Drugs Therapeutic Drug Monitoring
Drugs Therapeutic Drug Monitoring
Drugs Therapeutic Drug Monitoring
and Pharmacogenetics
3
General Criteria for TDM
• Narrow therapeutic index
• Defined therapeutic range and toxic threshold
• Good relationship between [blood] and clinical/toxic
effect
• Poor relationship between drug dose and [blood]
• Significant inter-individual variation
• Serious consequences for under- or over-dosing
• Subject to drug-drug interactions
• Knowledge of the drug level influences management
• When toxicity mimics indication for which drug is
prescribed
Therapeutic Window
Steady-state and therapeutic index
Dose response Relationship
ED50 = the dose of drug in which 50% of treated individuals will experience benefit
TD50 = the dose of drug in which 50% of individuals will experience toxic adverse effects
LD50 = the dose of drug in which 50% of individuals will result in morbidity
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Factors that influence TDM Results
Factors that influence TDM Results
Drug Formulation
Route of administration
Dose regimen
Pharmacokinetics (Vd, half-life, metabolites)
Patient Age (pediatric, geriatric)
Body composition
Renal function
Hepatic function
Compliance
Pregnancy
Protein status
Pharmacogenetics
Disease / Malignacies
Factors that influence TDM Results
Factors that influence TDM Results
Specimen Collection tube, preservatives
Time collected relative to dose
Sampling methods
Storage
Handling
Analytical method Preanalytical processing (extraction)
Sensitivity
Specificity
Matrix effects
Other Concominant medications
Supplements
Diet
Clerical errors
Factors that influence TDM Results
Metabolism
Excretion
ADME - Absorption
“The transfer of a drug or other xenobiotic from its
site of administration to the bloodstream”
• Drug Partitioning
• drugs can be characterized by “partition coefficients”
• ratio of solubility in an aqueous, polar solvent vs. a
lipophilic, non-polar solvent
• lipophilic drugs are rapidly absorbed
• variables:
• body composition
• pH (blood and urine)
• ionization – function of pKa (markedly reduces
lipophilicity)
ADME - Absorption – Drug Transport
• Passive diffusion - transport driven by conc.
gradient (95% of all drugs)
• Active transport – transport against the conc.
gradient requires energy, can be receptor mediated
• Facilitated transport – follows the conc.
gradient, requires energy, can be receptor
mediated
• Convection transport – transport through water
filled pores
• Pinocytosis – cell engulfs the drug
ADME - Distribution
“Movement of a drug or xenobiotic from the bloodstream to
the site of action”
1) Drug remains in blood
2) Drug enters extravascular fluids
3) Drug migrates into various tissues/organs
Limitations:
- does not estimate actual sites of distribution
- does not account for individual differences
- requires drug distribution to be complete = Css
Applications of Vd:
1) Loading dose = Vd x [drug]ss
2) Dose adjustments = Vd ([drug]desired –
[drug]initial)
ADME - Metabolism
Defined as
.
•common medicines not being effective in treating large numbers
of patients
Mercaptopurine
Warfarin
Irinotecan
Specificity of Common PGx Biomarkers
PGx Case : Opiate Metabolism
Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-
prescribed mother. Lancet 368:704, 2006
Day 1 – full-term healthy male infant delivered, mother on 30 mg
codeine/500 mg APAP for pain
Day 7 – difficulty breastfeeding and lethargy
Day 11 – well-baby visit, baby had regained birthweight
Day 12 – grey skin and milk intake decreased
Day 13 – infant found dead
Postmortem – morphine blood concentration = 70
ng/mL
(normal in neonates breastfed by mothers on codeine
0-2.2 ng/mL)