Transcript BASIC PRINCIPLES IN CLINICAL PHARMACOKINETICS

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
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)
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)
IMPORTANT PARAMETERS (CONT’)
Compartment Model
1
One Compartment Model
1
2
Two Compartment Model
IMPORTANT PARAMETERS (CONT’)
Compartment Model
1
2
3
Multi Compartment Model
IMPORTANT PARAMETERS (CONT’)
• Elimination
Cp
• Kinetic Orders
Cp
-20 mg/L/H
-20 mg/L/H
-50%/H
y = ln Cp
-20 mg/L/H
-50%/H
-50%/H
t
Zero Order Kinetic
Amount of drug eliminated per unit time
t
First Order Kinetic
Percentage of drug eliminated per unit time
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)
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
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)
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 
CONCENTRATION TERMS
Steady-state
C
Cmax
Cave
Cmin
Cp
Cp
t
INDICATION FOR
THERAPEUTIC DRUG MONITORING
“ To determine, to solve and to prevent drug-related
problems, toward rational drug use”
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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.
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
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
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.
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.
THANK YOU