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Basic Concepts
of Pharmacokinetics
Achiel Van Peer, Ph.D.

Clinical Pharmacology
Gent, 24 August 2007/avpeer

1
Some introductory Examples

2
15 mg of Drug X in a slow release OROS capsule
administered in fasting en fed conditions
in comparison to 15 mg in solution fasting

3
Prediction of drug plasma concentrations
before the first dose in a human
NOAEL in female rat
NOAEL in female dog
NOAEL in male dog

NOAEL in male rat
First dose 5 mg
Fabs 100%
Fabs 50%
Fabs 20%

4
Allometric Scaling

5
Pharmacokinetics:
Time Profile of Drug Amounts
Drug at absorption site
Metabolites
Percent of dose
Drug in body
Excreted drug
Time (arbitrary units)

Rowland and Tozer,
Clinical Pharmacokinetics: Concepts and Applications, 3rd Ed. 1995

6
Definition of Pharmacokinetics ?
Pharmacokinetics is the science describing drug
absorption from the administration site

distribution to
tissues,
target sites of desired and/or undesired activity
metabolism
excretion
PK= ADME

7
We will cover
Some introductory Examples

Model-independent Approach
Compartmental Approaches
Drug Distribution and Elimination
Multiple-Dose Pharmacokinetics
Drug Absorption and Oral Bioavailability
Role of Pharmacokinetics

8
The simplest approach
observational pharmacokinetics
The Model-independent Approach
Cmax : maximum observed concentration

Tmax : time of Cmax
AUC : area under the curve

9
Cmax, Tmax and AUC in
Bioavailability and Bioequivalence Studies
Absolute bioavailability (Fabs)
compares the amount in the systemic circulation
after intravenous (reference) and extravascular (usually oral) dosing
Fabs = AUCpo/AUCiv for the same dose
between 0 and 100% (occasionally >100%)
Relative bioavailability (Frel)

compares one drug product (e.g. tablet)
relative to another drug product (solution)
Bioequivalence (BE): a particular Frel

Two drug products with the same absorption rate (Cmax, Tmax)
and the same extent (AUC) of absorption
(90% confidence intervals for Frel between 80-125%)
10
Absolute oral bioavailability
flunarizine, J&J data on file
Other example: nebivolol:

10% in extensive metabolisers; 100% in poor metabolisers

11
Area under the curve
Trapezoidal rule: divide the plasma concentration-time profile

to several trapezoids, and add the AUCs of these trapezoids
Conc
C1 + C 2 Units, e.g. ng.h/mL
AUC t1 - t2 =( ).(t 2 t1)
2
Clast
AUCextrapolated =
z
0
0 Time
12
Elimination half-life ?
Half-life (t1/2) : time the drug concentration

needs
to decrease by 50%

13
visual inspection

14
visual inspection or alternatives ?
Half-life (t1/2) : time to decrease by 50%
T1/2 = 6 hrs
Derived from
a semilog plot
T1/2 = 0.693/z

15
From Whole-Body Physiologically based
Pharmacokinetics to Compartmental Models
Poggesi et al., Nerviano Medical Science

16
Compartmental Approach
drug distributes very rapidly to all tissues

via the systemic circulation
an equilibrium is rapidly established between the blood
and the tissues, the body behaves like
one (lumped) compartment
does not mean that the concentrations in the different
tissues are the same
One-compartment PK model
Drug
Absorption Body
compartment Drug Elimination

17
One compartment behaviour
more often observed after oral drug intake
1000
100
Poor metabolisers
10
Extensive metabolisers
1
0 8 16 24 32 40 48
Time, hours

18
Intravenous dose of 0.2 mg Levocabastine
(J&J data on file)

19
Depending on rate of equilibration with
the systemic circulation, lumping tissues together,
and simplification is possible
Multi-Tissue or Multi-Compartment
Whole Body Pharmacokinetic model
Tri-compartment model
Two-compartment model
One-compartment model

20
Zero-order rate drug administration
and first-order rate drug elimination
Amount A
in blood, plasma
Infusion rate Rate of elimination is

mg/min proportional to
the Amount
in blood/plasma
dDose/dt = Ko = mg/min dA/dt = -k.A
[Often K=Kel=K10]

21
First-order rate of drug disappearance
Rate of elimination
Amount A
is proportional to
[or Concentration C]
the Amount or
in blood, plasma
Concentration in
blood, plasma
dA/dt = -k.A = -k.Vd.C

Intravenous
bolus
If A = Amount in plasma, then V= Plasma volume

If A = Remaining amount in the body, then
Vd= Total volume of distribution

22
A single iv dose of 5 mg
for a drug with immediate equilibration
(one compartment behaviour)
dA/dt = -k10.A = -k10.V.C
dA/dt = -k10.A = -CL.C

dC/dt = -k10.C
C = C0. e-k10.t

23
C = C0 e-k10.t
lnC = lnC0 - k10.t
Remark for log10 scale:

slope = k10/2.303
24
ln C = lnC0 - k10.t
ln C1 ln C 2 0.693
k10 = =
t 2 t1 t 2 t1
Slope=k10
= the elimination rate constant
Half-life =
C2 0.693/k10
= half of
C1

25
dose 5000000ng
Vd = = = 30.9 L
Cpo 162ng / mL
Vd = volume of distribution,
relates the drug concentration
to the drug amount
in the body

26
One-Compartment model
after intravenous administration
Vd = volume of distribution,
relates the drug concentration at a particular time
to the drug amount in the body at that time
k10= (first-order) elimination rate constant
Clearance (CL) = Vd.K10

The volume of drug in the body cleared per unit time
Half-life = 0.693 . Vd/CL

27
Compartmental Approach
after intravenous dosing
Distribution
Central Peripheral
compartment compartment
Re-distribution
Elimination
Rapidly equilibrating tissues:

plasma, red blood cells, liver, kidney,
Slower equilibrating:
adipose tissues, muscle,
Usually peripheral compartment
Slowly redistribution reason
for long terminal half-life

28
Intravenous dose of 0.2 mg levocabastine
K12= 0.84 h-1
V1 = 44 L V2 = 35 L
K21= 1.05 h-
1
K10 = 0.4 h-1

29
Cld= k12.V1= 36.7 L/h
V1 = 44 L V2 = 35 L
Cld= k21.V2= 36.7 L/h
Cl=K10 .V1=Dose/AUC= 1.77 L/h=30 mL/min
Vdss = V1 + V2

30
Rates of drug exchange
DAp/dt = - K10.Vc.Cp - K12.Vc.Cp + K21.Vt.Ct
DAt/dt = K12.Vc.Cp - k12.Vt.Ct
Initially very fast decay due to distribution to tissues and

elimination (distribution phase) until equilibrium is
reached (influx into and efflux from tissue is equal)
After a pseudo-equilibrium is reached, there is only loss of

drug from the body (elimination phase), but is in fact
combination of redistribution from tissues and elimination
Rate of redistribution may differ significantly across drugs;

long terminal half-life is compounds sticks somewhere

31
Cp=A.e-.t+B.e-.t
Cp=2.1.e-1.91 .t+2.5.e- 0.0224.t
0.693 0.693
t =t 1 / 2 = = = 31h
0.0224h 1
1 / 2 term
Vd = CL/=Dose/(AUC. )=Vdarea

32
Two-compartmental model
Central K12
Compartment Peripheral
Vc Compartment
K21 Vt
K10
K10, K12, K21 are first order rate constants
hybrid first-order rate constants and for the so-called

distribution phase and elimination phases, T1/2 and T1/2
Vc, Vdss, Vd or Vdarea are Vd of

central compartment, at steady-state, during elimination phase

33
Compartmental approach
Shallow Peripheral
Central compartment
compartment
Deep Peripheral
compartment
Compartments serve
as reservoirs with different drug amounts (concentrations),
different volumes, and
different rates of exchange of drug with the central compartment.
The shape of the plasma concentration-time profile

empirically defines the number of compartmentsl

34
Intravenous
Sufentanil
Gepts et al., Anesthesiology,

83:1194-1204, 1995

35
Three compartmental model
Sufentanil Pharmacokinetics
Mixed-effects Population PK analysis
(N =23)
Population
CV (%)
Average
Volume of distribution (L)
Central (V1) 14.6 22
Rapidly equilibrating (V2) 66 31
Slowly equilibrating (V3) 608 76
At steady-state 689
Clearance (L/min)
Systemic (CL or CL1) 0.88 23
Rapid distribution (CL2) 1.7 48
Slow distribution (CL3) 0.67 78
Gepts et al., Anesthesiology, 83:1194-1204, 1995

36
Three compartmental model
Sufentanil Pharmacokinetics
Fractional Rate constants
Coefficients (min-1)
A 0.94 K10 0.06
B 0.058 K12 0.11
C 0.0048 K13 0.05
K21 0.025
K31 0.0011
Exponents (min-1) Half-lives (min)
0.24 t1/2 2.9
0.012 t1/2 59
0.0006 t1/2 1129
Gepts et al., Anesthesiology, 83:1194-1204, 1995

37
Compartmental approach
Central Shallow Peripheral

Deep Peripheral
compartment
Central Peripheral
Effect site

38
Time profile of opioid concentrations
in plasma and the predicted
concentrations at the effect site
based upon an effect compartment
PK-PD model
(expressed as percentage of the
initial plasma concentration)
Effect site concentration profile

reflect difference
in onset time of analgesia
Shafer and Varvel,

Anesthesiology 74:53-63, 1991

39
Rate of Drug Distribution
perfusion-limited tissue distribution
immediate equilibrium of drug in blood and in

tissue
only limited by blood flow
highly perfused : liver, kidneys, lung, brain
poorly perfused : skin, fat, bone, muscle
Permeability rate limitations or membrane barriers
blood-brain barrier (BBB)

blood-testis barrier (BTB)
placenta

40
Unbound Fraction and Drug Disposition
Plasma Cell Tissue

membrane
Receptor-bound
drug
Protein-bound Free drug Free drug Protein-bound

drug (non-ionized) (non-ionized) drug
Ionized drug Ionized drug

(free) (free)
Pka-pH, affinity for plasma and tissue proteins,

permeability,
41
Physicochemistry, PK and EEG PD
of narcotic analgesics
A lfe n ta n il F e n ta n y l S u fe n ta n il
pKa 6 .5 8 .4 3 8 .0 1
% u n io n iz e d a t p H 7 .4 89 8 10
P o c t/w a te r 130 810 1750
% u n b o u n d in p la s m a 8 16 8
V d s s (L ) 23 358 541
C l (L /m in ) 0 .2 0 0 .6 2 1 .2
t1 /2 k e o E E G (m in ) 1 .1 6 .6 6 .2
C e 5 0 , E E G (n g /m l) 520 8 .1 0 .6 8
C e50, unb (n g /m l) 41 1 .2 0 .0 5 1
K i (n g /m l) 7 .9 0 .5 4 0 .0 3 9
Shafer SL, Varvel JR: Pharmacokinetics, pharmacodynamics, and rational opioid selection.
Anesthesiology 1991; 74:53-63; DR Stanski, J Mandema (diverse papers)

42
Localisation and Role of Drug Transporters
Zhang et al., FDA web site and Mol. Pharmaceutics 3, 62-69, 2006

43
Apparent Volume
of Distribution
Vd = Amount of drug in
body/concentration in plasma
Minimum Vd for any drug is ~3L, the
plasma volume in an adult, for ethanol:
equal to body water
For most basic drugs very high due to
sequestering in specific organs (liver,
muscle, fat, etc.)
Rowland and Tozer,

Clinical Pharmacokinetics: Concepts and Applications,
3rd Ed., 1995

44
Vd (L/kg) after iv dosing
in rat and human (J&J data)

45
Multiple Dosing
Concepts

46
Dosing to Steady-state
On continued drug administration, the amount in the body
will initially increase but attain a steady-state, when the rate of elimination
(drug loss per unit time) equals the amount administered per unit time
Amount A in body
Cplasma.Vdss
Fractional loss of A or Cp
mg/day
First-order rate
- K.A; - CL.Cp
1. Initial increase when ko > -K10.Abody
2. Steady state when ko = K.Abody= CL.C
3. Ass or Css constant

as long ko constant and CL constant

47
Time to steady-state
Half-life of 24 hr and dosing interval of 24 hrs
Steady-state when drug loss per day

equals drug intake per day

48
Cmax
Cavg,ss
Cavg,ss = AUCss/ Cmin

AUC at steady state = AUC single dose
AUCss/ AUCfirst dose= Accumulation Index

49
Steady-state
The amount in the body at steady-state (Ass)
Ko
Ass =
Kel
The plasma concentration at steady-state (Css,Cavgss)
Ko Ko
Cpss = =
Kel.Vdss Cl
Css is proportional to the dosing rate (zero-order input)

and
inversely proportional to the first-order elimination rate
or clearance

50
Cmax
Cavg,ss
Cmin
C=Css(1-e-k.t)
5-6 half-lives to reach steady-state

51
An effective half-life reflects drug accumulation
Drug A: A=20 ng/mL; B=80 ng/mL; T1/2=3 h; T1/2=24 h
Drug B: A=80 ng/mL; B=20 ng/mL; T1/2=3 h; T1/2=24 h

52
An effective half-life reflects drug accumulation
AUCss, 1
Accumulation ratio = =
AUC 0 1 exp( Keff . )
Drug A: T1/2eff= 20 h
Drug B: T1/2eff= 10 h
C=Css(1-e-keff.t)
Boxenbaum, J Clin Pharmcol 35:763-766, 1995

53
Mean residence time = MRT
MRT is the time the drug, on average,

resides in the body.
MRT = Vdss/Cl

54
Loading and Maintenance Dose
Maintenance Dose
= desired Css x CL
Loading Dose
= desired Css X Vd
Loading dose can be high for

drugs with large Vd,
then LD divided
over various administrations
(J&J data on file)

55
Total body clearance (CL)
A measure of the efficiency of all eliminating organs
to metabolize or excrete the drug
Volume of plasma/blood cleared from drug per unit time
CL = k10.Vc = z.Vdz= MRT.Vdss
CL= Dose / AUCplasma

56
Physiological approach to Clearance
Amount A
or Concentration C
Rate in in blood Rate out
Q.Cpv
Q.Cpa
Q(Cpa - Cpv) fu.Clint

Clearance = = Q.
Cpa Q + fu.Clint
Clearance = QE
Low hepatic clearance High hepatic clearance

if extraction ratio E <<1 if E 1
eg. Risperidone (Fabs 85%) eg. Nebivolol (Fabs 10%)

57
Bioavailability F
After oral administration,

not all drug may reach the systemic circulation
The fraction of the administered dose

that reaches the systemic circulation
is called the bioavailability F

58
Oral drug absorption,
Influx and Efflux Transporters, Drug Loss by First-pass
Gut
lumen
Portal
Uptake and effluxVein
transporters
Systemic
Tablet circulation
disintegration
Drug Liver
dissolution Gut wall Hepatic Metabolism
Metabolism
Biliary secretion
Uptake and efflux
Into transporters
faeces
F= Fabsorbed.(1-Egut).(1-Eliver)

59
Grapefruit inhibits gut-wall metabolism
(J&J data on file)
140
Mean (N=13)
120
Plasma cisapride conc. (ng/mL)
Cisapride 10 mg q.i.d./ GFJ

100 Cisapride 10 mg q.i.d./ water
80
60
40
20
0
0 8 16 24 32 40 48
Time after morning dose on day 6 (hours)

60
Total body clearance (CL)
Intravenous clearance
Cl = k10.Vc = z.Vdz = MRT.Vdss
CL= Dose / AUCiv
Apparent oral clearance
Oral clearance CL/F= Dose / AUCoral

61
Biopharmaceutical Classification
Amidon et al., Pharm Res 12: 413-420, 1995; www.fda.gov
High Solubility Low Solubility
Permeability
Class 1 Class 2
High
High Permeability High Permeability

Rapid Dissolution
Class 3 Class 4
Permeability

Low
Low Permeability Low Permeability

62
Predicting Drug Disposition via BCS
Wu and Benet, Pharm Res 22:11-23, 2005
Permeability
Class 1 Class 2
Transporter Efflux transporter
High
effects minimal effects

predominate
Class 3 Class 4
Permeability
Absorptive Absorptive and

Low
transporter efflux transporter

effects effects could be
predominate important
63
Predicting Drug Disposition via BCS
Wu and Benet, Pharm Res 22:11-23, 2005
Permeability
Class 1 Class 2
Metabolism Metabolism
High
Class 3 Class 4
Permeability
Renal & Biliary Renal & Biliary

Low
Elimination of Elimination of
Unchanged Drug Unchanged Drug

64
Biliary Excretion: Enterohepatic Recycling
Excretion Drug The drug in the GI tract

in urine in blood is depleted.
Re-absorption
Biliary excreted drug
Metabolism is reabsorbed
Drug in
Intestine
Conjugate
in
Liver
Enzymatic
breakdown
of glucuronide
Conjugate Conjugate Excretion

in bile in intestine
Dumped in feces
from
gall bladder

65
Highly variable drugs and drug products
Drugs with high within-subject variability

in Cmax and AUC (> 30% coefficient of
variation) are called highly-variable drugs
Highly-variable drug products are

pharmaceutical products in
which the drug is not highly variable, but the
product is of poor pharmaceutical quality

66
From PK to relevant information for the patient
Compound X
Tablets and oral solution

Pharmacokinetics: The estimated mean SD half-life
at steady-state of compound X after intravenous
infusion was 35.4 29.4 hours.
Renal impairment: The oral bioavailability of
compound X may be lower in patients with renal
insufficiency. A dose adjustment may be considered.
Other medicines: Do not combine compound X with
certain medicines called azoles that are given for fungal
infections. Examples of azoles are ketoconazole,
itraconazole, miconazole and fluconazole.
You should not take compound X with grapefruit juice.


67
Useful Material
Handbooks
Pharmacokinetics, 2nd Ed., by Milo Gibaldi
Clinical Pharmacokinetics, Concepts and Applications,
3rd Ed., by Malcolm Rowland and Thomas N. Tozer
Pharmacokinetic & Pharmacodynamic Data Analysis:
Concepts and Applications, 4th Ed.,
by Johan Gabrielsson and Dan Weiner
WinNonLin software, Pharsight

Noncompartmental and Compartmental analysis
Pharmacokinetic-pharmacodynamic analysis
Statistical Bioequivalence analysis
In vitro-in vivo Correlation for drug products

68
Thank for your attention !

69
Rates and Orders
of pharmacokinetic processes
The rate of a process is the speed at which it occurs
The rate of drug elimination represents
the amount (A) of drug absorbed, distributed or
eliminated per unit time
Zero-order process or rate: constant amount per unit time

Input rate of infusion: mg per h
dA/dt = ko = zero order rate constant
First-order process or rate: rate is proportional to the

amount of drug available for the process
dA/dt = - k.A = -k.Volume.Concentration

70
Rates of drug exchange
Change of the drug amount in central compartment
DAplasma/dt = - K10. Aplasma - K12. Aplasma + K21. Aperipheral

DAplasma/dt = - K10.Vc.Cplasma - K12.Vc.Cplasma + K21.Vt.Cperipheral
DAplasma/dt = - CL.Cplasma - CLd.Cplasma + CLd.Cperipheral
DCp/dt = - K10.Cplasma - K12.Cplasma + K21.Cperipheral
Change of the drug amount in peripheral compartment
DAperipheral/dt = - K12.Vc.Cplasma + K21.Vt.Cperipheral

DAperipheral/dt = - CLd.Cplasma + CLd.Cperipheral
DCperipheral/dt = - K12.Cplasma + K21.Cperipheral

71

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Basic Concepts

Achiel Van Peer, Ph.D.

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

NOAEL in female dog

NOAEL in male dog

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Drug at absorption site

Time (arbitrary units)

Gent, 24 August 2007/avpeer

Pharmacokinetics is the science describing drug

absorption from the administration site

Gent, 24 August 2007/avpeer

Some introductory Examples

Gent, 24 August 2007/avpeer

Cmax : maximum observed concentration

Gent, 24 August 2007/avpeer

Fabs = AUCpo/AUCiv for the same dose

between 0 and 100% (occasionally >100%)

Relative bioavailability (Frel)

Bioequivalence (BE): a particular Frel

Other example: nebivolol:

Gent, 24 August 2007/avpeer

Trapezoidal rule: divide the plasma concentration-time profile

Half-life (t1/2) : time the drug concentration

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Half-life (t1/2) : time to decrease by 50%

Gent, 24 August 2007/avpeer

Poggesi et al., Nerviano Medical Science

Gent, 24 August 2007/avpeer

drug distributes very rapidly to all tissues

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Infusion rate Rate of elimination is

dDose/dt = Ko = mg/min dA/dt = -k.A

Gent, 24 August 2007/avpeer

dA/dt = -k.A = -k.Vd.C

If A = Amount in plasma, then V= Plasma volume

Gent, 24 August 2007/avpeer

dA/dt = -k10.A = -k10.V.C

dA/dt = -k10.A = -CL.C

Gent, 24 August 2007/avpeer

lnC = lnC0 - k10.t

Remark for log10 scale:

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

k10= (first-order) elimination rate constant

Clearance (CL) = Vd.K10

Half-life = 0.693 . Vd/CL

Gent, 24 August 2007/avpeer

Rapidly equilibrating tissues:

Gent, 24 August 2007/avpeer

K12= 0.84 h-1

K10 = 0.4 h-1

Gent, 24 August 2007/avpeer

Cld= k12.V1= 36.7 L/h

Cld= k21.V2= 36.7 L/h

Cl=K10 .V1=Dose/AUC= 1.77 L/h=30 mL/min