BASIC PRINCIPLES IN CLINICAL BASIC PRINCIPLES IN CLINICAL PHARMACOKINETICSPHARMACOKINETICS

Dr. Mohd Bin Makmor Bakry, Dr. Mohd Bin Makmor Bakry, PhD, RPhPhD, RPhSenior Lecturer in Clinical PharmacySenior Lecturer in Clinical Pharmacy

Intensive Care PreceptorIntensive Care PreceptorFaculty of PharmacyFaculty of Pharmacy

Universiti Kebangsaan MalaysiaUniversiti Kebangsaan Malaysia

IMPORTANT PARAMETERSIMPORTANT 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.

AAmaxmax = D / (1 – e = D / (1 – e-ke-ke ))

• AbsorptionAbsorption

• Absorption Rate (KAbsorption Rate (Kaa))

• 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)

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

• DistributionDistribution

• Volume of Distribution (VVolume of Distribution (Vdd))

• A ‘picture’ of volume which the drug distributes.A ‘picture’ of volume which the drug distributes.

• eg.: High Veg.: High Vdd; CSA = 85L, Metoprolol = 290L; CSA = 85L, Metoprolol = 290L

• eg.: Low Veg.: Low Vdd; Gentamicin = 18L, Vancomycin = 27L; 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 Multiple Compartment Model (two or more

compartment)compartment)

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

Compartment Model

11 2

One Compartment Model Two Compartment Model

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

Compartment Model

1 2

3

Multi Compartment Model

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

• EliminationElimination• Kinetic OrdersKinetic Orders

Zero Order Kinetic First Order Kinetic

t t

Cp Cp

y = ln Cp

Amount of drug eliminated per unit time Percentage of drug eliminated per unit time

-20 mg/L/H

-20 mg/L/H

-20 mg/L/H

-50%/H

-50%/H

-50%/H

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

• Constant Rate of Elimination (KConstant Rate of Elimination (Kee))

• KKee = Terminal Distribution Phase + Elimination Phase= Terminal Distribution Phase + Elimination Phase

• KKee = Elimination Phase (Important)= 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 (CLCreatinine Clearance (CLCrCr)(ml/min))(ml/min)

CLCLCrCr = = G x (140 – Age) WtG x (140 – Age) Wt ; G (male) = 1.23 ; G (male) = 1.23SrCrSrCr G (female) = 1.04 G (female) = 1.04

SrCr in SrCr in mol/Lmol/L

• Drug Clearance (CLDrug Clearance (CLdrugdrug)(ml/min or L/H))(ml/min or L/H)

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

• Elimination Half-life (t½)Elimination Half-life (t½)• The time taken for the concentration to drop to 50% of The time taken for the concentration to drop to 50% of

the previous value.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

• 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 = Cp = DD x x (1 – e(1 – e-nKe-nKe ) e ) e-Ket-Ket

VVd d ( 1 – e( 1 – e-Ke-Ke))

• Cp at steady-state (Cpss or CpCp at steady-state (Cpss or Cp))CpCp = = DD x x ( 1 ) e( 1 ) e-Ket-Ket

VVdd ( 1 – e ( 1 – e-Ke-Ke))

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

• Drug Concentration (con’t)Drug Concentration (con’t)• Maximum concentration at steady-state (CMaximum concentration at steady-state (Cmaxmax

))

CCmaxmax = = DD x x ( 1 )( 1 )

VVdd ( 1 – e ( 1 – e-Ke-Ke))

• Minimum concentration at steady-state (CMinimum concentration at steady-state (Cminmin))

CCminmin = C= Cmaxmax

ee-Ket-Ket

• Average Concentration at steady-state (CAverage Concentration at steady-state (Caveave))

CCaveave = = D . D .

KKee V Vdd

IMPORTANT PARAMETERS (CONT’)IMPORTANT PARAMETERS (CONT’)

CONCENTRATION TERMSCONCENTRATION TERMS

C

t

Cp

Cp

Cmax

Cave

Cmin

Steady-state

INDICATION FOR INDICATION FOR THERAPEUTIC DRUG MONITORINGTHERAPEUTIC DRUG MONITORING

“ “ To determine, to solve and to prevent drug-related To determine, to solve and to prevent drug-related problems, toward rational drug use”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 There is a disproportionate changes in plasma concentration with a

change in drug dose.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.

DRUG OF CHOICEDRUG 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 Difficulty in interpreting clinical evidence of therapeutic or toxic effecttherapeutic or toxic effect

LIST OF THERAPEUTIC AGENTSLIST 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

THERAPEUTIC DRUG MONITORING PRACTICETHERAPEUTIC 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 Drug indication, disease-drug interactions, organs function (liver

& kidney), other laboratory values.& 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 Increase, decrease or maintain the dose and the reason(s) for adjustment. Decision should consider the patient clinical states.adjustment. Decision should consider the patient clinical states.

QUESTION FOR PRACTICEQUESTION FOR PRACTICE

• 1000 mg of antibiotic Q given every 6 hours by repetitive 1000 mg of antibiotic Q given every 6 hours by repetitive bolus injections (Vbolus injections (Vdd = 20L, t½ = 3H) = 20L, t½ = 3H)

• Calculate the following:Calculate the following:

a) Plasma drug concentration at 3 hours after the 2a) Plasma drug concentration at 3 hours after the 2ndnd dose.dose.

b) The steady-state plasma drug concentration at 3 b) The steady-state plasma drug concentration at 3 hours after the last dose.hours after the last dose.

c) Maximum concentration achieved at steady state.c) Maximum concentration achieved at steady state.

d) Minimum concentration achieved at steady-state.d) Minimum concentration achieved at steady-state.

e) Average concentration achieved at steady-state.e) Average concentration achieved at steady-state.

THANK YOUTHANK YOU