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

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

4. IMPORTANT PARAMETERS (CONT’) Compartment Model 112 One Compartment Model Two Compartment Model

5. IMPORTANT PARAMETERS (CONT’) Compartment Model 12 3 Multi Compartment Model

6. IMPORTANT PARAMETERS (CONT’) EliminationElimination Kinetic OrdersKinetic Orders Zero Order KineticFirst Order Kinetic tt Cp y = ln Cp Amount of drug eliminated per unit timePercentage of drug eliminated per unit time -20 mg/L/H -50%/H

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

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

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

10. Drug Concentration (con’t)Drug Concentration (con’t) Maximum concentration at steady-state (C max  )Maximum concentration at steady-state (C max  ) C max  = D x ( 1 ) C max  = D x ( 1 ) V d ( 1 – e -Ke  ) V d ( 1 – e -Ke  ) Minimum concentration at steady-state (C min  )Minimum concentration at steady-state (C min  ) C min  = C max  e -Ket C min  = C max  e -Ket Average Concentration at steady-state (C ave  )Average Concentration at steady-state (C ave  ) C ave  = D. C ave  = D. K e V d  K e V d  IMPORTANT PARAMETERS (CONT’)

11. CONCENTRATION TERMS C t CpCp CpCp C max  C ave  C min  Steady-state

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.The pharmacologic response is difficult to quantify. Drug use as prophylactic agents.Drug use as prophylactic agents. The drug has narrow therapeutic window.The drug has narrow therapeutic window. There is a disproportionate changes in plasma concentration with a change in drug dose.There is a disproportionate changes in plasma concentration with a change in drug dose. Drug clearance rapidly or unpredictably.Drug clearance rapidly or unpredictably. Poor patient compliance.Poor patient compliance. The response to drug therapy is unexpected.The response to drug therapy is unexpected. The adverse effects of the drug may mimic the disease state.The adverse effects of the drug may mimic the disease state. Some cases of overdose.Some cases of overdose.

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

14. LIST OF THERAPEUTIC AGENTS AntibioticsAntibiotics Aminoglycosides: Gentamicin, Netilmycin, AmikacinAminoglycosides: Gentamicin, Netilmycin, Amikacin VancomycinVancomycin AntiepilepticsAntiepileptics Phenytoin, Vaproic acid, CarbamazepinePhenytoin, Vaproic acid, Carbamazepine DigoxinDigoxin TheophyllineTheophylline Ciclosporin ACiclosporin A LithiumLithium PoisoningPoisoning Paracetamol, SalicylatesParacetamol, Salicylates MethotrexateMethotrexate BarbituratesBarbiturates

15. THERAPEUTIC DRUG MONITORING PRACTICE Patient’s dataPatient’s data Age, gender, weight, height.Age, gender, weight, height. Disease stateDisease state Drug indication, disease-drug interactions, organs function (liver & kidney), other laboratory values.Drug indication, disease-drug interactions, organs function (liver & kidney), other laboratory values. Concomitant drug usedConcomitant drug used Drug-drug interactions.Drug-drug interactions. The TDM drugThe TDM drug Drug name, route, dose given, the interval, time given.Drug name, route, dose given, the interval, time given. Sampling informationSampling information Time the samples taken (eg. pre, post, random)Time the samples taken (eg. pre, post, random) Laboratory analysisLaboratory analysis CalculationCalculation ConsultationConsultation Increase, decrease or maintain the dose and the reason(s) for adjustment. Decision should consider the patient clinical states.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 (V d = 20L, t½ = 3H)1000 mg of antibiotic Q given every 6 hours by repetitive bolus injections (V d = 20L, t½ = 3H) Calculate the following:Calculate the following: a) Plasma drug concentration at 3 hours after the 2 nd 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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