Concepts and Applications of Pharmacokinetics Nimita Dave, Ph.D. [email protected].

Concepts and Applications of Pharmacokinetics

Nimita Dave, [email protected]

CONCEPTS OF PHARMACOKINETICS

Drug Discovery and Development Dynamics of Change Pre-clinical ADME Clinical Pharmacology Essentials of Pharmacokinetics Therapeutic Aspects

Pharmacokinetics: Time Course of ADME processes

Absorption: Passage of the drug from the site

of administration to the circulation

Distribution: Protein binding followed by target

specific and non-specific tissue uptake

ELIMINATION Metabolism: Phase I and Phase II

Excretion:Removal of Intact Drug

Renal and Biliary

Drug Administration

Pharmacokinetic Phase (Time course of ADME processes)

Absorption

Distribution

Pharmaceutical Phase

Disintegration of the Dosage Form Drug and Drug Dissolution

Active Site

Metabolism

Excretion

Accumulation

Pharmacodynamic PhasePharmacological

Effects

Therapeutic Effects Toxic Effects

Pharmacokinetics Vs. Pharmacodynamics

Pharmacokinetics: What the body does to the drug

Pharmacodynamics: What the drug does to the body

Drug Discovery & Development

Pre-Clinical (Non-Clinical?) Testing

Test Population: Laboratory and Animal Studies

Success Rate: 1 out 1000 enter clinical phase

Changes: High-throughput (cassette dosing)

Purpose: Assess safety and biological activity + mechanisms (conventional +

knock-out and transgenic mice)

Toxicity StudiesAcuteSub-chronicChronic

Phases of Clinical Drug Development

I IIa IIb III FDA

ReviewApprove

OrDisapprov

e

?

1-2

IVSubjects Healthy

Volunteers

First time in

patients

Patients Patients Patients

Number 20-100 25-75 50-200 > 300 > 1000

Measures DosageKineticsSafety

Equivalen.

Dose range

EfficacySafetyMOA

EfficacySafety

EfficacySafety

Co-variates

Idiosyn.Activity

New Uses

Value KineticsDynamics

Proof ofConcept

ConfirmMOA

ConfirmUsefulnes

s

Surveilance

Patent ExMarket

Exp

Cost(millions)

$ 8 $ 12 $7 $43 Varies with drug

Time (yrs)

1 – 1.5 1 1-1.5 3-6 1-2

Why do drug disposition Studies? Lead optimization during pre-clinical testing

(In vitro and In vivo tools) Goes hand-in –hand with toxicology studies

Acute Sub-chronic Chronic

Pre-clinical Phase

Clinical Phase

TDM Therapeutic Drug Monitoring

Individualize therapy Increase therapeutic effects Reduce adverse side effects

Integral Part of Clinical Trials Dose escalation in phase I Dose refinement and PK-PD measure in phase II Extensive PK-PD modeling in phase III

Clinical Pharmacology First in Human -Pharmacokinetically Guided

Dose Escalation/ Drug Tolerance Study Pharmacokinetics-Pharmacodynamics Drug Metabolism Mass Balance with Radiolabeled Compounds Bioequivalence:Generic compounds

Single and multiple doses Conventional versus controlled release formulations Bioavailability of metabolites

Drug-Drug/Drug Dietary Product Interactions Special Populations

Empirical Approach to Drug

Development Drugs such as penicillins and tetracyclines

dosed more frequently than digoxin Compounds like oxytocin best administered

as I.V. infusions Nitroglycerine is given as a sublingual pill or a

transdermal patch but not as an oral dosage form

Compounds such as isoniazid and dextromethorphan show marked variability in different “ethnic” groups

Seldane replaced by its active metabolite

Parenteral –Intravenous (IV)Intramuscular (IM)Subcutaneous (SC)IntracardiacIntrathecalIntrasynovial

OralSublingualBuccalInhalationEyeEar

RectalVaginalUrethralTopical

Routes of Drug Administration

Systemic Vs. Local Drug Action

Drug Input

•I.V. and I.A. injections:

- Bolus dosing

- Zero-Order Input (Infusions)

•Extravascular Administration

- First Order (majority)

- Zero Order

Factors Affecting Drug Distribution

Physico-chemical properties of the drug Small vs. Large mol.wt. Compounds Hydrophilic vs. Lipophilic compounds pH of the milieu and pKa of the drug

Anatomical restrictionsCNS- protected by the blood brain barrierTransport across placentaSalivary Drug Excretion (S/P ratios)Excretion of the drug in milk (M/P ratios)

Protein binding

Perfusion rate (blood flow/min/g tissue)