1. Concepts and Applications of Pharmacokinetics
Nimita Dave, Ph.D.

2. CONCEPTS OF PHARMACOKINETICS
Drug Discovery and Development
Dynamics of Change
Pre-clinical ADME
Clinical Pharmacology
Essentials of Pharmacokinetics
Therapeutic Aspects

3. 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

4. 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

5. Pharmacokinetics Vs. Pharmacodynamics
What the body does to the drug
Pharmacodynamics:
What the drug does to the body

6. Drug Discovery & Development

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. - 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

15. 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)