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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
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16 12 82024KmCp
Ro, Vm
Population Derived Orbit Graph For PHT
THANK YOUTHANK YOU