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PHARM 500 Quantitative Methods I

Pharmacokinetics I D. Shen, Pharmacy, 5-2920

Lecture Aims
Definition of and historical background on pharmacokinetics and pharmacodynamics Reasons for studying pharmacokinetics and pharmacodynamics Pharmacokinetic parameters describing drug absorption, distribution, metabolism and excretion Applications of pharmacokinetics

Pharmacokinetics study of the time course of drug disposition; i.e., absorption, distribution, excretion and metabolism (ADME) Pharmacodynamics study of the temporal pattern (e.g., time of onset and duration) of therapeutic and side effects of a drug
Pharmacokinetic-Pharmacodynamic (PK-PD) correlation

Historical Context
Pharmacokinetics as a sub-specialty within the pharmacological sciences Evolved from pharmaceutical chemistry (formulation and drug delivery) and biochemical pharmacology (drug metabolism) in the early 1960s Quantitative understanding of drug disposition is needed in order to optimize management of drug therapy clinical pharmacokinetics in 1970s Development of pharmacodynamics as an extension of pharmacokinetics in the early 1980s

Therapeutic Window
Concept of therapeutic window derives from the basic tenet of exposureresponse in pharmacology Rarely can we measure drug concentration at the site(s) of action Blood or plasma concentration is an accessible, surrogate measure of systemic exposure Question becomes how predictable is the dose-toconcentration and concentration-to-effect relationships

Intersubject Variability in Dose-Response

Daily dose of warfarin required to produce a similar degree of anticoagulation


Intersubject Variability in Dose-to-Plasma Concentration Relationship

Intersubject Variation in Plasma Concentration-to-Effect Relationship

Clinical Factors Influencing Dose-Conc.-Effect Relationships

Genetics Development & Age Diseases Life style

Pharmacokinetics Therapeutic Drug Monitoring (TDM)


Drug Absorption
Release of active drug from dosage form after its administration via a given route (oral, rectal, intramuscular, subcutaneous, intravenous, percutaneous or transdermal)
Disintegration and dissolution as critical steps in oral absorption

Drug permeability across gastrointestinal mucosa

Physicochemical properties and membrane transporters

Drug stability in GI fluid and susceptibility to drug metabolizing enzymes in the intestine and liver
First-pass metabolism

First-Pass Metabolism

Bioavailability Rate and Extent of Drug Absorption into the Systemic Circulation
Absorption Rate: Prod 1 > Prod 2 > Prod 3 Same Abdorption Extent
2 3

Blood Conc.

Blood Conc.

Absorption Extent: Prod 1 > Prod 2 > Prod 3 Same Absorption Rate




Rate of drug absorption mainly affects the time to onset of action ( ), as well as timing and magnitude of maximal effect ( ). Extent of absorption affects maximal effect and overall exposure as measured by area under the blood concentration-time curve (AUC).

Area under the Curve (AUC)

AUC estimated by numerical integration techniques; for example, trapezoidal rule as shown.

Drug Distribution into Tissues

Rate and extent of drug distribution into: 1) sites of therapeutic actions and toxicities, and 2) sites of drug elimination govern pharmacodynamics.
Factors governing tissue distribution: Tissue or organ blood flow rate Relative affinity of drug for blood and tissue constituents (protein binding, partitioning into fat) Transporters at membrane barriers

Tissue-to-blood equilibration Distribution Volume: V x Cp = body burden

Drug Metabolism
Metabolism (or biotransformation) renders a drug inactive and ready for excretion.
Phase I reactions (oxidation, reduction, hydrolysis) Phase II reactions (conjugation with polar endogenous compounds)

Major sites of metabolism are the intestinal mucosa and liver. Metabolites can be pharmacologically active; adds complexity to pharmacodynamics.

Drug Excretion
Major sites of drug and its metabolites excretion includes:
Kidneys (glomerular filtration, tubular secretion) Bile canaliculi in the liver Lungs for volatile agents (anesthetics)

Renal and biliary excretion often involves drug transporters that can concentrate drug in urine and bile, respectively.

Overall Rate of Drug Elimination

Most drugs are eliminated in an exponential or firstorder fashion.
elimination rate is the greatest at peak and decreases as body burden is lowered. fractional rate is constant.

Persistence of a drug in circulation (inferring retention in the body) is expressed by biologic or elimination half-life (T1/2). Overall rate of elimination over time is expressed by total body clearance, i.e., dose divided by area under the plasma concentration-time curve (AUC) for a given i.v. dose (in units of flow, ml/min or L/h). Both measures require serial blood sampling over time.

Elimination T1/2 defined as time it takes to eliminate 50% of the originating plasma concentration

One-Compartment Model




Two-Compartment Model
Central Peripheral




Elimination T1/2 determines accumulation and fluctuation in blood concentration at steady-state

Greater accumulation when drug is dosed more frequently relative to halflife (1 T1/2 vs. 0.5 T1/2) Repeating amount or conc.-time profiles reached at steady-state; average level (---, ---) proportional to dosing rate Longer dosing interval leads to greater fluctuation during steady-state

Drugs with Narrow Therapeutic Window and its Dosing Guided by Blood Concentration Monitoring and Pharmacokinetic Principles Antiepileptics
Phenytoin, Carbamazepine, Valproic acid, Phenobarbital

Aminoglycosides (gentamicin), Vancomycin

Digoxin Immunosuppressants
Cyclosporine, Tacrolimus, Mycophenolate

Antidepressants and Antipsychotics

Lithium, Clozapine, Nortriptyline


Application of Pharmacokinetic-Pharmacodynamic Principles in New Drug Development

Pharmacokinetics References [available at UW HSL]

M. Gibaldi, Biopharmaceutics and Clinical Pharmacokinetics, 4th ed., Lea & Febiger, Philadelphia, 1991 [QV 38 G437b, 2 copies] T.N. Tozer and M. Rowland, Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy, 1st ed., Lippincott, Williams & Wilkins, Philadelphia,2006 [QV 38 T757i]