Unidirectional flow..................................................................................................304
3.11.13 Pool model – Bidirectional flow....................................................................................................307
3.11.14 Comparisons with other models..................................................................................................309
3.11.15 Modeling of EEG-time data.........................................................................................................312
3.11.16 Some thoughts about tolerance and dependence models..........................................................316
3.12 Baseline models...............................................................................................................................317
3.12.1 Constant versus variable baseline models...................................................................................317
3.12.2 Oscillating turnover rates.............................................................................................................320
3.13 Transduction Models........................................................................................................................323
3.14 Synergistic Effects Modeled by Turnover Functions..........................................................................325
3.15 Synergistic Effects Modeled by Hyperbolic Functions.......................................................................327
3.16 Logistic Response Models...............................................................................................................329
3.17 Additional Reading...........................................................................................................................332

4. CHAPTER 4 – Modeling Strategies....................................................................................................333

4.1 Background.....................................................................................................................................333
4.2 Plot and Explore Data......................................................................................................................334
4.2.1 Understand your experimental data better...................................................................................334
4.2.2 Pooling of data from multiple subjects.........................................................................................335
4.2.3 Transformation for exploration ....................................................................................................337
4.2.4 Transformation for fitting .............................................................................................................339
4.2.5 Normalizing data.........................................................................................................................341
4.3 How Complicated a Model?........................................................................................................342
4.3.1 How many parameters?..............................................................................................................342
4.3.2 How do we specify the model?...................................................................................................343

XII
4.3.3 Combining several sources of data for analysis...........................................................................347
4.3.4 Parameter identifiability...............................................................................................................348
4.3.5 Ability to estimate parameters.....................................................................................................350
4.4 Obtaining Initial Estimates................................................................................................................352
4.4.1 Graphical methods and linear regression.....................................................................................353
4.4.1.1 Kinetic data............................................................................................................................353
4.4.1.2 Dynamic equilibrium data.......................................................................................................355
4.4.1.3 Dynamic non-steady state data..............................................................................................356
4.4.1.4 Dynamic repeated dose data.................................................................................................360
4.4.2 When all else fails........................................................................................................................363
4.5 Iterations .........................................................................................................................................365
4.7 Assessing the Goodness-of-Fit........................................................................................................368
4.7.1 Analyzing the residuals................................................................................................................369
4.7.2 Graphical presentation of residuals..............................................................................................371
4.7.3 Pure error versus lack of fit..........................................................................................................377
4.7.4 Parameter estimates - Accuracy.................................................................................................379
4.7.5 Parameter estimates - Precision..................................................................................................380
4.7.6 Correlation between observed and predicted values...................................................................381
4.7.7 Correlation between parameters ................................................................................................382
4.7.8 Some comments on the use of WRSS versus -2·Log Likelihood function ...................................386
4.8 Discrimination Between Rival Models...............................................................................................386
4.8.1 F test .........................................................................................................................................387
4.8.1.1 Background...........................................................................................................................387
4.8.1.2 The ordinary Emax versus the sigmoid Emax models..................................................................388
4.8.1.3 The ordinary Emax versus the linear response model................................................................388
4.8.1.4 The hepatic distributed versus parallel tube model.................................................................388
4.8.2 Akaike and Schwarz criteria........................................................................................................389
4.9 Outliers ...........................................................................................................................................390
4.10 A Checklist for Assessing Godness-of-Fit ........................................................................................391

5. CHAPTER 5 – Elements of Experimental Design...............................................................................393

5.1 Background.....................................................................................................................................393
5.2 Tools for Experimental Design..........................................................................................................394
5.2.1 Delta D function...........................................................................................................................394
5.2.2 Variance inflation factor .............................................................................................................396
5.2.3 Partial derivatives........................................................................................................................399
5.2.4 Sensitivity analysis.......................................................................................................................404
5.3 Challenges in Experimental Design...................................................................................................406
5.3.1 Bolus, infusion and first-order input.............................................................................................406
5.3.2 Concentration- and time-dependent kinetics...............................................................................410
5.3.3 Design of toxicokinetic studies....................................................................................................412
5.3.4 Acute versus chronic dosing.......................................................................................................415
5.3.5 Schedule dependence................................................................................................................418
5.3.6 A Strategy for increasing information to model building – individualization of dosing....................419
5.3.7 Active metabolites.......................................................................................................................420

XIII
Pharmacokinetic and Pharmacodynamic Data Analysis

6. CHAPTER 6 – Pattern Recognition....................................................................................................423

6.1 Background.....................................................................................................................................423
6.1 Single and multiple response-time profiles I......................................................................................424
6.3 Single and multiple response-time profiles II.....................................................................................429
6.4 Single and multiple response-time and concentration-response profiles III........................................437
6.5 Single and multiple response-time and concentration-response profiles IV.......................................442
6.6 Single and multiple response-time profiles V.....................................................................................447
6.7 Single and multiple concentration-time profiles VI.............................................................................453
6.8 Single and multiple concentration-time, dose-concentration and parameter-time profiles VII............461
6.9 Conclusions – Pharmacokinetic and Pharmacodynamic Applications...............................................465

Pharmacokinetic Applications............................................................................................................467
PK1 One-compartment intravenous bolus dosing....................................................................................469
PK2 One-compartment oral dosing.........................................................................................................476
PK3 One-compartment 1st- and 0-order input.........................................................................................483
PK4 One-compartment oral dosing ........................................................................................................487
PK5 One-compartment intravenous plasma/urine I ................................................................................494
PK6 One-compartment intravenous plasma/urine II ................................................................................500
PK7 Two-compartment intravenous bolus dosing ...................................................................................505
PK8 Two-compartment distribution models ............................................................................................513
PK9 Modeling of fraction absorbed and nonlinear bioavailability across the liver:
Simultaneously fitting intravenous and oral data..........................................................................518
PK10 Simultaneous fitting of iv/po data ....................................................................................................525
PK11 Two-compartment repeated oral dosing...........................................................................................528
PK12 Intravenous and oral dosing.............................................................................................................532
PK13 Bolus plus constant rate infusion......................................................................................................537
PK14 Multi-compartment model oral dosing..............................................................................................540
PK15 Toxicokinetics ..................................................................................................................................546
PK16 Two-compartment intravenous plasma/urine ...................................................................................549
PK17 Nonlinear kinetics - Capacity I..........................................................................................................553
PK18 Capacity II – Ethanol kinetics............................................................................................................556
PK19 Capacity III - Metabolite kinetics.......................................................................................................563
PK20 Capacity IV - Nonlinear kinetics........................................................................................................570
PK21 Nonlinear kinetics – Heteroinduction ................................................................................................575
PK22 Nonlinear kinetics - Autoinduction ...................................................................................................580
PK23 Nonlinear kinetics - Flow I.................................................................................................................586
PK24 Nonlinear kinetics - Flow II................................................................................................................590
PK25 Two-compartment plasma and urine analysis with rate and ARE plots..............................................596
PK26 Modelling of antibody kinetics after i.v. doses to man.......................................................................599
PK27 Target mediated drug disposition.....................................................................................................602
PK28 Allometry – Elementary Dedrick plot ................................................................................................611
PK29 Allometry - Complex Dedrick Plot.....................................................................................................615
PK30 Turnover I – Sc dosing of hormone...................................................................................................621
PK31 Turnover II – Intravenous dosing of hormone....................................................................................624
PK32 Turnover III – Nonlinear disposition...................................................................................................629
PK33 Transdermal input and kinetics.........................................................................................................634

XIV
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about without even a patch to hide the holes in their shoes, seems
to be more than most mothers can bear. And the saddest part of the
business is they are sacrificing themselves quite uselessly, to a mere
fetish. For very few of them have any thought of hygiene in their
heads, when they toil and moil, pinch and save, that their children
may have shoes: their thought is all of respectability. They are firmly
convinced that to let them go barefoot would be to rob them of all
claim to rank with the respectable, would be to dub them little
ragamuffins in fact, and thus render them pariahs. And better than
that work all night, no matter what it may lead to.
If these mothers were forced to let their children go barefoot,
things would of course be otherwise; and they would be forced,
practically, were they called upon to do so for patriotism’s sake, for
the sake of saving leather that the soldiers might have plenty of
good shoes. There would be no loss of caste then in banishing shoes
and stockings; on the contrary, it would be the correct thing to do,
the ‘just so’; and they would do it right gladly, thankful that they
could do it without exciting comment. And by doing it, they would
both lighten immeasurably the heavy burden they themselves bear,
and add to their children’s chance of developing into sturdy men and
women, men and women able to do good work for their country,
securing for themselves a fair share of life’s comfort and pleasure
the while. For there is proof and to spare that boys and girls alike
are better off all round, stronger, more vigorous, more active,
without shoes than with them, unless the shoes be of better quality
than those most of the respectable poor can afford to buy. Never
would the Strassburg Committee have ventured to call upon parents
to let their offspring go barefoot had they not known that, even so
far as health was concerned, quite apart from the saving of leather,
good, not harm, would result. For in Germany, whoever else may go
on short commons, children, the Fatherland’s future defenders, are
always well cared for. One of the reasons, indeed, that the
Committee give for issuing their notice is that going barefoot is not
only economical, and therefore, as things are, patriotic, but also
hygienic. And that it is, most of us can see for ourselves.
 There are districts both in Scotland and Ireland, to say nothing of
Norway, Sweden, and Switzerland, where there is hardly a shoe to
be found. Yet the people there are more stalwart than in any district
in England where every foot has its shoe. The finest lads I have ever
come across are certainly the Montenegrin; and not one in twenty of
them has either a shoe or a stocking. The only reformatory I have
known where the little inmates are physically quite on a par with
other children, as strong, alert, and light-hearted as other children,
is the Eggenburg Reformatory, in Lower Austria, where both boys
and girls all go barefoot, in winter as well as in summer.
Eggenburg is the one public institution, so far as I know, where
the going-barefoot experiment has been tried, on a large scale, for
the express purpose of benefiting the health of the inmates. And it
was tried there under conditions that were just about as
unfavourable as any conditions the wit of man could have devised.
For the Eggenburg children are for the most part of the poorest of
the poor class, the most demoralised, the criminal or semi-criminal
class; and such children almost always start life heavily handicapped
physically, as well as morally. Everyone who goes to this Reformatory
must have given proof, before he—or she—goes, that his natural
bent is to do what is wrong; that he turns to the left rather than the
right instinctively; that he takes to evil ways, in fact, just as a
duckling takes to water. There were nearly 400 inmates the first time
I was there; and among them, although the eldest was under
sixteen, there were sixty convicted thieves, nine incendiaries, and a
murderer. One boy had been forty times in the hands of the police
before he went to Eggenburg; another, a tiny little fellow, was
suffering from alcoholism when he arrived there. Nor was that all:
very many of the children were being cruelly ill-treated, beaten,
tortured, or starved, when the police took possession of them. Thus
to try this experiment with such material as they were was to invite
failure. And to try it in the Eggenburg district was certainly not to
invite success. For the climate there is bitterly cold in winter. I have
seen snow five feet deep around the Reformatory, and it lies there
for months together. If folk can go barefoot there with impunity, they
can assuredly go barefoot anywhere in England.
To make matters worse, the very officials who were told off to try
the experiment were against it: they resented being called upon to
try it, so sure were they that it was foredoomed. Not one among
them was inclined, therefore, to do his best to render it a success. I
very much doubt, indeed, judging by what they themselves told me
later, whether anyone among them had even the wish that it should
be a success. When Dr. Schöffel, the Provincial Home Minister,
informed them that their charges were to go barefoot, every man in
the institution, every woman too, rose up indignantly and denounced
his project as quite wicked. The Directress of the girls’ wing stoutly
refused to have lot or parcel with any such doings. If he chose to kill
the boys, that was no concern of hers, but kill her girls he should
not, she told him roundly. And to make them go barefoot would be
to kill them, it would be downright murder, she declared; and she
had never a doubt in her mind but that it would.
The storm spread from Eggenburg to Vienna, where public opinion
was strongly on the side of the officials and against their Chief. The
Viennese professed themselves quite shocked at his meanness.
Questions were asked in the Landtag. ‘Is Lower Austria so poor that
she cannot buy shoes for her own adopted children?’ member after
member demanded indignantly. Dr. Schöffel stood his ground firmly,
however. That the experiment should be tried, he was determined;
and for the children’s sake, not the rate-payers’. He was responsible
for the children; it was his duty to see that the best that could be
done for them should be done; and the best was not being done, he
declared. When they arrived at Eggenburg they were almost all
physically below the average of children of their age; they were
lacking in stamina even when not tainted with disease. That in itself
was bad, he maintained; but, what was worse, most of them were
still below the average when they left. These children must each one
of them, while at the Reformatory, be put on a par so far as in them
lay with other children, he insisted. Otherwise they would later, when
out in the world, be handicapped in the struggle for life, unable,
therefore, to hold their own and earn their daily bread. It was, as he
told me himself, for the express purpose of trying to put them
physically on a par with other children, and thus give them a fair
chance of making their way in the world, that he had determined
they should go barefoot.
Consumption is terribly prevalent among the very poor in Lower
Austria, it must be remembered; and it was at that time very
prevalent at Eggenburg. The doctors had long been insisting that the
little inmates ought to live practically out of doors the whole year
round, working on the land, tending cattle. Arrangements had
already been made for them to do so, but a difficulty had arisen.
Working on the land and tending cattle in deep snow meant wet
feet, wet stockings as well as wet shoes; and that for many of them
spelt disaster. Dr. Schöffel was convinced, however, that it was not
the wet feet that did the harm, but the wet shoes and stockings;
and many of the doctors whom he consulted agreed with him. It
was with their warm approval that he had decided to banish
stockings and shoes and leave feet to take care of themselves—to
try the going-barefoot experiment, in fact.
The experiment had long passed the experimental stage when I
paid my first visit to Eggenburg; for, by that time, the inmates had
already been going barefoot for some ten years. From the first it had
proved a marked success, the very officials who had done everything
they could to prevent its being tried, frankly admitted; so marked a
success, indeed, that they had all become hearty supporters of the
new system. Even the Directress of the girls’ wing, who had almost
broken her heart when the change was made, and would have
resigned her post forthwith but for her devotion to her charges,
spoke enthusiastically of the good it had wrought among them. Most
of them were at a trying age, between twelve and sixteen; and most
of them were delicate, never free from coughs and colds. She was
as sure as of life itself, therefore, the first day they went barefoot,
that they would all be ill in bed on the morrow. To her amazement,
however, as she told me, when the morrow came, there was no sign
of special illness among them. On the contrary, instead of coughing
more than usual, they coughed less, and were in less urgent need of
pocket-handkerchiefs. Before a week had passed the great majority
of them had ceased coughing at all, and not one of them had a cold
in her head.
The Director told me much the same tale; as it was with the girls
so was it with the boys. By banishing shoes and stockings, he
declared, Dr. Schöffel had practically banished colds with all their
attendant evils. Under the new system, it was a rare thing for any
boy to develop a cold after being at Eggenburg a week. The general
health of all the children had improved quite wonderfully, both he
and the Directress assured me, since going barefoot had become the
order of the day. And what they said was confirmed by what I heard
from every doctor I came across who knew Eggenburg; was
confirmed, too, by what I saw there with my own eyes. For a finer
set of youngsters than the boys and girls there I have never seen in
any institution, and have not often seen anywhere else.
I had hardly crossed the threshold of Eggenburg before I heard,
what I rarely hear in institutions, peal after peal of hearty laughter;
and I saw little urchins flying as the wind in pursuit of something, I
could not tell what. The very way they threw up their heels as they
ran, the speed with which they went, showed the stuff of which they
were made, the strength of their legs and backs; while the cries they
raised left no doubt as to the strength of their lungs. There was not
a laggard among them, not a weakling. Some of them, it is true,
would have been all the better for more flesh on their bones, I found
when I came to examine them; and some few were not quite so well
grown as they ought to have been. Still they were a wonderfully
vigorous set, considering the handicap with which they had started
in life; and they were as alert as they were vigorous. They swarmed
up poles and twirled themselves round bars, in quite professional
style; and went through their drill with head erect and soldierly
swing. Evidently they were not troubled with nerves at all, nor had
they any fear at all of strangers. They met my advances in the most
friendly fashion; and answered my questions intelligently without
hesitation, looking at me straight the while. Their eyes, I noticed,
were not only bright, but, oddly enough, full of fun, many of them.
They were a light-hearted set, it was easy to see, bubbling over with
delight at being alive; they were a kindly sociable set, too, on good
terms with themselves, one another, and even the officials.
This Eggenburg experiment certainly proves that both boys and
girls are the better, not the worse, for going barefoot. Why, then,
should they wear shoes? The wearing of them is sheer waste,
surely; and in war days waste of any sort is unpatriotic, especially
waste in shoes. For leather is none too plentiful, and is becoming
scarcer and scarcer from day to day; while it is only by straining
every nerve that shoemakers can keep the men at the Front even
decently well shod. Were all the children in England to go barefoot,
even if only for the next three months, our soldiers would many of
them have much better shoes than they have. And most children
would be delighted to go barefoot; and very many mothers would be
delighted to save the money they now spend on shoes, if only the
School Authorities, by appealing to them to do so for their country’s
sake, would give them the chance of doing so without offence to
their fetish, respectability. Unfortunately, many of these Authorities
seem to prefer the worst of leaking, toe-crippling shoes to bare feet.
I once asked a certain Head Master to let a little Gipsy, who was
sojourning in his district, go to his school without shoes. She had
never worn them and did not wish to wear them. He was quite
shocked. Such a thing was impossible, he assured me. The tone of
the whole school would be lowered were a barefoot child to cross its
threshold!
Edith Sellers.
 LONG ODDS.
by boyd cable.

This story belongs to an officer of the Canadians who at the time

of its happening was playing a part in the opening months of the
war as a private in the French Foreign Legion. In that capacity he
saw a good deal of the men of our first Expeditionary Force, and
although he is full of good stories of their amazing doings, he tells
this particular one as perhaps the best and most typical example he
met of the cold-blooded contempt of certain death, the calm
indifference to consequences, the matter-of-fact tackling of the
impossible which were such commonplaces with the old Regular
Army in the first days, and which perhaps were the main factors in
the performance of so many historic feats of arms.
It was during the Retreat, in the middle of that constant series of
forced marches and hard fighting, when the remnants of retiring
regiments were inextricably mixed, when the wounded were left
behind, and the unwounded who were unable to keep up with their
column or who strayed from it in the darkness found themselves
blundering about the countryside, dodging groups of enemy cavalry
and columns of enemy infantry, being fed and guided by the French
villagers, working always towards the sound of the guns and
struggling to rejoin their own army, that three just such stragglers
after a careful reconnaissance ventured into the outskirts of a tiny
French hamlet. One, the Canadian (who had been in Paris on the
outbreak of war and, fearing that it would be months before a British
force could take the field, had signed on in the French Foreign
Legion and so made sure of an early and ample dose of the
fighting), wore the picturesque dress of a private of the Legion;
another was a French infantry of the Lines-man, and the third a
private of a British infantry regiment. The ‘khaki,’ for no particular
reason, except that he apparently took it for granted that it should
be so, more or less took command of the party, while the Canadian,
who spoke fluent French, acted as interpreter both between the
party and the French ‘civvies,’ as the local inhabitants were
indiscriminately described by the Englishman, and in conveying the
orders of the self-appointed C.O. to the non-English-speaking ‘piou-
piou.’
Enquiry of the villagers brought the information that there were no
Germans in the hamlet, that a party of Uhlans had ridden through
towards the south an hour before, and that nothing had been seen
of any Germans since.
‘Good enough,’ said the khaki man on hearing this. ‘I’m just about
ready for a shut-eye myself after trekkin’ all last night. We’d better
lie up till it’s gettin’ dark again, and then shove on an’ see if we can
get the touch with our own push. You might ask ’em if this dorp has
anythin’ goin’ in the way o’ rations—rooty an’ cheese an’ a pot o’
beer would just suit my present complaint.’
But the village did better than bread and cheese. The village—
women, old men, and children—escorted the three warriors to the
estaminet in the main street and with voluble explanations handed
them over to the estaminet keeper.
‘Food? But assuredly yes—soup, good strong soup, and all ready
and hot; an omelette, a very large omelette for three, to be ready
the moment the soup was finished with; and then a veal stew, and
cream cheese, and wine—wine white or red, whichever messieurs
preferred.’
‘Fust class. Canada, tell ’er fust bloomin’ class. I’ll give up dinin’ at
the Carlton an’ Savoy an’ come ’ere reg’lar in future, tell ’er. An’ how
long before the bugle sounds for dinner?’
At once, they were told. If they would enter, the soup would be
served as soon as they were seated. But the khaki demurred at that.
‘I must ’ave a wash first,’ he declared. ‘I ’aven’t ’ad a decent wash
for days. Just ask ’er if she’ll show me where the pump is.’ He
extracted soap and a very dirty towel from his haversack and
followed his conductress out to the back, whence presently came the
sound of pumping water, a vigorous splashing and mighty blowing.
‘Come on, Tommy,’ said the Canadian when the other appeared
again clean, save for the stubble on his chin, glowing and rosy.
‘We’ve started the soup. Good goods too. Pitch in.’
‘That looks good,’ said Tommy sniffing hungrily. He pulled down
his shirt-sleeves and carefully deposited in the corner near his chair
the rifle, haversack, and ammunition-pouches he had carried with
him out to the pump and in again. ‘But we don’t want them Oo-lans
’oppin’ in an’ spoilin’ the dessert. There ain’t enough o’ us to post
proper pickets an’ outposts, but wot’s the matter wi’ enlistin’ some o’
them kids for temporary duty? I’ll bet they’d spot a Oo-lan a mile off
an’ tip us the wink if they was comin’ this way.’
There were plenty of volunteers for the duty, and half a dozen of
the old men of the village hobbled off to post themselves at various
points, each with several enthusiastic small boy gallopers in
attendance to carry urgent despatches as required.
Then Tommy sat down, and the three ate and drank ravenously.
They devoured the soup, the omelette, and the stew, and were
proceeding with the cheese when they heard the patter and rush of
flying feet outside. Next instant one boy burst into the room,
another followed in a whirlwind rush, and the two broke into
breathless and excited speech.
The first dozen words were enough for the Canadian. ‘They’re
coming,’ he said abruptly to the others and jumped from his seat.
‘Very many Germans, the kid says. Come on, we must hustle out of
this quick.’
He ran to the door and looked out, the small boys following, still
talking rapidly and pointing and gesticulating. The Canadian took
one look and stepped back instantly under cover, the French piou-
piou, who had followed close on his heels, doing the same. ‘They’re
not in sight yet, but from what the kids say they should be round the
corner and in sight in minutes. They’re coming from the north, so
we’d better slide out south—or hike out into the fields and find a
hole to hide up in.’
‘Comin’ from the north, eh?’ said the Englishman. He was quickly
but methodically stowing the remains of the long loaf in his
haversack, and that done slipped quickly into his accoutrements.
‘That means they’re goin’ on the way we was tryin’ to stop ’em goin’,
an’ pushin’ up into the firin’ line.’
The Canadian and the piou-piou were engaged in rapid talk with
the landlady and a few other women and a couple of old men who
had hurried in. Tommy walked over to the door, stepped outside,
and had a careful look round. ‘Look ’ere,’ he said calmly, stepping
back into the room. ‘There’s a good ditch on both sides o’ the road.
You an’ Froggy ’ad better take a side each. I’ll take the middle o’ the
road, an’ there’s a barrel outside I can roll out there for cover.’
The Canadian stared at him blankly. ‘What d’ you mean?’ he said.
‘What are you going to do?’
‘Why, we’re goin’ to stop them, of course,’ said Tommy, looking at
him with an air of slight surprise. ‘You said they was Germans an’
goin’ south. That means they’re goin’ to reinforce their firin’ line, so
we’ll ’ave to stop their reinforcin’ game. Come on, you two ’ad better
take cover, an’ we’ll give ’em socks as they come round the corner.’
He walked outside and proceeded to roll the empty barrel into the
middle of the road a little way down from the estaminet, which was
the last house of the village. He left an utterly dumbfounded
Canadian and an impatient and non-comprehending Frenchman who
was rapidly reduced to a state of incredulous amazement by the
information which the Canadian, after a long breath and a longer
pause, proceeded to impart to him.
Now the Canadian, who is responsible for this story, openly
confesses that the last thing on earth he should have thought of
attempting was any resistance of the German advance, and more
than that, that it was with the greatest possible reluctance he did
finally join the imperturbable Tommy in the impossible task. He tried
first to point out the folly of it.
‘See here, Tommy,’ he called from the inn door. ‘You don’t rightly
understand. There’s hundreds of these chaps coming, thousands of
’em for all I know, but at least a regiment from what the old man
says who saw them. We can’t do anything to a lot like that. We’d far
better get off the grass while we’ve a chance.’
But Tommy had planted his empty barrel fairly in the middle of the
road and was settling himself snugly at full length behind it, his legs
spread wide and left shoulder well advanced after the approved
fashion of his musketry instructor. ‘They’re goin’ south,’ he called
back. ‘An’ we come over ’ere to stop ’em going south. So we’ll just
’ave to stop ’em.’ And he commenced to lay cartridges in a
convenient little pile at his elbow and push a clip into his rifle
magazine.
Even then the Canadian hesitated. The whole thing was so utterly
mad, such a senseless throwing away of their three lives that he was
still inclined to clear out and away. But that prone figure in the road
held him. He felt, as he puts it himself, that he couldn’t decently
leave the beggar there and run away. And a call from outside settled
the matter by the calm assurance it held that the two of them were
going to stand by and see the game through. ‘You two ’ad better be
jildi.[3] I can see the dust risin’ just round the corner.’
The Canadian flung a last hurried sentence to the piou-piou, ran
out and across the road and dropped into the ditch in line with the
barrel. The Frenchman looked round at the women and old men,
shrugged his shoulders and laughed shortly. ‘These mad English,’ he
said hopelessly, ‘but, name of a name, what can a Frenchman do but
die along with them?’ and he too ran out and took his place in the
nearer ditch in line with the others.
Tommy looked over his shoulder at him and nodded
encouragingly. ‘Good man, Froggy,’ he said loudly, and then turning
to the Canadian and lowering his voice to a confidential undertone,
‘I’m glad to see Froggy roll up, for the credit of ’is reg’ment’s sake—
whatever ’is reg’ment may be. ’E was so long, I was beginnin’ to
think ’e was funkin’ it.’ The Canadian admits to a queer relief that he
himself had not ‘funked it,’ but he had little time to think about it.
A thin dust rose slowly from the road at the distant bend, and ‘’Ere
they come,’ said Tommy. ‘Don’t begin shootin’ till I do. We want to
get into the brown of ’em before we start, an’ we haven’t cartridges
enough to keep goin’ long. I think about four ’undred should be near
enough the range, but I’ll try a sightin’ shot first at that an’ you’ll see
where it lands.’
For long interminably dragging minutes the three lay there, and
then suddenly, in a bang that made him jump, the Canadian heard
the soldier’s first shot. ‘Just short,’ said Tommy coolly. ‘Better put
your sights four fifty an’ take a fine sight. Come on, let ’em ’ave it.’
The three rifles opened in a crackle of rapid fire, and far down the
road a swirl of dust and a stampede of grey-coated figures to the
sides of the road showed the alarm that the sudden onslaught had
raised. It took several minutes for the crowd to get to any sort of
cover, and before they did so they evidently began to understand
how weak was the force opposed to them. The grey mass dropped
to the road and next minute a steady drum of rifle fire and a storm
of bullets came beating down on the three. The road was pavé,
floored with the flat cobble-stones common on first-class French
roads, and on these the bullets cracked and smacked with vicious
emphasis, ricochetted and rose with ugly screams and whirrs and
singings. A dozen times in that first minute the hollow barrel banged
to the blow of a bullet, but the figure behind it kept on firing steadily
and without a pause. And presently the Germans, impatient of the
delay perhaps, or angered by the impudence of the attack of such a
handful as they were now sure blocked the way, began to climb over
the fence along the roadside and move along the fields firing as they
came, while another group commenced to trot steadily straight down
the road. ‘Now then, Canada,’ called Tommy, ‘pick your target an’ tell
Froggy we’ll fire in turns. We can’t afford to waste shots.’
 So the three commenced to fire steadily and in turn, each waiting
after the other’s shot to see if a man fell, each calling to the others
in triumph if a man went down after their shot, growling angrily if
the shot missed. They made good shooting amongst them, the man
in the middle of the road an unmistakable best and the Canadian
second. Their shooting in fact was so good that it broke the attack
down the road, and presently the remainder of this force ran
crouching to the ditches, jumped into them, and stayed there.
But because the ammunition of the three was almost gone the
affair was almost over, and now there appeared a new factor that
looked like ending it even before their cartridges gave out. Back in
the ranks of the main body three or four men grouped about a
machine-gun opened a rapid fire, and the hailing bullets clashed on
the walls of the estaminet, swept down on to the stones of the pavé,
found their range and began drumming and banging on the barrel.
The soldier beside it quietly laid down his empty rifle and looked
towards the Canadian. ‘I’m done in,’ he called. ‘Punctured ’arf a
dozen places.... You two better keep down ... let ’em come close,
then finish it ... wi’ the bayonet.’
That struck the Canadian as the last word in lunacy; but before he
could speak, he saw the barrel dissolved in splintering wreckage
about the figure lying on the road. Tommy raised his head a little
and called once more, but faintly. ‘Good fight. We did all we could ...
to stop ’em. We did stop ’em all a good time ... an’ we stopped a lot
for good.’ A gust of bullets swept lower, clattered on the stones, set
the broken barrel staves dancing, hailed drumming and thudding on
the prone figure in the road.
Both the Canadian and the Frenchman were wounded severely,
but they still had the strength to crawl back along the ditch, and the
luck to emerge from it amongst the houses in time to be hidden
away by the villagers before the Germans arrived. And that night
after they had passed through and gone, the Canadian went back
and found the body of the soldier where it had been flung in the
ditch—a body riddled and rent to pieces with innumerable bullet
wounds.
The Canadian had the villagers bury the body there close outside
the village, and wrote on a smooth board the number and name he
took from the identity disc about the dead man’s neck. And
underneath it he wrote in indelible pencil ‘A good fighting man,’ and
the last words he had heard the fighter gasp—‘We did all we could
to stop them; stopped them all a good time, and stopped a lot for
good.’
And as the Canadian said afterwards, ‘That same, if you
remember their record and their fate, being a fairly close fitting
epitaph for the old Contemptible Little Army.’

FOOTNOTES
[3] ‘Jildi’—quick.
 A PEEP AT AN OLD PARLIAMENT.
by sir henry lucy.

A short time ago an unknown friend, ‘thinking it may interest you,’

sent me what turned out to be a precious volume. Its full title runs
thus: ‘Random Recollections of the House of Commons from the
Year 1830 to the Close of 1835, including Personal Sketches of the
Leading Members of all Parties; by One of No Party.’ Readers of the
Cornhill will be not the less attracted by it since, as the imprint
shows, it was published in 1836 by the eminent firm of Smith, Elder
& Co., at that date located at Cornhill.
Throughout the volume ‘One of No Party,’ whom, for the sake of
brevity, I will in future refer to by the letter Q, preserves his
anonymity. In a modest preface he describes himself as ‘during a
very regular attendance in the House of Commons for several years
past being in the habit of taking notes of what was most interesting
in the proceedings, as well as of the personal and oratorical
peculiarities of the leading members.’ As ‘One of No Party’ and all
the historical personages who live again under the magic of his
graphic pen have long since passed on to another state, it would not
be indiscreet if the day-books of the old firm in Cornhill for the year
1835 were looked through and his identity revealed.
Alas, poor Yorick! The final—to be precise, the penultimate—
chapter of the life-story of his book has something touching in its
sadness. Its price on the day of publication is not mentioned. Pencil
memoranda on the fly-sheet indicate that fourscore years later the
second-hand bookseller to whom its possession fell temptingly
offered it at the price of one shilling. There being apparently no
bidding, the shilling was crossed out and sixpence substituted.
Finally, oh ye who pass by remaining obdurate or worse still
indifferent, the volume, with its old-fashioned brown paper back
bound with a strip of cloth, was thrown into the fourpenny box,
receptacle of many unrecognised but memorable treasures. As
affording a vivid peep at an historic Parliament, few have exceeded
the intrinsic value of this time-and-weather-stained volume.
Beginning his record in the Unreformed Parliament of 1830, Q
indulged himself in the production of a series of thumb-nail sketches
of eminent members long since gone to another place, whose names
live in history. Here we have the men as they lived and dressed,
moved or spoke, depicted by a keen-sighted independent looker-on.
In this Parliament Sir Charles Wetherell, Member for Bristol, high
Tory of a type now extinct, held a prominent and popular place.

‘He never opened his mouth,’ Q says, ‘but the House was
convulsed with laughter, Wetherell himself preserving a
countenance morose in its gravity.’

His personal appearance sufficed to attract attention.

‘His clothes are always threadbare. I never saw a suit on

him for which a Jew old-clothes man would give ten shillings.
They always look as if made by accident, hanging loosely
about his tall figure. As for braces, he has an unconquerable
aversion to them.’

There is a story about the famous Member for Bristol which Q

must have heard but does not relate. When with frequent gestures
he addressed the House his unbraced trousers parted from his
waistcoat, displaying a considerable rim of shirt. A member, gravely
rising to a point of order, once called the attention of the Speaker to
the lapse. Manners Sutton, who filled the Chair at the time, with
equal gravity declined to interfere. ‘It is,’ he said, ‘the hon.
gentleman’s only lucid interval.’
 Leaving the House at a quarter past seven one morning, having
fought the Reform Bill in Committee through a long series of
divisions, Wetherell discovered it was raining heavily. ‘By G—,’ he
said, ‘if I had known this we would have had a few more divisions.’
A contemporary of Wetherell’s, an active fellow-worker against the
Reform Bill, was Croker, object of Macaulay’s particular aversion, a
prejudice shared by Disraeli. Q describes him as tall, well-made, full
six feet in height.

‘He is bald-headed and has been so for ten or twelve years.

He is about sixty years of age, for one half of which time he
has been in Parliament. He is a very fluent speaker, but his
elocution is impaired by the circumstance of his not being
able to pronounce the letter R. His gestures are violent, often
theatrically so. He makes infinitely varied evolution, wheeling
his body round and round, by that means managing to
address by turns not only every part of the House, but almost
every member in it. Like a hen on a hot girdle, as an Irish
member describes him.’

Through a series of weeks Croker spoke every night against

clauses of the Reform Bill. Some nights he made as many as twenty
speeches occupying three hours of the sitting. His apprehension of
disastrous results accruing from the passing of the Bill, fear shared
by Sir Charles Wetherell, was justified by the event. In both cases
the enlarged constituencies rejected their candidature.
At the date of this fascinating record, which closes with the
session of 1835, neither Disraeli nor Gladstone was yet in the House.
Sir Robert Peel, unconscious of what was in store for him in the way
of personal connection with them, was Leader of the Tory party in
the House of Commons, a post to which he succeeded on the death
of Canning. Q gives us one of his vivid sketches of the living man:
 ‘He is remarkably good-looking, rather above the usual size,
and finely proportioned. He is of clear complexion, full round
face, and red-haired. His usual dress is a green surtout, a
light waistcoat, and dark trousers. He generally displays a
watch-chain on his breast, with a bunch of gold seals of
unusually large dimensions and great splendour. He can
scarcely be called a dandy, and yet he sacrifices a good deal
to these graces. I hardly know a public man who dresses in
better taste. He is in the prime of life, being forty-seven years
of age. His whole appearance indicates health. He is capable
of undergoing a great deal of fatigue.’

It was Peel’s custom to remain in the House till one or two o’clock
in the morning, later if necessary. Nor was he a quiescent listener,
following the debate with tireless attention and occasionally
intervening. In this respect Disraeli and Gladstone, brought up at his
feet, were equally close in their attendance and attention. Up to the
last both, whether in office or in Opposition, seated themselves
when the Speaker took the Chair, and with brief interval for dinner
remained till the House was up. The fashion of to-day is widely
different, the habit of the Premier and the Leader of the Opposition
(when there was one) being to withdraw to the privacy of their
respective rooms as soon as questions are over, an example loyally
followed by their colleagues.
I don’t know why, but it is something of a surprise to learn that Sir
Robert Peel was a red-haired man. His son Arthur, who for many
years added grace and authority to the Speaker’s Chair, had raven
locks. The circumstance lends support to Q’s quaint theory that in
the House of Commons red hair is the concomitant of supreme
ability. There is none in the present House.
It is curious and interesting to find in this close contemporaneous
study of Sir Robert Peel two mannerisms strongly marked in his most
famous disciple when in due time he filled his master’s official place
in the House of Commons. Q describes how Sir Robert, when
speaking on any great question, was accustomed to strike at regular
intervals the brass-bound box which lies on the table, in front of
which a Minister is habituated to stand whilst addressing the House.
Nothing if not precise, Q, with his eye on the clock, reckoned that
Peel smote the box at the rate of two strokes a minute. Old
members of the House of Commons will recall this curious habit as
practised by Gladstone. It was occasionally varied by another trick of
driving home his argument by smiting the open palm of his left hand
with his right. The consequence was that he frequently drowned in
the clamour the concluding words of his leading sentences.
Another trick of Peel’s, unconsciously imitated by his pupil, was
that of turning his back on the Speaker and addressing passages of
his speech directly to supporters on the bench behind him or seated
below the gangway. This is a violation of the fundamental rule of
order requiring a member on his legs to address himself directly to
the Chair. In Gladstone’s case it afforded opportunity for welcome
diversion on the part of members on the benches opposite, who
lustily cried ‘Order! Order!’ Interrupted in the flow of his argument
and not immediately recognising the cause, he added to the
merriment by turning round with inquiring look at his tormentors.

‘Sir Robert is the idol of the Tory Party,’ writes this shrewd
observer. ‘With the Conservatives in the House of Commons
everything he says is oracular. He can do with them and make
of them what he pleases. They are the mere creatures of his
will, are as much under his control, and as ready to be
formed and fashioned in any way he chooses, as is the clay in
the hands of the potter.’

Ten years later Peel, counting upon this deference, and believing
with Q that the Tory Party was in all matters submissive to his
command, declared himself a Free Trader. Whereupon, as happened
in the old potter’s shop visited by Omar Khayyam, there was revolt
by the clay population.
 And suddenly one more impatient cried:
‘Who is the Potter, pray, and who the Pot?’
The awkward question was answered by Peel’s former vassals
uprising and turning out his Government.

The name of Colonel Sibthorpe lingers in the Parliamentary gallery

of notabilities of the Unreformed Parliament. Q describes him as
woefully deficient in judgment.

‘If there be a right and a wrong side to any subject he is

sure to adopt the wrong one. He never makes a very long
speech because he cannot. But he speaks on every subject,
and in Committee it is no unusual thing for him to make
fifteen or twenty speeches in one night.’

Like the maid in the pastoral poem, Colonel Sibthorpe’s face was
his fortune, at least the early making of it.

‘Two or three Senators rejoice in tufts,’ Q writes, ‘and a few

more in whiskers of decent proportions. Compared with the
moustache and whiskers of the gallant Colonel one feels
indignant that they should be dignified by the name. The
lower section of his face, drawing a straight line from ear to
ear immediately under his nose, is one great forest of hair.
You hardly know whether he has a mouth or not, so
completely is it buried amidst the surrounding crop of hair.’

This personal peculiarity elicited from O’Connell a fair example of

the sort of humour that in these past times appealed to an assembly
grateful for temporary deliverance from a state of boredom.
Sibthorpe, making one of his incoherent attacks upon the Liberal
majority, said:
 ‘I am no party man. I have never acted from party feelings,
but I must say I do not like the countenances of hon.
gentlemen opposite.’

O’Connell, following, retorted amid what Q describes as peals of

laughter:

‘We who sit on this side certainly have not such remarkable
countenances as that of the gallant Colonel. I would not
abate him a single hair’—here resounded a peal of laughter
—‘in good humour on this or any other ordinary occasion.’

Macaulay, seated in the Commons as Member for Leeds, a

connection broken when he went out to India as a Member of
Council, did not escape Q’s searching and shrewd observation. He
gives a description of his personal appearance founded on the style
of the ‘Police News’ circulating particulars respecting an absconded
criminal:

‘His personal appearance is prepossessing. In stature he is

about middle size and well formed. His eyes are of a deep
blue and have a very intelligent expression. His complexion is
dark, his hair of a beautiful jet black. His face is rather
inclined to the oval form. His features are small and regular.
He is now in the thirty-eighth year of his age.’

Passing through the stately hall of the Reform Club, I often stop to
look at a portrait of Macaulay hung on the wall at the foot of the
stairway. One would not recognise it from this minute description of
the Member for Leeds who sat in the Parliament in the early ’thirties
of the last century. But between the printed letter and the painted
canvas a period of thirty years stretched.
In his incomparable biography of his uncle, Sir George Trevelyan
tells of the success of his maiden speech. Q, who heard it, describes
it as electrifying the House. He adds that by refraining from early
reappearance in debate Macaulay shrewdly preserved his laurels.

‘He had no gift for extemporaneous speeches. His

contributions to debate were carefully studied and committed
to memory. He bestowed a world of labour on their
preparation. In every sentence we saw the man of genius,
the profound scholar, the deep thinker, the close and powerful
reasoner. His diction was faultless. As a speaker, he was not
forcible or vehement, carrying his audience away with him as
by force. Rather, by his dulcet tones and engaging manner, he
took his hearers with him willing captives.’

Whilst the late Duke of Devonshire sat in the House of Commons

as Lord Hartington, I frequently found in him curiously close
resemblance, mental and physical, to Lord Althorpe, Leader of the
House of Commons during Lord Grey’s premiership, and the short
duration of the first administration of Lord Melbourne. The
impression is confirmed by Q’s description.

‘He was one of the worst speakers in the House. It was a

truly melancholy spectacle to see him vindicating the
Government when in the progress of the Irish Coercion Bill of
1833 it was assailed by O’Connell, Sheil, and other Irish
Members. He could not put three or four sentences together
without stammering, recalling his words over and over again.’

This is an exaggerated description of Lord Hartington’s manner of

speech. In later days he with sedulous practice improved. His
speeches, found to be surprisingly good when read from verbatim
report, suffered considerably by ineffective delivery.
We come nearer to Lord Hartington as Q proceeds with his study
of Lord Althorpe.
 ‘He has a sound judgment, which makes him invariably
take the common-sense view of a subject. With all his faults
as a speaker he was much esteemed by men of all parties. It
was impossible for anyone, however much he might differ
from him in sentiment, not to respect him. Nothing could
make him lose his temper. In the most violent altercations,
amid scenes of greatest uproar and confusion, there he stood
motionless as a statue, his face shadowing forth the most
perfect placidness of mind.’

This might have been written of Lord Hartington through many a

stormy scene in the House of Commons, as he sat on the front
Opposition Bench, one hand in his trouser pocket, his hat tilted over
his nose, his face as stony as that of the Sphinx.
It is common experience in modern Parliaments that men who
have attained the highest position at the Bar have been failures in
the House of Commons. Illustrations of the rule are provided in the
cases of Lord Davey and Lord Russell of Killowen. The former, who
probably never opened his mouth in a Court of Law under a fee of
one hundred guineas, when as Sir Horace Davey he spoke in the
House of Commons was as successful as the traditional dinner bell in
emptying the Chamber. During a long parliamentary career Sir
Charles Russell only once rose to the height of his fame as an
advocate at the Bar. It was when in debate he pleaded the cause of
Home Rule, whose final triumph he did not live to see. Exceptions
are found in the cases of Sir John Herschell, who, entering the
House of Commons as an unknown barrister, won his way to the
Woolsack, and Sir Edward Clarke, who, if he had set his mind on the
same goal, would certainly have reached it.
That this state of things, though paradoxical, is not new appears
from the case of Lord Jeffrey as narrated by this shrewd observer.
Apart from his pre-eminence at the Scottish Bar, Jeffrey’s editorship
of the ‘Edinburgh Review’ invested him with double personal
interest. His maiden speech was looked forward to with absorbing
interest. He rose in a crowded House. According to the implacable Q,
the effort was a failure so lamentable that he never repeated it,
content with briefly taking part in debate only when the duty was
imposed upon him in connection with his office as Lord Advocate. In
delivering his maiden speech he spoke for an hour and twenty
minutes with unparalleled rapidity of delivery. Unfaltering, he
proceeded to the end.

‘His manner was graceful, his voice clear and pleasant.

Both lacked variety and flexibility. The discourse was as
unintelligible to the majority of its auditory as if he had
spoken some abstruse article intended for the “Edinburgh
Review” in answer to Kant or some other German
metaphysician.’

Jeffrey was approaching his fiftieth year when he entered

Parliament. He is described as being

‘Below the middle size and slender in make. His face is

small and compact, inclining to the angular form. His
eyelashes are prominent. His forehead is remarkably low
considering the intellectual character of the man. His
complexion is dark and his hair black.’

Cobbett, who at the age of seventy-three sat in the same

Parliament with Jeffrey, was of a different physical type. Six foot two
in height, he was one of the stoutest men in the House.

‘His ruddy complexion was crowned by a shock of milk-

white hair. His usual dress was a light grey coat, a white
waistcoat, and kerseymere breeches of sandy colour, into
whose pockets he used to thrust his hands when he walked
about the House. There was something so dull and heavy
about his whole appearance that anyone who did not know
 him would have set him down for a country clodpoll—to use a
favourite expression of his own—who not only never read a
book or had a single idea in his head, but was a mere mass of
mortality without a particle of sensibility of any kind.’

Lord John Russell, at this time a member of Lord Melbourne’s

Cabinet equally with Jeffrey, had nothing in common with Cobbett
except a light-coloured waistcoat and kerseymere trousers of a
sandy complexion. His height was even less than that attained by
the famous editor of the ‘Edinburgh.’ Q describes him as

‘Considerably below middle size, slenderly made, and

presenting the appearance of a person of weakened
constitution. His features are large and broadly marked, his
complexion pale, his countenance of a pensive cast. He
scarcely ever indulges in a smile.’

He is roundly described as one of the worst speakers in the

House. His voice was weak and his enunciation imperfect, hampered
by stammer or stutter at every fourth or fifth sentence. He had a
habit of repeating frequently three or four times the first two or
three words of a sentence. His oratorical style was further
embellished by a hesitating cough. Q supplies a verbatim note taken
down as Lord John stood inanimate at the table, his voice inaudible
to one-half of his audience. ‘I—I—I—hem—think the motion of the
honourable member is—is ill-timed at the—at the—hem—present
moment.’
Q is inexplicably hard on Palmerston, who at the early age of
forty-five attained the position of Foreign Secretary.

‘The situation he fills in the Cabinet,’ he writes with solitary

touch of personal rancour, ‘gives him a certain degree of
prominence in the eyes of the country which he certainly does
 not possess in Parliament. His talents are by no means of a
high order.’

He is described as an indifferent speaker, handicapped like his

colleague Lord John Russell by a vocal trick of stuttering and
stammering. ‘He is very indolent, irregular in his attendance upon his
parliamentary duties, and when in the House by no means active in
defence of his principles or his friends.’
Tall and handsome in person, he was always dressed in the height
of fashion, a habit which we are told suggested to The Times the
sobriquet of ‘Cupid,’ by which, with levity unknown in Printing House
Square in these later days, it was accustomed to make editorial
allusion to the Foreign Secretary.
Hume is described as head of the country Liberal Party.

‘He is short-necked, and his head is one of the largest I

have seen. His hair, of dark brown tipped with grey, is long
and bushy; his face fat and round, and his complexion has
that rough, healthy aspect common among gentlemen-
farmers.’

Hume was impervious to ridicule or sarcasm, heedless of abuse

however virulent. It was calculated that in the course of a session he
delivered more speeches than the aggregate of any other three
members. On a May night, when the House was in Committee on
Civil Service Estimates, he spoke for forty minutes. His hat played a
prominent part in these parliamentary incursions. He invariably
brought it into the House cram-full of papers. When he rose to speak
he planted it out on the bench or floor within arm’s length, as if it
were a cabbage. When he interposed to make a passing remark, he
had an odd trick of putting his hat under his left arm at an angle
that dexterously precluded its contents tumbling out on the floor.
There is somewhere in existence a caricature sketch of him by H.B.
thus possessed of his hat. In his ordinary attire he lightened up his
speeches, which though learned were a little dull, by presentation of
a compact costume of a blue coat, a tartan waistcoat, and the
apparently popular light-coloured ‘cassimere trousers.’
Roebuck, in his thirty-third year, was a member of this House.
Here is a pen-picture of him:

‘He is much under the middle size, so slender withal that he

has quite a boyish appearance. His countenance is pale and
sickly, with very little flesh on it. His nose is rather prominent;
his eyes are disproportionately large and sunken. There is a
scowl so visibly impressed on his brow that the merest novice
in physiognomy must observe it. He is not a favourite in the
House, and the limited popularity he has acquired out of
doors seems to be on the decline.’

Q evidently did not like Roebuck, who, when more than forty years
later he reappeared on the parliamentary scene as Member for
Sheffield, disclosed a natural talent for getting himself disliked. He
came back with the flood of Toryism that in the General Election of
1874 swamped Mr. Gladstone. Dillwyn, an old and generally
esteemed member, secured the corner seat below the gangway on
the Opposition side, a place made historic in a later Parliament by
the occupancy of Lord Randolph Churchill. Roebuck hankered after
this seat, which he might have obtained by the regulation process of
attendance at prayer-time. He preferred to arrive later and turn out
Dillwyn, making himself otherwise pleasant by prodding his stick
along the back of the bench, regardless of the presence of
honourable members.
Dillwyn stood this for a long time. At length his patience was
exhausted. I remember one afternoon when Roebuck, arriving as
usual midway in the course of questions, made for the corner seat
and stood there expecting Dillwyn to rise. The Member for Swansea,
studiously unaware of his presence, made no sign. After a pause
watched with eager eyes by a crowded House, Roebuck turned
about and amid a ringing cheer from the Ministerialists crossed over
to the Tory camp, where politically he was more at home.
In the days when Roebuck represented Bath, Q describes him as

‘One of the most petulant, discontented, and conceited of

men in the House. Full of airs, he was in his own estimation
one of the most consequential men within the walls of
Parliament. He spoke frequently, in a voice feeble but clear
and distinct.’

‘A man of fair talent but nothing more,’ is Q’s summing-up of one

who, alike in his early prime and in his old age, filled a prominent
place in the House of Commons.
O’Connell was closer to Q’s heart. He devotes an exceptional
number of pages to a study of the Great Beggarman. Tall and
athletic in person, O’Connell’s complexion had about it a freshness
and ruddiness indicative of good health and excellent spirits. In a
voice clear and strong he spoke with broad Irish accent. Occasionally
he stammered, not from physical defect, but because he had upon
his mind two or more ideas struggling for priority of expression. He
was known occasionally to break off in the middle of a sentence,
leaving it unfinished whilst he expounded a brilliant thought that
struck him as he spoke.
His gestures and attitude were of endless variety. He had a trick of
stretching out his neck and making wry faces at the Speaker. The
next moment his arms were raised above his head, his fists firmly
clenched as he declaimed a passionate passage of denunciation. He
wore a wig, which suffered greatly in the course of a busy session.
He would suddenly seize it with both hands as if about to tear it to
pieces. He was merely half-consciously intent upon adjusting it.
During a memorable speech advocating the repeal of the Union in
1834 he amazed the House by untying his cravat, taking it off, and
laying it on the bench beside him. In the height of oratorical
happiness he felt incommoded by the tightening of his neckcloth,
and the simplest thing to do obviously was to remove it.
Among Irish members of this epoch Sheil ranked next to
O’Connell. His eloquence commanded attention on both sides of the
House. It was, however, hampered by several eccentricities. Mr.
Gladstone, who preserved to the last a vivid impression of him, told
me that when addressing the House he started on a loud key and
rather screeched than spoke. Another tradition coming down to
modern Parliaments describes him as bending down to scrape the
floor with his thumbnail and thanking God he had no gestures. This
reads like fable, but it is confirmed from Q’s personal observation.

‘Sometimes,’ he wrote, ‘Mr. Sheil bends his body to such a

degree that you are not without fear he may lose his
equilibrium and fall head prostrate on the floor. At other times
he advances to the table, gives three or four lusty strokes on
the box, and then suddenly retreats backwards four or five
steps. In a few seconds we see him by another sudden bound
leaning over the table, stretching out his neck as if trying to
reach some hon. member opposite. In addition to an
unmelodious voice, Sheil’s articulation is indistinct, his
utterance reaching a stage of amazing rapidity.’

Feargus O’Connor, best known in connection with the Chartist

movement, by favour of O’Connell represented County Cork in the
session of 1834. Among stories told in the smoking-room of the
House of Commons during the Parliament of 1874-80 was one that
does not seem to have reached Q’s ear. It ran to the effect that,
strolling about behind the Speaker’s Chair in the old House of
Commons, O’Connor observed through the open door of the
Speaker’s private room preparations for the right hon. gentleman’s
early evening meal. Feargus, so the story ran, whether in a moment
of absence of mind or in a preliminary state of mental defection that
some years later necessitated incarceration in an asylum for the
insane, seated himself at the table and ate the Speaker’s chop.
 Differing in all ways from these illustrious unconventional Irishmen
was Edward Bulwer Lytton, who sat in the session of 1835 as
Member for Lincoln. Q describes him as

‘Artificial throughout, the mere creature of self-discipline. A

fine-looking man, tall and handsome, he always dressed in
the extreme of fashion. His manner of speaking, like his
manner in all other respects, was affected. He wrote his
speeches out, learned them off by heart, and delivered them
with great rapidity in a weak voice, made more difficult to
follow by reason of affected pronunciation. He did not often
speak, and was rewarded for his moderation in this respect
by finding the benches crowded when he interposed in
debate.’