26 July 2001

Multicompartment Pharmacokinetic Models

Objectives
To draw schemes and write differential equations for multicompartment models To recognize and use integrated equations to calculate dosage regimens To determine parameter values using the method of residuals To calculate various V values To use the non-compartmental method of parameter estimation

Multicompartment Models
Rapid equilibration assumption not always true Distribution may take some finite time Body may be represented by two equilibrated compartments with distribution between the two Semi-log figure will show a distribution phase

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One Compartment Model

Linear Plot
10

Concentration (mg/L)

Dose = 100 mg; V = 12.5 L; kel = 0.15 hr-1

0 -kelt Cp = Cp e

0 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

One Compartment Model

Semi-log Plot
10

0 -kelt Cp = Cp e

Concentration (mg/L)

Dose = 100 mg; V = 12.5 L; kel = 0.15 hr-1

0.1 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

Drug Disposition
Distribution Commonly observed when early data are collected Deviation from a single exponential line A rapid drop followed by a slower terminal phase Body can be represented by two (or more) compartments

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Two Compartment
Semi-log Plot
100

Concentration (mg/L)

first phase
10

second phase

0.1

Cp = 24 e
0.01 0 2 4 6

-1.5t
8

+6e
10 12

-0.25t
14 16 18 20 22 24

Time (hr)

Two Compartments
Central compartment
rapidly perfused tissues

Peripheral compartment
slowly perfused tissues

Two Compartment
Scheme
Blood Kidney Liver

X1 Central

k12 k21 kel

X2 Peripheral Fat Bone

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Two Compartment
Differential Equations Central Compartment
dX1 = kelX1 k12X1 + k21X 2 dt

Peripheral Compartment
dX 2 = k12X1 k21X 2 dt

The Differential Equations

dX1 = k21X 2 k12X1 kelX1 dt dX 2 = k12X1 k21X 2 dt

Take Laplace of the Equations

s X 1 X1(0) = k21X 2 k12X 1 kelX 1 s X 2 X2 (0) = k12X1 k21X 2

Since X1(0) = Dose and X 2(0) = 0

X2 =

k12X1 (s + k21)

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Substitute and Rearrange

s X 1 Dose = k21k12X1 (k12 + kel)X1 (s + k21)

k21k12X1 = Dose (s + k21) X1 [s(s + k21) + (k12 + kel)(s + k21) k21k12] = Dose (s + k21) s X 1 + (k12 + kel)X1

X1 [s 2 + s(k21 + k12 + kel) + k21kel] = Dose(s + k21)

Notice the similarity with [s2 + s ( + ) + ] = (s +)(s +)

Getting close now

If ( + ) = k21 + k12 + kel and = k21kel

X1 [s 2 + s ( + ) + ] = Dose(s + k21) X1 (s + )(s + ) = Dose(s + k21) Dose(s + k21) X1 = (s + )(s +)

Back Transforming
X1 = Dose(s + k21) (s +)(s +)

The denominator has a power of 2 in s and no repeat terms. Note the numerator has a power of 1 in s Considering the denominator: (s + )(s + ) = 0 Roots or solutions are - and -

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Root 1
X1 = Dose(s + k21) (s +)(s +)

First root is -

Dose(s + k21) (s + )(s +)

Dose(k21 ) t e ( )

Root 2
X1 = Dose(s + k21) (s +)(s +)

Second root is -

Dose(s + k21) (s + )(s +)

Dose(k21 ) t e ( )

Putting It Together
Dose( k21) t e ( )

Dose(k21 ) t e ( )

Dose( k21) t + Dose(k21 ) t e e ( ) ( ) OR

Cp = A e-t + B e-t where A = Dose( k21) V1 ( ) and Dose(k21 ) B= V1 ( )

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Integrated Equation
Cp = A e-t + B e-t

+ = kel + k12 + k21 = kelk21 , = or , =

( + ) ( + )2 4
2

(kel + k12 + k21) ( kel + k12 + k21)2 4 k e l k 2 1 2

Parameter Determination
Method of Residuals Parameters A, B, and can be determined using the method of residuals Since > (if / > 5)
e-t approaches 0 quickly

Terminal data points will be on a line

Method of Residuals
Cplate = B e-t

Plotted on semi-log graph paper should give a straight line Calculate from the terminal slope

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26 July 2001

Terminal Slope
100

Concentration (mg/L)

10

slope >
1

0.1

Cp = 24 e-1.5t + 6 e-0.25t
0.01 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

Terminal Half-life
t1/2 = ln(2)/ Biological or terminal half-life [= equivalent to ln(2)/kel with one compartment model]

Residual
Residual = Cp - Cplate = Ae-t
100

Concentration (mg/L)

10

>

0.1

slope ->

0.01 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

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Now Calculate k21, kel, k12

A + B A+B kel = k21 k12 = + k21 kel k21 =

Effect of k12 and k21 Ratio

10 k12/k21 = 1/4 k12/k21 = 1/2 k12/k21 = 1/1 k12/k21 = 2/1 k12/k21 = 4/1

Concentration (mg/L)

9 8 7 6 5 4 3 2 1 0 0 1 2 3

Time (hour)

Effect of k12 and k21 Ratio

Effect of k12/k21 ratio The higher the ratio greater the distribution into the peripheral compartment At the extremes
low ratio - less distribution into second compartment high ratio and no early data - looks like one compartment model

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Magnitude of k12 and k21

10 k12/k21 = 0.5/0.25 k12/k21 = 1/0.5 k12/k21 = 2/1 k12/k21 = 4/2 k12/k21 = 8/4 k12/21 = 16/8

Concentration (mg/L)

9 8 7 6 5 4 3 2 1 0 0 1 2

Time (hour)

Magnitude of k21 and k12

Larger values approach one compartment assumption

Volume of Distribution
V1 V1 Apparent volume of central compartment
V1 = Dose Dose = since A+B=Cp0 A + B Cp 0

Use to calculate Cp0 after an IV bolus administration

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Volume of Distribution
Varea Varea (= V)
Varea = Dose V kel Clearance = 1 = AUC

Useful for dosing calculations, easy to calculate from Dose and AUC

Volume of Distribution
Vextrap Vextrap Volume extrapolated
Vextrap = Dose B

Ignores distribution phase

Volume of Distribution
Vss Vss Steady state volume
Vss = V1 k12 + k21 k21

Relates total amount in the body (at steady state) with drug concentrations in plasma or blood

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Steady State Volume

100

Concentration (mg/L)

10

X 1 X2

1 0 2 4 6 8 10 12

Time (hr)

Volumes of Distribution

Vextrap > Varea > Vss > V1

Example Calculation
Time (hr)
0.5 1 2 3 4 6 8 10 12

Cp (mg/L)
20.6 13.4 7.3 5.0 3.7 2.2 1.4 0.82 0.50

Cplate (mg/L)
8.8 7.8 6.1 4.7

Residual (mg/L)
11.8 5.6 1.2 0.3

I.V. Bolus 500 mg

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The Plots
100 Cp Residual 10

Concentration (mg/L)

0.1 0 2 4 6 8 10 12

Time (hr)

Calculations
B = 10 mg/L, = (ln 10 - ln 0.5)/12 = 2.996/12 = 0.25 hr-1 A = 25 mg/L, = (ln 25 - ln 0.27)/3 = 4.528/3 = 1.51 hr-1 Cp = 25 e-1.51 x t + 10 e-0.25 x t

Microconstants
A + B 25 0.25 + 10 1.51 = = 0.61 hr -1 25 + 10 A+B 1.51 0.25 = = 0.62 hr -1 kel = 0.61 k21 k21 = k12 = + k21 kel = 1.51 + 0.25 0.61 0.62 = 0.53 hr -1

Chapter 30

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Volumes of Distribution
V1 = Dose 500 = = 14.3 L A + B 25 +10 500 Dose = = 34.3 L Varea = AUC 0.25 58.3 Dose 500 = = 50 L Vextrap = 10 B 0.61 + 0.53 k21 + k12 = 14.3 = 26.7 L Vss = V1 0.61 k21 Note:V extrap > Varea > Vss > V1

[50 > 34.3 > 26.7 > 14.3]

AUC = 56.3 + 2.0 = 58.3 mg.hr.L -1

Dosage Calculations
Initial Concentration, Cp0
V1 = Dose Cp0

Dose = V1 Cp 0 required

To achieve a Cp0 of 20 mg/L give 600 mg with V1 = 30 L If V1 = 16 L an IV Bolus Dose of 500 mg would result in a Cp0 of 31.3 mg/L (=500/16)

Dosage Calculation
Continuous Infusion
Cpss = k0 k0 k0 = = kelV1 Clearance Varea

k0 = Cpss k e l V1

If V1 = 15 L and kel = 0.2 hr-1 a k0 of 90 mg/hr is required to produce a Cpss of 30 mg/L

Chapter 30

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Plasma Concentration
Time to Steady State Cp can be calculated after an IV bolus dose from A, B, and Cp after an IV infusion somewhat more involved Time to steady state controlled by value Can be slow with long biological half-life

I.V. Bolus and Infusion

40

Concentration (mg/L)

I.V. Bolus and Infusion

30

20

10

-1 -1 kel = 0.2 hr ; k12 = 2 hr ; k21 = 1 hr-1; V = 15 L; 1 Bolus = 450 mg; k0 = 90 mg/hr

0 12 24 36 48

Time (hr)

I.V. Bolus and Infusion

40

Concentration (mg/L)

I.V. Bolus and Infusion

30

20

10

kel = 0.2 hr-1; k12 = 2 hr-1; -1 k21 = 1 hr ; V1 = 15 L; Bolus = 300 or 600 mg; k0 = 90 mg/hr
0 12 24 36 48

Time (hr)

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Fast and Slow I.V. Infusion

40

I.V. Infusion - Fast/Slow

Concentration (mg/L)

30

20

10

kel = 0.2 hr-1; k12 = 2 hr-1; k21 = 1 hr-1; V1 = 15 L; Infusion Rate 300 mg/hr for 4 hr then 90 mg/hr
0 12 24 36 48

Time (hr)

Oral Administration
Scheme
Drug in GI Tract

ka

X1 Central

k12 k21 kel

X2 Peripheral

Differential Equation

dX1 = kaXg + k21X 2 ( k12 + kel) X 1 dt

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26 July 2001

Semi-log Plot
100

Concentration (mg/L)

Oral - Two Compartment with Distribution Phase A = 20 mg/L; B = 15 mg/L; C = -35 mg/L; = 1 hr-1; -1 -1 = 0.1 hr ; ka = 2 hr

10

1 0 12 24 36 48

Time (hr)

Semi-log Plot
10

Concentration (mg/L)

Oral - Two Compartment without Distribution Phase

0.1

0.01

A = 20 mg/L; B = 15 mg/L; C = -35 mg/L; -1 -1 -1 = 1.5 hr ; = 0.16 hr ; ka = 1 hr

0 12 24 36 48

0.001

Time (hr)

Oral Dose
Two Compartment Model
Bioavailability calculations the same as for a one compartment model
Use AUC comparison or Use U comparison

These method work for any linear system (first order disposition) Method of residuals could be used to calculate , , and ka (if sufficiently different)

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Cp Calculations
Average Cp of 20 mg/L required with V1 = 15 L, kel = 0.15 hr-1, F = 0.9, and = 12 hr
Cp = FDose FDose FDose = = Clearance k e l V V 20 15 0.15 12 = 600 mg q12h 0.9

Dose =

MacKinetics
Two compartment Demo

Example Data - 100 mg IV Bolus Dose

Time (hr)
0.25 0.5 1 2 4 6 8 10 12

Concentration (mg/L)
1.7 1.4 1.1 0.95 0.75 0.60 0.50 0.40 0.34

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Clinical Example
Lidocaine - Rapidly attain and maintain effective concentrations (2 - 6 mg/L)
Multiple bolus over 15 or 30 min + infusion Exponentially declining infusion Stepwise, tapering infusion

k10 = 0.035 min-1 t1/2 = 20 min k12 = 0.058 min-1 t1/2 = 12 min k21 = 0.023 min-1 t1/2 = 30 min V1 = 0.49 L/kg = 34 L (70 kg patient)

Evans, Schentag, and Jusko Applied Pharmacokinetics, 3rd ed., Applied Therapeutics, Vancouver, WA 1992

Lidocaine - Loading Dose

Usual Dose - 50 to 100 mg followed by an infusion of 1 - 4 mg/min
Dip in concentration below therapeutic range Increasing the loading dose to 200 - 300 mg may cause toxic doses

Multiple Loading dose approach

Initial 75 mg followed by up to six 50 mg bolus doses to effect
Ectopic ventricular beats to less than 5 per minute and no complex ventricular arrhymias

Lidocaine - Usual Dose

min

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26 July 2001

Usual Dose - Simulation

Minutes

Multiple Bolus Doses

Minutes

Non Compartmental Analysis

Linear Disposition First order elimination and distribution No assumptions about number of compartments Use tmax , Cpmax , AUC, AUMC New parameters:
AUMC (area under moment curve) MRT (mean residence time) MAT (mean absorption time)

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26 July 2001

AUMC
Area under the Moment Curve Use trapezoidal rule with t versus Cpt data Last segment from
Cp last t last Cplast + k k2

where k is slowest (last) exponential

Non Compartmental Analysis

Time (hr) 0 1 2 3 4 6 9 12 18 24 Cp (mg/L) 0 7.09 6.29 5.58 4.95 3.89 2.71 1.89 0.92 0.44 Cpt AUC AUMC (mg.hr/L) (mg.hr/L) (mg.hr2/L) 0 0 0 7.09 7.54 3.54 12.6 14.2 13.4 16.7 20.2 28.1 19.8 25.4 46.3 23.4 34.3 89.5 24.5 44.2 161.2 22.7 51.1 232 16.6 59.6 350 10.8 63.7 432 67.4 553

Linear System - 100 mg IV

Plot of Cp versus t
IV Data
10

Concentration (mg/L)

0 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

Chapter 30

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26 July 2001

Plot of Cpt versus t

IV Data
25 20

Cp t (mg.hr/L)

15

10

0 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

Parameter Calculations
AUMC 553 = = 8.2 hr AUC 67.4 1 1 = = 0.122 hr -1 k= MRT 8.2 Dose 100 = = 1.48 L/hr Cl = AUC 67.4 Vss = ClMRT = 1.48 8.2 = 12.2 L MRT =

Non Compartmental Analysis

Time Cp Cpt AUC AUMC (hr) (mg/L) (mg.hr/L) (mg.hr/L) (mg.hr2/L)

0 1 2 3 4 6 9 12 18 24

0 12.2 14.1 13.4 12.2 9.64 6.73 4.69 2.28 1.11

0 12.2 28.3 40.3 48.6 57.9 60.6 56.4 41.2 26.7

0 6.09 19.2 33.0 45.8 67.6 92.2 109 130 141 150

0 6.09 26.3 60.6 105 212 389 565 857 1061 1361

Linear System - 250 mg PO

Chapter 30

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26 July 2001

Plot of Cp versus t
PO Data
15

Concentration (mg/L)

10

0 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

Plot of Cpt versus t

PO Data
80

Cp t (mg.hr/L)

60

40

20

0 0 2 4 6 8 10 12 14 16 18 20 22 24

Time (hr)

Parameter Calculations
AUMC 1361 = = 9.08 hr AUC 150 MAT=MRT(PO ) MRT (IV) = 9.08 8.20 = 0.88 hr MRT( PO) = 1 1 = = 1.14 hr -1 MAT 0.88 AUCPO Dose IV 150 100 F= = = 0.89 AUCIV Dose PO 67.4 250 ka =

Chapter 30

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26 July 2001

Objectives
To draw schemes and write differential equations for multicompartment models To recognize and use integrated equations to calculate dosage regimens To determine parameter values using the method of residuals To calculate various V values To use the non-compartmental method of parameter estimation

Chapter 30

24