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VARIABILITY IN PHARMACOKINETICS & PATIENT RESPONSE

VARIABILITY IN PHARMACOKINETICS & PATIENT RESPONSE. Dr. Mohd B. Makmor Bakry, Ph.D., RPh Senior Lecturer in Clinical Pharmacy Universiti Kebangsaan Malaysia Kuala Lumpur. TYPES OF VARIABILITY.

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VARIABILITY IN PHARMACOKINETICS & PATIENT RESPONSE

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  1. VARIABILITY INPHARMACOKINETICS & PATIENT RESPONSE Dr. Mohd B. Makmor Bakry, Ph.D., RPh Senior Lecturer in Clinical Pharmacy Universiti Kebangsaan Malaysia Kuala Lumpur

  2. TYPES OF VARIABILITY • Variability in adsorption, distribution, metabolism and excretion will affects the plasma drug level/concentration. • Intra-individual • Difference within the same individual. • eg. Difference in drug plasma level between day and night. • Inter-individual • Difference between individual to other individual.

  3. CONTRIBUTING FACTORS • Drug or Product • Active Metabolite • Primidone ---- phenobarbitone • Procainamide --- N-acetyl procainamide • Tolerance and Resistance; antibiotics • Formulation; generic differences • Route of Administration; oral vs intravenous • Drug Interaction; Theophylline with Rifampicin • Foods; Potassium rich foods with Digoxin • Pollutants; Smoking with Theophylline • Time and Season; Day vs Night for Theophylline • Location; Humidity for oral tablets

  4. CLVPA 30mg/kg/D CBZ 20mg/kg/D CBZ 10mg/kg/D CBZ TBW Drug-Drug Interaction between VPA-CBZ

  5. CONTRIBUTING FACTORS (CONT’) • Patient characteristics • Genetic • Slow vs fast acetylator • Asian vs Western population • Disease state • Mild vs severe, organ impairment • Compliance • Good vs poor • Age • Very young vs very old • Weight • Obesity, malnutrition • Gender • Male vs female, fat distribution, hormonal effects

  6. Plasma [ ] Phenylbutazone Fraternal Twins Identical Twins Days Genetic differences between twins

  7. THE EFFECTS OF DISEASE ON PHARMACOKINETICS • Hepatic Diseases • Alteration of pharmacokinetic principles and determinants of hepatic elimination. • Intrinsic clearance, hepatic blood flow and protein binding. • Renal Diseases • Effects on Vd, elimination and protein binding. • Uremia may decreased protein binding to acidic drug.

  8. THE EFFECTS OF DISEASE ON P’KINETICS (CONT’) • Cardiac Diseases • Not directly • Cardiac failure: decrease in cardiac output leading to a decrease in blood flow to major tissues and organs. • Others: Congestion of vital organs, edema formation, redistribution of blood flow, increase in myocardial muscle mass. • Thyroid Diseases • Variable effects on hepatic metabolism. • Gastrointestinal disturbance.

  9. THE EFFECTS OF DISEASE ON P’KINETICS (CONT’) • Pulmonary Diseases • Gas exchange defects. • Hemodynamic changes (secondary to increase pulmonary vascular resistance) • Burn • Effects the cardiovascular, renal, dermatologic and hepatic systems. • Malnutrition • Neoplastic Diseases

  10. PHARMACOKINETIC VARIABILITY IN SPECIAL GROUPS • Pediatrics (Infant 0 – 2 years old) • Variation in: • Body composition • Maturity of liver • Maturity of kidney • Hepatic function • Attained at third week of life • Oxidative processes fairly develops. • Deficiency in conjugating enzymes. • Renal function • Newborns show 30 – 50% the renal activity of adults.

  11. P’KINETIC VARIABILITY IN SPECIAL GROUPS (CONT’) Physiologic Factors influencing Drug Disposition in Infant

  12. P’KINETIC VARIABILITY IN SPECIAL GROUPS (CONT’) • Geriatrics (more than 60 years old) • Variation in: • Quantitative: decline number of drug receptors. • Qualitative: a change in affinity • Absorption • Decline splanchnic blood flow • Reduce gastrointestinal motility • Reduced gastrointestinal surface • Distribution • Decrease albumin concentration • Decrease muscle mass • Increase body fat

  13. P’KINETIC VARIABILITY IN SPECIAL GROUPS (CONT’) • Geriatrics (cont’) • Metabolism • Decrease enzymes • Chronic Diseases • Decline organ function (liver & kidney) • Decrease blood flow (cardiac failure) • Multiple drug used

  14. P’KINETIC VARIABILITY IN SPECIAL GROUPS (CONT’) • Obese Patients • Actual body weight exceeds ideal body weight by 20% • Distribution • Smaller total body water (increase in fat) • Lipophilic drugs vs hydrophobic drugs • Metabolism • Fatty infiltration of the liver affects the metabolism processes • Excretion • Cardiovascular changes may affect renal blood flow

  15. POPULATION PHARMACOKINETICS • Analysis of population pharmacokinetic data: • Pooled data of plasma drug concentration from large group of subjects. • Considered kinetic and non-kinetic related factors. • Examined in the specific model eg. NONMEM (Non-linear mixed effect model)/ Bayesian Model • Estimated basic pharmacokinetics and random effect parameters. • Population pharmacokinetic parameters is used to calculate the initial dose or to adjust the dose.

  16. Population Derived Orbit Graph For PHT Ro, Vm 14 12 10 8 6 4 2 Cp Km 24 20 16 12 8 4 0 4 8 12 16

  17. THANK YOU

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