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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)