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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


. absorption. i.. 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 1960’s • Quantitative understanding of drug disposition is needed in order to optimize management of drug therapy → clinical pharmacokinetics in 1970’s • Development of pharmacodynamics as an extension of pharmacokinetics in the early 1980’s 2 .Definitions • Pharmacokinetics ─ study of the time course of drug disposition.e. excretion and metabolism (ADME) • Pharmacodynamics ─ study of the temporal pattern (e.g. distribution.

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 3 .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.

10x Intersubject Variability in Dose-to-Plasma Concentration Relationship Intersubject Variation in Plasma Concentration-to-Effect Relationship 4 .

intravenous. subcutaneous. rectal. intramuscular.Clinical Factors Influencing Dose-Conc.-Effect Relationships Genetics Development & Age Diseases Life style Pharmacokinetics → Therapeutic Drug Monitoring (TDM) Pharmacodynamics Drug Absorption • Release of active drug from dosage form after its administration via a given route (oral. 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 5 .

Absorption Extent: Prod 1 > Prod 2 > Prod 3 Same Absorption Rate 2 MEC 3 Time Time • Rate of drug absorption mainly affects the time to onset of action ( ).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 1 1 Blood Conc. as well as timing and magnitude of maximal effect ( ). Blood Conc. • Extent of absorption affects maximal effect and overall exposure as measured by area under the blood concentration-time curve (AUC). 6 .

for example. trapezoidal rule as shown. partitioning into fat) − Transporters at membrane barriers Tissue-to-blood equilibration → Distribution Volume: V x Cp = body burden 7 . Drug Distribution into Tissues Rate and extent of drug distribution into: 1) sites of therapeutic actions and toxicities.Area under the Curve (AUC) AUC estimated by numerical integration techniques. Factors governing tissue distribution: − Tissue or organ blood flow rate − Relative affinity of drug for blood and tissue constituents (protein binding. and 2) sites of drug elimination govern pharmacodynamics.

Drug Excretion • Major sites of drug and its metabolites excretion includes: – Kidneys (glomerular filtration. reduction. 8 . 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. • Metabolites can be pharmacologically active. adds complexity to pharmacodynamics.Drug Metabolism • Metabolism (or biotransformation) renders a drug inactive and ready for excretion. – Phase I reactions (oxidation. respectively. hydrolysis) – Phase II reactions (conjugation with polar endogenous compounds) • Major sites of metabolism are the intestinal mucosa and liver.

e. • Persistence of a drug in circulation (inferring retention in the body) is expressed by biologic or elimination half-life (T1/2).Overall Rate of Drug Elimination • Most drugs are eliminated in an exponential or firstorder fashion. – fractional rate is constant. – elimination rate is the greatest at peak and decreases as body burden is lowered. dose divided by area under the plasma concentration-time curve (AUC) for a given i. Elimination T1/2 defined as time it takes to eliminate 50% of the originating plasma concentration C0 One-Compartment Model Conc Conc C ½C T1/2 Time Time Two-Compartment Model Conc Conc Central Peripheral C ½C T1/2 Time Time 9 . ml/min or L/h). i. • Both measures require serial blood sampling over time. dose (in units of flow.. • Overall rate of elimination over time is expressed by total body clearance.v.

Nortriptyline 10 . Valproic acid.5 T1/2) • Repeating amount or conc. Clozapine. Mycophenolate • Antidepressants and Antipsychotics Lithium.-time profiles reached at steady-state. Carbamazepine.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. average level (---. Vancomycin • Digoxin • Immunosuppressants Cyclosporine. Tacrolimus. ---) 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. Phenobarbital • Antibiotics Aminoglycosides (gentamicin).

Philadelphia. Gibaldi. Williams & Wilkins.2006 [QV 38 T757i] 11 .. Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy. Lea & Febiger.N.Application of Pharmacokinetic-Pharmacodynamic Principles in New Drug Development Pharmacokinetics References [available at UW HSL] • M. Philadelphia. Lippincott. 1st ed. Rowland. Biopharmaceutics and Clinical Pharmacokinetics. Tozer and M. 4th ed. 2 copies] • T.. 1991 [QV 38 G437b.