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 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.

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

CL VPA 30mg/kg/D CBZ 10mg/kg/D CBZ 20mg/kg/D CBZ TBW Drug-Drug Interaction between VPA-CBZ

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

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

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 V d, elimination and protein binding. Uremia may decreased protein binding to acidic drug.

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.

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

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.

P’KINETIC VARIABILITY IN SPECIAL GROUPS (CONT’) Average InfantAverage Adult Body Weight3.570 Body Water % (L)77 (2.7)58 (41) Disposition ParameterPhysiologic VariablePharmacokinetics Results Absorption  Gastric pHF  for basic drugs/  for acidic drugs  Motility? of F  Motility? of F  Bile acids  F Distribution  Body water  V d  Albumin/protein binding  V d & free drug Cp Metabolism  Enzyme capacity  t½ &  CL drug  Enzyme capacity  t½ &  CL drug Excretion  Glomerular function  t½  Tubular function  t½ Physiologic Factors influencing Drug Disposition in Infant

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 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 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 P’KINETIC VARIABILITY IN SPECIAL GROUPS (CONT’)

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.

KmKm CpCp R o, V m Population Derived Orbit Graph For PHT

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