Clinical Pharmacokinetics and

Therapeutic Drug Monitoring

Kalidi Rajab
7th Oct 2013
Pharmacokinetics vs pharmacodynamics

 Pharmacokinetics  Pharmacodynamics
 “what the body does to the drug”  “what the drug does to the body”
• Absorption • wanted effects - efficacy
• Distribution • unwanted effects - toxicity
• Metabolism
• Elimination

disposition
 Pharmacokinetics Pharmacodynamics

Dose regimen Exposure Response

Site of action
Pharmacokinetics
• The study of drug absorption, distribution,
metabolism and excretion
– The clinical effectiveness of a drug is related to
it’s plasma/blood concentration
– This is dependent upon dosage, rate of
absorption, rate of distribution and rate of
metabolism/excretion
– Quantification of the bodies response to
individual drug and their metabolites
mathematically
Clinical Pharmacokinetics

“Clinical pharmacokinetics may be defined as the

study of the time course of the absorption,
distribution, metabolism and excretion of drugs
and their corresponding pharmacological
response”
Sequence of Drug Absorption,
Distribution and Elimination
Drug at site of administration
Absorption
Drug in plasma
Distribution
Drug in tissues / Drug at sites of action
Elimination
Drug excreted unchanged and/or Drug metabolised
and metabolites excreted
Plasma Concentration Time Curve

80
Absorption Elimination exceeds absorption
70
exceeds
60 elimination
Plasma Concentration

50

40

30
Absorption
20
equals
10 elimination
0
0 5 15 30 72 80 92
Time
Techniques for representing
pharmacokinetics
• Variety of techniques for representing the
pharmacokinetics of drugs
 Compartment models: body consisting of
compartments between which drug moves
and from which elimination occurs
 Rate constants: transfer of drug between
these compartments
Rates of reaction
• Velocity with which the reaction proceeds
described as either zero order or first order
• Zero order: rate of rxn proceeds at a constant
rate and is independent of the concentration of
the drug in the body e.g alcohol elimination.
• First order: rate of rxn proceeds at a rate
proportional to the amount of the drug in the
body e.g. most drugs used at therapeutic doses.
Pharmacokinetic models
• Hypothetical structures used to describe the fate of a
drug in a biological system following its administration
 One compartment model: assumes that drug achieves
instantaneous distribution throughout the body and that it
equilibrates instantaneously between tissues.
 Two compartment model: following drug administration
into the central compartment, the drug distributes btn
that compartment and the peripheral compartment but
no instantaneous distribution i.e. equilibrium btn the two
compartments
 Multicompartment model: distribution into more than one
compartment
 Compartment models

One-Compartment Model Dose

1
Assumes body as one compartment

Two-Compartment Model
Central compartment (drug entry and elimination) Dose
1 2
Tissue compartment (drug distributes)

k
The one compartment model linear
assumes that the drug in question is
evenly distributed throughout the
body into a single compartment.

This model is only appropriate for drugs

which rapidly and readily distribute
between the plasma and other body
tissues.
The distribution phase for aminoglycosides is only 15-30
minutes, therefore, we can use a one-compartment model
with a high degree of accuracy
Drugs which exhibit a slow
equilibration with peripheral
tissues, are best described with a
two compartment model
Vancomycin is the classic example, it's distribution phase is 1 to 2
hours. Therefore, the serum level time curve of vancomycin may be
more accurately represented by a 2-compartment model.
Pharmacokinetic parameters
• Absorption • Elimination ½ life
– can be defined as the – is the time taken for the
uptake of a particular drug concentration of drug in
from the site of the plasma/body to fall by
administration into the half
systemic circulation • Bioavailability
• Volume of distribution – the fraction/percentage of
– the volume of fluid into the dose administered
which reaches the
which a dose of drug
systemic circulation
would have to be
distributed in order to give • Clearance
a uniform concentration – the volume of plasma
equal to that measured in completely emptied of drug
the plasma per unit time (liver/kidney)
Absorption
Key concepts
• Ionisation- pH and PK
• Permeation of membranes- Solubility,
concentration gradient, surface area,
vascularity, membrane thickness and M.W
of drug
• Transport mechanisms- Passive diffusion,
facilitated diffusion & Active tpt.
 Anatomical Considerations
Gut Lumen

Portal Vein

Liver
Gut Wall
Systemic
Circulation
Metabolism Metabolism

Release + Dissolution

Permeation Elimination
Absorption
Bioavailability
Bioavailability
• Oral Administration
– What factors may effect bioavailability?
• Salt Factor
– E.g. 100mg of phenytoin sodium contains
92% (92mg) phenytoin base
– 225mg of aminophylline contains 80%
(180mg) of theophylline
• Weak acids and weak bases (ionisation)
 Bioavailability
Absolute Bioavailability

 requires I.V. administration

 Ratio of the oral:intravenous AUC values normalized for dose
 Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral)

Relative Bioavailability

 no I.V. reference
 comparison AUC values (ratio) of different dosage forms /
formulations
 Frel = (AUC a / AUC b) * (Dose b /Dose a)
 Area Under the Concentration – Time Curve
(AUC)
 A quantitative measure for exposure
Concentration (Units/ml)

from dosing time to time ‘t’

10
 An important parameter in PK
 AUC(t) and AUC(inf)
1
 Determined by trapezoidal method
0.1
 AUC(inf) = AUC(t) + Ct/k
Units: Conc*t (mg/L * h)
0.01
 Proportional to Dose (linear PK)
0 5 10 15 20  Accuracy of the estimate depends on
frequency of sampling
Time (hr)

Area Under the Curve (AUC)

Bioavailability
• LD=VdxCp/F; F is bioavailability
• LD=VdxCp/FxS; S is salt factor
• F= AUCpo/AUCiv
Distribution
• Distribution to the tissue is dependent on the
rate of blood flow, the mass of tissue and the
partition characteristics of the drug between
plasma and tissues
• Drugs that are highly protein bound may
remain within the plasma; drugs that are
highly lipid soluble are distributed within the
body fat and small water soluble molecules
are distributed throughout the body water
• Barriers to distribution- Placental and BBB
Apparent Volume of Distribution
• Vd term used to signify the extent of
distribution, is defined as the volume of
fluid required to account for the total
amount of drug in the body if it were
present throughout the body in the
concentration observed in the plasma
Vd (L or L/Kg) = Total amount of drug in the body
Concentration in the plasma
Elimination rate constant
• Consider single IV bolus injection of drug
X
• dX/dt=-kX, 1st order kinetics
• X =Xoexp (-kt)
• Cpt=Cpoexp(-kt)
Half life
• t1/2=0.693/K
• Can be used to estimate how long should
a drug be stopped if a patient has toxic
drug levels assuming one compartment
kinetics
• E.g. patient has toxic digoxin level of
4.5µg/L. t1/2 of digoxin is 60h. How long
should the drug be stopped to reduce the
dose to 1.5μg/L. Ans 4 days
Elimination
k 
lny  ln  y
2
e
T1/2

lny  lny  ln2

ke 
T1/2

ln2
ke 
T1/2

0.693
ke 
T1/2
 “Rule of Five”

5x the elimination ½ life = time at which

the drug is “completely” (97%) eliminated
from the body
1x ½ life - 50% of the original drug
removed
2x ½ life - 75%
3x ½ life - 87.5%
4x ½ life - 93.75%
5x ½ life - 96.875%
 Clearance

“Of the concepts in pharmacokinetics, clearance has the greatest

potential for clinical applications.
It is also the most useful parameter for the evaluation of an
elimination mechanism.”

Rowland & Tozer

 Clearance

 Quantifies Elimination

 Is the volume of body fluid cleared

per time unit (L/h, mL/min)

 Is Usually Constant
 Clearance
Proportionality factor relating rate of drug elimination to
plasma drug concentration

Rate of eliminatio n  CL  C

Rate of eliminatio n
CL 
C
(dx/dt)
CL 
C
Integrate
DoseIV
CL 
AUC
 Clearance
Rate of elimination is proportional to the amount (A) of drug present

Rate of eliminatio n  k * A

Rate of eliminatio n  k * V * C

Rate of eliminatio n
k *V
C
Clearance  k * V
0.693 * V
Clearance 
Half - life
Dependence of Half-life on Clearance and Volume
Why is Clearance Important?

Clearance is the one parameter that

determines the maintenance dose rate
required to achieve a desired plasma
conc.

Dosing rate = clearance X desired

plasma conc.
For a given dose rate, the blood drug concentration is inversely
proportional to clearance
Clearance
• CLtotal=CLrenal + CLnonrenal
• CL=k x Vd, k is elimination rate constant
• t1/2=0.693xVd/CL
• CL of 2L/h means 2L of the Vd is cleared
of drug per hr. if Cp is 10mg/L, then 20mg
of drug is cleared per hr.
 Concentration
Multiple Dose Administration

Time (hr)
 Minimum and maximum conc should be within therapeutic window – depends
on dose, frequency and t1/2
 Depending on dosing frequency and t1/2, accumulation occurs
 Degree of accumulation is important for safety assessment purposes
Multiple doses-steady state
• Steady state: amount of drug administered in
any time period equal to amt of drug eliminated
in that same period
• Dose: the higher the dose, the higher the steady
state levels
• Dosing interval:>t1/2 low accumulation,<t1/2
higher steady state levels more accumulation
• Time to reach steady state: proportional to t1/2.
Steady state
• Rate of administration=rate of elimination
• Rate of administration=S x F x D/τ
• Rate of drug elimination= CLxCpss
• Cpss =S x F x D/CL x τ
• Assumed to be reached in 4-5 half lives
Loading dose
Intravenous infusion
• LD = Vd x Cpss
• LD = Vd x (Cpss-Cpinitial)
• LD = Vd X (Cpss-Cpinitial)/S
Oral administration
• LD = Vd x Cp/F
• LD = Vd x Cp/F x S
Summary of key equations
Single dose equations Multiple doses or
• Vd=D/Co infusion rates
• Vd=SxFxD/Co • Ko=CL x Css
• t1/2=0.693/k • LD=Vd x Css
• CL=k x Vd • LD=Cl x Css x т
• Cpt=Cpo exp (-kt)
Case1
• Pt prescribed 100mg of drug X every 8h.
At steady state two plasma concns are
measured:
• Sample 1 taken at 1h post dose: 9.6mg/l
• Sample 2 taken pre dose: 2.9mg/l
• Calculate the elimination rate constant (k)
and half life. If Vd is 11.8L, calculate CL
• Ans k=0.171per h, t1/2=4.1h, CL=2.02L/h
TDM
• Therapeutic Drug Concentration
Monitoring
• Use of drug levels, pharmacokinetic
principles and pharmacodynamic factors
to optimise drug therapy in individual
patients
• Optimisation of drug therapy may involve
minimising the risk of toxicity or increasing
the probability of efficacy
Why TDM?
• TDM useful if:
– Poor relationship between drug dose/levels
– Narrow therapeutic range
– Non compliance suspected
– Toxicity suspected
– Adverse effects similar to effects
– Altered kinetics present e.g. smoking
Therapeutic Range
• A therapeutic range is a range of drug
concentrations within which the probability of the
desired clinical response is relatively high and the
probability of unacceptable toxicity is relatively low
• A therapeutic range should never be considered in
absolute terms as it only represents a combination
of probability charts
• Moreover, there are discrete subpopulations for
whom concentration-effect relationships differ
from the norm
Interpretation of drug serum
concentrations
Drug, patient, logistical and analytical variables
influence
the interpretation of drug concentration data:
• Time of drug administration
• Route
• Dose
• Time of sampling
• Handling and storage of samples
• Precision and accuracy of the analytical method
Variability in drug dosage
requirements
• Age
• Body weight
• Gender
• Renal function
• Liver function
• Genetic factors
• Drug interactions
Genetic Factors
• Genetic polymorphisms that lead to the
production of isoenzymes with reduced or
no activity or to multiple copies of an
enzyme with high activity make a major
contribution to the variability in the dose
requirements of drugs that are eliminated by
hepatic metabolism.
• Cytochrome P4502D6 isoenzyme
• Transporter proteins
Enzyme induction of Cytochrome
P450
• Barbiturates (CYP2C9)
• Rifampicin (CYP2C9)
• Griseofulvin (CYP2A6)
• Carbamazepine (CYP1A2,
2B6, 2C8, 2C9 and 3A4)
• Chronic Alcohol
consumption (CYP2E1)
Enzyme inhibition of Cytochrome
P450
• Cimetidine (CYP1A2) • Fluoxetine, Sertraline &
• Omeprazole (CYP2C19) Paroxetine (CYP2D6)
• Phenylbutazone (CYP2C9) • Acute alcohol
consumption
• Amiodarone ((CYP2D6)
• Metronidazole (CYP3A4)
• Erythromycin (CYP3A4)
• Clarithromycin (CYP1A2 &
3A4)
• Ciprofloxacin (CYP1A2)
• Fluconazole (CYP3A4)
Common drugs looked at

• Digoxin
• Amiodarone
• Warfarin
• Antibiotics: aminoglycosides, vancomycin
• Anticonvulsants: phenytoin, sodium valproate,
carbamazepine
• Others: theophylline, lithium
• Immunosuppressants: cyclosporin, tacrolimus