E-Book - Basic Concepts of Pharmacokinetics

Basic Concepts of Pharmacokinetics
Achiel Van Peer, Ph.D. Clinical Pharmacology
Gent, 24 August 2007/avpeer
Some introductory Examples
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
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%
Allometric Scaling
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
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

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
The simplest approach observational pharmacokinetics The Model-independent Approach

Cmax : maximum observed concentration Tmax : time of Cmax AUC : area under the curve
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

Conc
Trapezoidal rule: divide the plasma concentration-time profile to several trapezoids, and add the AUCs of these trapezoids
AUC
t1 - t2
C1 + C 2 =( ).(t 2 t1) 2
Units, e.g. ng.h/mL
AUCextrapolated =
Clast z
0 0
Time
12
Elimination half-life ?
Half-life (t1/2) : time the drug concentration needs to decrease by 50%
13
Elimination half-life ? visual inspection
14
Elimination half-life ? 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
1 0
Extensive metabolisers
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 mg/min Rate of elimination is proportional to the Amount in blood/plasma dA/dt = -k.A
dDose/dt = Ko = mg/min
[Often K=Kel=K10]
21
First-order rate of drug disappearance

Amount A [or Concentration C] in blood, plasma Rate of elimination is proportional to the Amount or 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
A single iv dose of 5 mg C = C0 e-k10.t lnC = lnC0 - k10.t
Remark for log10 scale: slope = k10/2.303

24
A single iv dose of 5 mg ln C = lnC0 - k10.t

k10 = ln C1 ln C 2 0.693 = t 2 t1 t 2 t1
Slope=k10 = the elimination rate constant
C2 = half of C1
Half-life = 0.693/k10
25
A single iv dose of 5 mg
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 compartment
Re-distribution
Peripheral compartment
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 K21= 1.05 h1
V2 = 35 L
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
1 / 2 term
=t
1 / 2
0.693
0.693 = 31h 0.0224h 1
Vd = CL/=Dose/(AUC. )=Vdarea
32
Two-compartmental model
Central Compartment Vc
K10 K21 K12
Peripheral Compartment Vt
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 after intravenous dosing

Central compartment Shallow Peripheral 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 Average Volume of distribution (L) Central (V1) Rapidly equilibrating (V2) Slowly equilibrating (V3) At steady-state Clearance (L/min) Systemic (CL or CL1) Rapid distribution (CL2) Slow distribution (CL3) 0.88 1.7 0.67 14.6 66 608 689
CV (%)
22 31 76
23 48 78

36
Three compartmental model Sufentanil Pharmacokinetics

Fractional Coefficients A B C 0.94 0.058 0.0048 Rate constants (min-1) K10 K12 K13 K21 K31 Exponents (min-1) 0.24 0.012 0.0006 Half-lives (min) t1/2 t1/2 t1/2 2.9 59 1129 0.06 0.11 0.05 0.025 0.0011

37
Compartmental approach after intravenous dosing

Central compartment Shallow Peripheral compartment Deep Peripheral compartment
Central compartment
Peripheral compartment 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 membrane
Tissue
Receptor-bound drug
Protein-bound drug
Free drug (non-ionized)
Free drug (non-ionized)
Protein-bound drug
Ionized drug (free)
Ionized drug (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 pKa % u n io n iz e d a t p H 7 .4 P o c t/w a te r % u n b o u n d in p la s m a V d s s (L ) C l (L /m in ) t1 /2 k e o E E G (m in ) C e 5 0 , E E G (n g /m l) C e50, unb K i (n g /m l) (n g /m l) 6 .5 89 130 8 23 0 .2 0 1 .1 520 41 7 .9 F e n ta n y l 8 .4 3 8 810 16 358 0 .6 2 6 .6 8 .1 1 .2 0 .5 4 S u fe n ta n il 8 .0 1 10 1750 8 541 1 .2 6 .2 0 .6 8 0 .0 5 1 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 mg/day 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 Fractional loss of A or Cp First-order rate - K.A; - CL.Cp
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)
Ass = Ko Kel
The plasma concentration at steady-state (Css,Cavgss)

Cpss = Ko Ko = 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
C=Css(1-e-k.t)
Cmin
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

Accumulation ratio = AUCss, 1 = 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 in blood
Rate in Q.Cpa
Rate out Q.Cpv
Clearance =
Q(Cpa - Cpv) fu.Clint = Q. Cpa Q + fu.Clint
Clearance = QE
Low hepatic clearance if extraction ratio E <<1 eg. Risperidone (Fabs 85%) High hepatic clearance if E 1 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 Tablet disintegration Drug dissolution
Systemic circulation
Liver
Gut wall Metabolism
Hepatic Metabolism Biliary secretion
Into faeces
Uptake and efflux transporters
F= Fabsorbed.(1-Egut).(1-Eliver)
59
Grapefruit inhibits gut-wall metabolism

(J&J data on file)
140
Mean (N=13)
Plasma cisapride conc. (ng/mL) 120 100 80 60 40 20 0 0 8 16 24 32 40 Time after morning dose on day 6 (hours)
Cisapride 10 mg q.i.d./ GFJ Cisapride 10 mg q.i.d./ water
48 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 High Permeability
Low Solubility
Class 1
High Solubility High Permeability Rapid Dissolution
Class 2
Low Solubility High Permeability
Low Permeability
Class 3
High Solubility Low Permeability
Class 4
Low Solubility Low Permeability
62
Predicting Drug Disposition via BCS

Wu and Benet, Pharm Res 22:11-23, 2005
Low Solubility
Class 1
Transporter effects minimal
Class 2
Efflux transporter effects predominate
Low Permeability
Class 3
Absorptive transporter effects predominate
Class 4
Absorptive and efflux transporter effects could be important
63
Predicting Drug Disposition via BCS

Wu and Benet, Pharm Res 22:11-23, 2005
Low Solubility
Class 1
Metabolism
Class 2
Metabolism
Low Permeability
Class 3
Renal & Biliary Elimination of Unchanged Drug
Class 4
Renal & Biliary Elimination of Unchanged Drug
64
Biliary Excretion: Enterohepatic Recycling
Excretion in urine
Drug in blood
Re-absorption
Drug in Intestine
The drug in the GI tract is depleted. Biliary excreted drug is reabsorbed
Metabolism
Conjugate in Liver
Enzymatic breakdown of glucuronide Conjugate in intestine
Conjugate in bile
Dumped from gall bladder
Excretion in feces
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 DAplasma/dt DAplasma/dt DCp/dt = - K10. Aplasma - K12. Aplasma + K21. Aperipheral = - K10.Vc.Cplasma - K12.Vc.Cplasma + K21.Vt.Cperipheral = - CL.Cplasma - CLd.Cplasma + CLd.Cperipheral = - K10.Cplasma - K12.Cplasma + K21.Cperipheral
Change of the drug amount in peripheral compartment

DAperipheral/dt DAperipheral/dt DCperipheral/dt = - K12.Vc.Cplasma + K21.Vt.Cperipheral = - CLd.Cplasma + CLd.Cperipheral = - K12.Cplasma + K21.Cperipheral
71

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Basic Concepts of Pharmacokinetics

Achiel Van Peer, Ph.D. Clinical Pharmacology

Gent, 24 August 2007/avpeer

Some introductory Examples

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Prediction of drug plasma concentrations before the first dose in a human

First dose 5 mg Fabs 100% Fabs 50% Fabs 20%

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

Pharmacokinetics: Time Profile of Drug Amounts

Metabolites Percent of dose Drug in body

Time (arbitrary units)

metabolism excretion PK= ADME

Gent, 24 August 2007/avpeer

The simplest approach observational pharmacokinetics The Model-independent Approach

Gent, 24 August 2007/avpeer

Cmax, Tmax and AUC in Bioavailability and Bioequivalence Studies

Relative bioavailability (Frel)

Bioequivalence (BE): a particular Frel

Absolute oral bioavailability flunarizine, J&J data on file

Other example: nebivolol: 10% in extensive metabolisers; 100% in poor metabolisers

Area under the curve

Units, e.g. ng.h/mL

Half-life (t1/2) : time the drug concentration needs to decrease by 50%

Gent, 24 August 2007/avpeer

Elimination half-life ? visual inspection

Gent, 24 August 2007/avpeer

Elimination half-life ? visual inspection or alternatives ?

Gent, 24 August 2007/avpeer

From Whole-Body Physiologically based Pharmacokinetics to Compartmental Models

Poggesi et al., Nerviano Medical Science

Gent, 24 August 2007/avpeer

Intravenous dose of 0.2 mg Levocabastine

Gent, 24 August 2007/avpeer

Tri-compartment model Two-compartment model One-compartment model

Gent, 24 August 2007/avpeer

Zero-order rate drug administration and first-order rate drug elimination

Gent, 24 August 2007/avpeer

First-order rate of drug disappearance

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

Gent, 24 August 2007/avpeer

A single iv dose of 5 mg C = C0 e-k10.t lnC = lnC0 - k10.t

Remark for log10 scale: slope = k10/2.303

A single iv dose of 5 mg ln C = lnC0 - k10.t

Gent, 24 August 2007/avpeer

Gent, 24 August 2007/avpeer

One-Compartment model after intravenous administration

Half-life = 0.693 . Vd/CL

Gent, 24 August 2007/avpeer

Compartmental Approach after intravenous dosing

Intravenous dose of 0.2 mg levocabastine

K10 = 0.4 h-1

Gent, 24 August 2007/avpeer

Intravenous dose of 0.2 mg levocabastine

Gent, 24 August 2007/avpeer

Rates of drug exchange

Intravenous dose of 0.2 mg levocabastine

0.693 = 31h 0.0224h 1

Gent, 24 August 2007/avpeer

K10, K12, K21 are first order rate constants

Compartmental approach after intravenous dosing