Concepts and Applications of Pharmacokinetics Nimita Dave, Ph.D. davend@mail.uc.edu

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

Pharmacokinetic Phase (Time course of ADME processes) Metabolism Pharmaceutical Phase Drug Administration Disintegration of the Dosage Form Drug and Drug Dissolution Pharmacokinetic Phase (Time course of ADME processes) Metabolism Absorption Distribution Accumulation Excretion Active Site Pharmacodynamic Phase Pharmacological Effects Therapeutic Effects Toxic Effects

Pharmacokinetics Vs. Pharmacodynamics 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 Purpose: Assess safety and biological activity + mechanisms (conventional + knock-out and transgenic mice) Toxicity Studies Acute Sub-chronic Chronic Changes: High-throughput (cassette dosing) Success Rate: 1 out 1000 enter clinical phase

Phases of Clinical Drug Development IIa IIb III FDA Review Approve Or Disapprove ? 1-2 IV Subjects Healthy Volunteers First time in patients Patients Number 20-100 25-75 50-200 > 300 > 1000 Measures Dosage Kinetics Safety Equivalen. Dose range Efficacy MOA Co-variates Idiosyn. Activity New Uses Value Dynamics Proof of Concept Confirm Usefulness Surveilance Patent Ex Market Exp Cost (millions) $ 8 $ 12 $7 $43 Varies with drug Time (yrs) 1 – 1.5 1 1-1.5 3-6

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 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 Phase Therapeutic Drug Monitoring Individualize therapy Increase therapeutic effects Reduce adverse side effects TDM

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

Routes of Drug Administration Systemic Vs. Local Drug Action Parenteral – Intravenous (IV) Intramuscular (IM) Subcutaneous (SC) Intracardiac Intrathecal Intrasynovial Oral Sublingual Buccal Inhalation Eye Ear Rectal Vaginal Urethral Topical

- Zero-Order Input (Infusions) 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 Perfusion rate (blood flow/min/g tissue) Protein binding Anatomical restrictions CNS- protected by the blood brain barrier Transport across placenta Salivary Drug Excretion (S/P ratios) Excretion of the drug in milk (M/P ratios)