Biowaiver Approach
Biowaiver Approach
Biowaiver Approach
ABSTRACT: The dependency of metformin in vivo disposition on the rate and extent of
dissolution was studied. The analysis includes the use of fundamental principles of drug input,
permeability, and intestinal transit time within the framework of a compartmental absorption
transit model to predict key pharmacokinetic (PK) parameters and then compare the results to
clinical data. The simulations show that the maximum plasma concentration (Cmax ) and area
under the curve (AUC) are not significantly affected when 100% of drug is released within
2 h of oral dosing, which was confirmed with corresponding human PK data. Furthermore,
in vitro dissolution profiles measured in aqueous buffers at pH values of 1.2, 4.5, and 6.8 were
slower than in vivo release profiles generated by deconvolution of metformin products that were
bioequivalent. On the basis of this work, formulations of metformin that release 100% in vitro
in a time period equal to or less than two hours are indicated to be bioequivalent. The use of
modeling offers a mechanistic-based approach for demonstrating acceptable bioperformance for
metformin formulations without having to resort to in vivo bioequivalence studies and may be
more robust than statistical comparison of in vitro release profiles. This work further provides
a strategy for considering Biopharmaceutics Classification System (BCS) Class 3 compounds to
be included under biowaiver guidelines as for BCS Class 1 compounds. © 2012 Wiley Periodicals,
Inc. and the American Pharmacists Association J Pharm Sci 101:1773–1782, 2012
Keywords: oral absorption; Biopharmaceutics Classification System (BCS); mathematical
model; dissolution; permeability
decreased by 60% when perfused with a 200 :g/mL the limited permeability through the intestinal mem-
versus 50 :g/mL solution of metformin based on brane and the change in that profile throughout the
single-pass in situ perfusion experiments.8 Met- GI tract and has shown to be predictive based on clin-
formin is a Biopharmaceutics Classification System ical data for a wide range of in vitro release times.
Class 3 (BCS 3) compound (high solubility, poor This more detailed biopharmaceutics-based approach
permeability).9,10 to a biowaiver proposal avoids the need for very rapid
During the development of fixed dose combina- dissolution times and challenges of current similar-
tion (FDC) products containing metformin for global ity factor assessments for in vitro dissolution profiles,
regulatory submission, there was a need to assure which may show nonsimilarity for bioequivalent drug
equivalent bioperformance of metformin from the products.
fixed combination product to metformin marketed
in different territories. Drug release studies on met-
formin immediate-release tablets sourced from differ- MATERIALS AND METHODS
ent markets showed diverse drug release properties.
Software
During this investigation, one of the FDC products
had dissimilar in vitro dissolution profiles to the refer- Commercially available software, GastroPlusTM , ver-
ence product, yet was demonstrated as bioequivalent sion 7.0 (Simulations Plus, Inc., Lancaster, Califor-
in a subsequent clinical study. It was desired not to nia) was used to model the absorption, distribution,
undertake multiple bioequivalence studies for a well and elimination of metformin in humans. WinNonlin
established, widely studied drug-like metformin, but version 5.2.1 (Pharsight Corporation, Cary, North
to investigate whether a biowaiver approach might be Carolina) was used to perform the statistical analy-
feasible. sis for establishing bioequivalence between the model
A biowaiver approach allows, on the basis of com- simulations and clinical data and between study
parative in vitro release studies, the approval of groups.
changes to a drug product that are predicted not to
affect in vivo performance, minimizing review burden In Vitro Drug Release Studies
on regulators and avoiding unnecessary clinical stud-
Dissolution was determined using United States
ies, expense, and delay for the sponsor. Several groups
Pharmacopeia Apparatus 1 (basket), with a rotation
have argued that BCS 3 compounds should be eligi-
speed of 100 rpm in 1000 mL of dissolution medium
ble for biowaiver status in a similar fashion to BCS
for pH 1.2, 4.5, and 6.8. Dissolution media (1000 mL,
1 compounds because the controlling factors in the
37◦ C) used were 50 mM potassium phosphate (pH
absorption process from the drug product are not the
6.8), 50 mM sodium acetate buffer (pH 4.5), and
drug substance solubility.9,11–16 Because the absorp-
0.1 N HCl (pH 1.2). Samples were withdrawn at 15,
tion profile of BCS 3 compounds is also affected by the
30, 45, and 60 min and filtered, and quantitation of
gastrointestinal (GI) transit time, release times must
metformin in the samples was achieved using high-
be within the boundaries of the absorption window in
performance liquid chromatography with ultraviolet
the intestine for two products to be bioequivalent, and
detection at 232 nm. In vitro dissolution data are
any biowaiver approach accommodating BCS 3 drugs
presented in Figures 1–4.
has to consider this.
To date, however, biowaivers are only broadly
In Vivo Clinical Studies
recognized as applicable to BCS 1, highly soluble,
highly permeable, compounds, although European Descriptions of the clinical studies presented in this
Medicines Agency guidelines allow application of paper, that is, study size, test conditions, pharma-
biowaiver in the case of BCS 3 compounds under very cokinetics (PK) results, and so on, are provided in
specific conditions of excipient composition of the com- Table 1. The clinical data for the immediate-release
pared materials and where dissolution is very rapid, formulations that are presented were dosed under fed
not less than 85% dissolved in 15 min across the phys- conditions per approved dosage and administration
iological pH range.17 requirements noted in the product package insert.18
This present work represents a thorough approach The extended-release clinical data used were gener-
using validated computer simulations from a mecha- ated under fasted conditions.
nistically based in silico absorption model to predict
performance for use as a biowaiver for this BCS 3 com- In Silico Model Development
pound by modeling within the range of gastric transit
Parameter Input
times expected in human subjects in order to show
the broad range of release rates that are expected to The data used in developing the metformin model for
have no impact on AUC and Cmax and therefore re- a 500 mg dose were taken from the literature and the
sult in bioequivalence. The model used accounts for parameter input values are listed in Table 2. The
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012 DOI 10.1002/jps
BIOWAIVER APPROACH FOR BCS 3 COMPOUND METFORMIN HYDROCHLORIDE 1775
Figure 1. (a) In vitro dissolution profile for test and reference products used in clinical studies
a. The f2 test values for this plot is 52. (b) In vitro dissolution profile for test and reference
products used in clinical studies a. The f2 test value for this plot is 42. (c) In vitro dissolution
profile for test and reference products used in clinical studies a. The f2 test values for this plot
could not be calculated. (d) In vitro dissolution profile for test and reference products used in
clinical studies b. The f2 test value for this plot is 57. (e) In vitro dissolution profile for test
and reference products used in clinical studies b. The f2 test value for this plot is 43. (f) In vitro
dissolution profile for test and reference products used in clinical studies b. The f2 test values for
this plot could not be calculated. (g) In vitro dissolution profile for test and reference products
used in clinical studies c. The f2 test value for this plot is 31. (h) In vitro dissolution profile
for test and reference products used in clinical studies c. The f2 test value for this plot is 32.
(i) In vitro dissolution profile for test and reference products used in clinical studies C. The f2
test values for this plot could not be calculated.
absorption and clearance parameters used in the a 500 mg solution of metformin.19 This study also
model are based on literature values for intravenous showed that the drug was primarily absorbed in the
dosing and data generated from a clinical study de- proximal small intestine and the primary route for
signed to determine the site-specific absorption for elimination is the kidneys, which is in agreement with
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012
1776 CRISON ET AL.
Table 1. Clinical Study Details—Metformin Reference Product (Discovery Medicine and Clinical Pharmacology, Bristol–Myers Squibb)
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012 DOI 10.1002/jps
BIOWAIVER APPROACH FOR BCS 3 COMPOUND METFORMIN HYDROCHLORIDE 1777
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012
1778 CRISON ET AL.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012 DOI 10.1002/jps
BIOWAIVER APPROACH FOR BCS 3 COMPOUND METFORMIN HYDROCHLORIDE 1779
Table 3. Results of Model Simulations and Statistical Comparison of the Cmax and AUC(0– T) to Clinical Data
for Four 500 mg Metformin Products
for the Study a metformin reference, whereas there not closely similar. The test infers that if the f2 value
is a greater dependence on pH for the metformin is less than 50, the two products that are being com-
reference products used in Studies B and C based pared are not bioequivalent. In addition to the implicit
on the in vitro dissolution even though the products nature of this test, there are other restrictions to this
were bioequivalent. calculation. The f2 calculation is based on the sum of
Figure 1b shows the in vitro dissolution profiles the square of the errors and therefore is dependent on
of the metformin products tested from Study a that the selection of the sample points.27–29 As a result, the
were bioequivalent but did not meet the f2 criteria two products under consideration may or may not be
for equivalence, that is, the dissolution at pH 4.5 had equivalent depending on the reasons described above.
an f2 = 42 and therefore did not meet the similarity Two metformin products were compared using
criteria. in vitro dissolution at pH 1.2, 0.5, and 6.8. When
the dissolution at pH 4.5 did not pass the f2 test, a
Comparison of In Vitro Release Profiles to In Vivo clinical study of 24 subjects was conducted for the
Performance for Metformin FDC and single entity metformin products under fed
Although generally limited to BCS 1 compounds and conditions. The AUC(0-T) and Cmax for the individual
in vitro–in vivo correlations, comparison of in vitro subjects were compared and the two products were
release profiles has been also proposed as an argu- found to be bioequivalent based on the lower and up-
ment for waiving bioequivalence studies for BCS 3 per 90% confidence intervals being within 0.80 and
compounds. The scientific argument for BCS 3 com- 1.25, respectively (Study a, Table 4).
pounds is the same as for a BCS 1 compound, that is, if Use of Modeling and Simulation to Establish
two drug products have the same in vivo dissolution Bioequivalence
profile under all luminal conditions, they will have
the same rate and extent of drug absorption and as- The use of in silico tools has expanded in recent years
sumes that any difference in bioavailability between to include contributions of the dosage form, release
two products will be due to the release of drug from rate, and GI and physiological properties in addition
the product and not permeability.26 However, it must to classical compartmental PK to model and predict
be noted that for BCS 3 compounds, the phrase “un- the drug absorption process.30,31 The advantage of us-
der all luminal conditions” is more limited than for ing these models to predict PK outcomes is that they
BCS 1 compounds in that changes in the GI transit go beyond comparison of the in vitro dissolution data
time can have a greater impact on the fraction dose by adding GI transit time, permeability, and clear-
absorbed due to the drug’s low permeability. As both ance. The model developed for this current analysis
BCS 1 and 3 compounds have high solubility through- combines the dissolution rate of metformin from the
out the luminal pH range, in vitro dissolution testing formulation, GI permeability and transit, and physi-
may be considered adequate to show the similarity in ological variability to provide an accurate prediction
the dissolution of the two products. The pH values of- of the Cmax and AUC.
ten used to represent “all” luminal conditions are 1.2,
Additional Considerations Regarding the Relationship
4.5, and 6.8 and the statistical test used to determine
Between the In Vitro Dissolution, In Vivo Release, and
if two profiles are the same is the f2 similarity test.25
the Fraction Dose Absorbed
It is important to note that although the f2 similar-
ity test adequately determines when two dissolution To help understand why this range of in vivo release
profiles are similar, that is, less than 10% difference will result in no significant change to the AUC and
between time points, it does not provide any informa- Cmax , the in silico model was used to simulate the
tion pertaining to bioequivalence if the profiles are plasma concentration versus time curves using a wide
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012
1780 CRISON ET AL.
Table 4. Clinical Trial Results Showing Bioequivalence Statistics of the Test and Reference Metformin Products
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 5, MAY 2012 DOI 10.1002/jps
BIOWAIVER APPROACH FOR BCS 3 COMPOUND METFORMIN HYDROCHLORIDE 1781
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