SIGNIFICANCE OF DRUG PHAMACOKINETICSBy Amad Islam

LIFE HISTORY OF DRUG

Dosage Regimen

Concentration in Plasma

Concentration at the site of action

AbsorptionDistributionMetabolismExcretion

Pharmacokinetics

Pharmacodynamics

Effect

WHY DO WE DO IT?

DRUG R&D

Drug discovery and development•10-15 years to develop a new medicine•Cost $800 million – 1 billion dollars (US)•Likelihood of success: 10%

Reasons for Failure in Development

Toxicity (22%)Lack of Efficacy (31%)Market Reasons (6%)Poor Biopharmaceutical (PK) Properties (41%)

•From 1898 through to 1910 heroin was marketed as a non-addictive morphine substitute and cough medicine for children. Bayer marketed heroin as a cure for morphine addiction•Heroin is converted to morphine when metabolized in the liver

DRUG SAFETY AND EFFECTIVENESS Not all people respond to a similar dose of a drug in the exact

same manner, this variability is based upon individual differences and is associated with toxicity. This variability is thought to be caused by: Pharmacokinetic factors contribute to differing concentrations

of the drug at the target area. Pharmacodynamic factors contribute to differing physiological

responses to the same drug concentration. Unusual, idiosyncratic, genetically determined or allergic,

immunologically sensitized responses.

TARGET LEVEL STRATEGY Low safety margin drugs (anticonvulsants,

antidepressants, Lithium, Theophylline etc) maintained at certain concentration within therapeutic range

Drugs with short half-life (2-3 Hrs) – drugs are administered at conventional intervals (6-12 Hrs) – fluctuations are therapeutically acceptable

Long acting drugs: Loading dose: Single dose or repeated dose in

quick succession – to attain target conc. Quickly Loading dose = target Cp X V/F

Maintenance dose: dose to be repeated at specific intervals

MONITORING OF PLASMA CONCENTRATION Useful in

Narrow safety margin drugs – digoxin, anticonvulsants, antiarrhythmics and aminoglycosides etc

Large individual variation – lithium and antidepressants

Renal failure cases Poisoning cases

Not useful in Response mesurable drugs – antihypertensives,

diuretics etc Drugs activated in body – levodopa Hit and run drugs – Reseprpine, MAO inhibitors Irreversible action drugs – Orgnophosphorous

compounds

PROLONGATION OF DRUG ACTION By prolonging absorption from the site of

action – Oral and parenteral (LORELIN DEPOT)

By increasing plasma protein binding (OXALIPLATIN MEDAC)

By retarding rate of metabolism (LIPAD)(LIPOPLATIN)(HAMSYL) By retarding renal excretion(CONTRARY TO DISODIUM PAMIDRONATE)

Ideal PK Properties of a Drug

• Must be efficacious with once/day dosing

(EXCEPT THROMBOMAX)• One or two dose levels should be safe

and efficacious in all individuals• No dosing adjustments should be

required with multiple dosing.

From a Marketing Perspective

Ideal PK Properties of a Drug

• Should give consistent plasma concentrations in all individuals (patients) from one dose.• No variability in metabolism • Excretion by both renal and hepatic

mechanisms for those with liver or kidney problems

• Rapid, predictable onset of action• Clearance high enough so compound is removed

from body if any untoward side-effects are observed.

• No accumulation • No interaction with co-administered drugs due to

• High Protein Binding• Metabolism (induction or inhibition)• Interference with Excretion

From a Clinical Perspective

Products PK Property Indication

Oxaliplatin High Plasma Protein Binding and (MHRA certificate)

Decreased Frequency and Approved efficacy

Pamidronate Disodium Preparation (MHRA Certificate)

Rapid excretion and low adverse effect and dose adjustments

Lorelin Depot Formulation Decreased absorption and delay frequency

Lipoplatin Peg-Liposomal Formulation

Decreased Metabolism, Elimination and increased half life. Results in Increase Effectiveness and decreased ADRs.

Lipad Peg-Liposomal Formulation As Above.

Hamsyl Pegylated Formulation Delayed dosing and increase effectiveness

Amgofil Recombinant Human Low Toxicity

Thrombomax As Above As Above

Weaponry of AMGOMED