BASIC PRINCIPLES IN CLINICAL PHARMACOKINETICS

1. BASIC PRINCIPLES IN CLINICAL PHARMACOKINETICS Dr. Mohd Bin Makmor Bakry, PhD, RPh Senior Lecturer in Clinical Pharmacy Intensive Care Preceptor Faculty of Pharmacy Universiti Kebangsaan Malaysia

2. IMPORTANT PARAMETERS • Dose (D) • Amount of drug been introduced into the body. • Accumulation may occur with repetitive dosing. Amax = D / (1 – e-ke ) • Absorption • Absorption Rate (Ka) • Important for oral dosing • Bioavailability (F) • Depends on route of administration & dosage form • eg.: PHT Na (oral)= 0.9, DGX (tablet)= 0.7, CSA (oral)= 0.23 • Salt Factor (S) • Depends on physicochemical charateristics • eg.: THP (oral) = 0.8 x Aminophylline (IV)

3. IMPORTANT PARAMETERS (CONT’) • Distribution • Volume of Distribution (Vd) • A ‘picture’ of volume which the drug distributes. • eg.: High Vd; CSA = 85L, Metoprolol = 290L • eg.: Low Vd; Gentamicin = 18L, Vancomycin = 27L • Compartment Model • A ‘picture’ of where and how the drug is distributed. • One Compartment Model • Multiple Compartment Model (two or more compartment)

4. IMPORTANT PARAMETERS (CONT’) Compartment Model 1 1 2 Two Compartment Model One Compartment Model

5. IMPORTANT PARAMETERS (CONT’) Compartment Model 1 2 3 Multi Compartment Model

6. IMPORTANT PARAMETERS (CONT’) • Elimination • Kinetic Orders Cp Cp -20 mg/L/H y = ln Cp -20 mg/L/H -50%/H -20 mg/L/H -50%/H -50%/H t t Zero Order Kinetic First Order Kinetic Amount of drug eliminated per unit time Percentage of drug eliminated per unit time

7. IMPORTANT PARAMETERS (CONT’) • Constant Rate of Elimination (Ke) • Ke= Terminal Distribution Phase + Elimination Phase • Ke= Elimination Phase (Important) • Clearance • Linear Clearance (First Order Kinetic) • eg.: Gentamicin, theophylline • Non-linear Clearance (Zero Order Kinetic) • eg.: Phenytoin, Carbamazepine • Creatinine Clearance (CLCr)(ml/min) CLCr = G x (140 – Age) Wt ; G (male) = 1.23 SrCr G (female) = 1.04 SrCr in mol/L • Drug Clearance (CLdrug)(ml/min or L/H)

8. IMPORTANT PARAMETERS (CONT’) • Elimination Half-life (t½) • The time taken for the concentration to drop to 50% of the previous value. • eg.: CBZ = 15H, DGX = 39H, Gentamicin = 2 – 3H, • THP = 8.1H • Dosing Interval () • The frequency of dose given • eg.: Q6H, Q8H, Q12H, Q24H, OD, EOD

9. IMPORTANT PARAMETERS (CONT’) • Drug Serum/Plasma Concentration (Cp) • Target Concentration • Antibiotics: Peak Conc. and Trough Conc. • Other drugs: Trough Concentration • Drug Concentration • Plasma Concentration (Cp) Cp = D x (1 – e-nKe ) e-Ket Vd ( 1 – e-Ke) • Cp at steady-state (Cpss or Cp) Cp = D x ( 1 ) e-Ket Vd ( 1 – e-Ke)

10. IMPORTANT PARAMETERS (CONT’) • Drug Concentration (con’t) • Maximum concentration at steady-state (Cmax) Cmax = D x ( 1 ) Vd ( 1 – e-Ke) • Minimum concentration at steady-state (Cmin) Cmin = Cmax e-Ket • Average Concentration at steady-state (Cave) Cave = D . Ke Vd 

11. CONCENTRATION TERMS Steady-state C Cmax Cave Cmin Cp Cp t

12. INDICATION FOR THERAPEUTIC DRUG MONITORING “ To determine, to solve and to prevent drug-related problems, toward rational drug use” • The pharmacologic response is difficult to quantify. • Drug use as prophylactic agents. • The drug has narrow therapeutic window. • There is a disproportionate changes in plasma concentration with a change in drug dose. • Drug clearance rapidly or unpredictably. • Poor patient compliance. • The response to drug therapy is unexpected. • The adverse effects of the drug may mimic the disease state. • Some cases of overdose.

13. DRUG OF CHOICE • Narrow therapeutic window • Good concentration-response relationship • Plasma concentration-therapeutic response • Plasma concentration-toxic response • Difficulty in interpreting clinical evidence of therapeutic or toxic effect

14. LIST OF THERAPEUTIC AGENTS • Antibiotics • Aminoglycosides: Gentamicin, Netilmycin, Amikacin • Vancomycin • Antiepileptics • Phenytoin, Vaproic acid, Carbamazepine • Digoxin • Theophylline • Ciclosporin A • Lithium • Poisoning • Paracetamol, Salicylates • Methotrexate • Barbiturates

15. THERAPEUTIC DRUG MONITORING PRACTICE • Patient’s data • Age, gender, weight, height. • Disease state • Drug indication, disease-drug interactions, organs function (liver & kidney), other laboratory values. • Concomitant drug used • Drug-drug interactions. • The TDM drug • Drug name, route, dose given, the interval, time given. • Sampling information • Time the samples taken (eg. pre, post, random) • Laboratory analysis • Calculation • Consultation • Increase, decrease or maintain the dose and the reason(s) for adjustment. Decision should consider the patient clinical states.

16. QUESTION FOR PRACTICE • 1000 mg of antibiotic Q given every 6 hours by repetitive bolus injections (Vd = 20L, t½ = 3H) • Calculate the following: a) Plasma drug concentration at 3 hours after the 2nd dose. b) The steady-state plasma drug concentration at 3 hours after the last dose. c) Maximum concentration achieved at steady state. d) Minimum concentration achieved at steady-state. e) Average concentration achieved at steady-state.

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