VARIABILITY INVARIABILITY IN PHARMACOKINETICS & PHARMACOKINETICS &

PATIENT RESPONSEPATIENT RESPONSE

Dr. Mohd B. Makmor Bakry, Ph.D., RPhSenior Lecturer in Clinical Pharmacy

Universiti Kebangsaan MalaysiaKuala Lumpur

TYPES OF VARIABILITYTYPES 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 FACTORSCONTRIBUTING 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

CLVPA

30mg/kg/D CBZ

10mg/kg/D CBZ

20mg/kg/D CBZ

TBW

Drug-Drug Interaction between VPA-CBZ

CONTRIBUTING FACTORS (CONT’)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

DaysGenetic differences between twins

Fraternal Twins

Identical Twins

THE EFFECTS OF DISEASE THE EFFECTS OF DISEASE ON PHARMACOKINETICSON 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.

THE EFFECTS OF DISEASE ON P’KINETICS (CONT’)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’)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 PHARMACOKINETIC VARIABILITY IN SPECIAL GROUPSIN SPECIAL GROUPS

Pediatrics (Infant 0 – 2 years old) Variation in:

Body compositionMaturity of liverMaturity 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 Infant Average Adult

Body Weight 3.5 70

Body Water % (L) 77 (2.7) 58 (41)

Disposition Parameter Physiologic Variable Pharmacokinetics Results

Absorption Gastric pH F for basic drugs/ for acidic drugs

Motility ? of F

Motility ? of F

Bile acids F

Distribution Body water Vd

Albumin/protein binding Vd & free drug Cp

Metabolism Enzyme capacity t½ & CLdrug

Enzyme capacity t½ & CLdrug

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

MetabolismFatty infiltration of the liver affects the metabolism

processes Excretion

Cardiovascular changes may affect renal blood flow

P’KINETIC VARIABILITY IN SPECIAL GROUPS (CONT’)

POPULATION PHARMACOKINETICSPOPULATION 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.

4 1612840

14

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16 12 82024KmCp

Ro, Vm

Population Derived Orbit Graph For PHT

THANK YOUTHANK YOU