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