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Multicompartment Modeling

Author: Michael Makoid Reviewer: Phillip Vuchetich

OBJECTIVES

1. This chapter is not completed.

Basic Pharmacokinetics

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11-1

Multicompartment Modeling

11.1 Executive Summary

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Multicompartment Modeling

11.2 Equations

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Multicompartment Modeling

11.3 PHARMCOKINETICS: MAMMILLARY MODELS

For many drugs the equilibrium between drug concentrations in different tissues is not achieved rapidly. Thus, one of the assumptions of the one-compartment open model sometimes becomes invalid. A more complex mammillary open model is often necessary to describe mathematically the plasma concentration data (for example) seen after the administration of some drugs. The simplest mammillary open model is a two-compartment open model: for example:

Compartment One (central compartment) can be sampled through the blood (or plasma, or serum). It may consist of organs or tissues which, being highly perfused with blood, are in rapid equilibrium distribution with the blood.

Compartnent Two (peripheral compartment) cannot normally be sampled. It may consist or organs or tissues which, being poorly perfused with blood, are in slow equilibrium distribution with the blood.

**The Body is the sum of both compartments.
**

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Multicompartment Modeling

1. Biexponential Properties of Two-Compartment Open Model

Following an intravenous bolus injection, the plasma concentration against time profile has two phases:

a. Initial phase - ( α - phase)

b. Terminal phase - ( β - phase)

On semilogarithmic paper the terminal phase is linear, indicating that initial distribution has been completed and that equilibrium has been attained. The terminal half-life ( t 1 ⁄ 2 ) can be measured from the terminal phase.

2. Intravenous Bolus Administration: Plasma Concentration Data For a one-compartment open model,

Cp = ( Cp )o e

– kt

(EQ 10-26)

i.e., the concentration of drug in the plasma declines exponentially with time

**For a two-compartment open model,
**

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Multicompartment Modeling

Cp = ( A1 e

– αt

+ B1 e

– βt

)

(EQ 10-27)

i.e., the concentration of drug in the plasma declines biexponentially with time

2.1 Symbols

A 1 and B1 are intercept constants ( M ⁄ L )

3

α and β are hybrid rate constants ( T )

–1

**V 1 is the apparent volume of unchanged drug distribution in compartment one (L )
**

3

k 10, k 12 , and , k 21 are “micro” rate constants ( T )

–1

2.2 Relationships (for reference, except Eq. 3)

α = 0.5 [ ( k 10 + k 12 + k 21 ) + ( k 10 + k 12 + k 21 ) – 4k 10k 12 ]

2

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Multicompartment Modeling

β = 0.5 [ ( k 10 + k 12 + k 21 ) – ( k 10 + k 12 + k 21 ) – 4k 10k 12 ] D- ( α – k 21 ) A 1 = ----- • --------------------V1 ( α – β ) D- ( k 21 – β ) B 1 = ----- • --------------------V1 ( α – β ) A 1 + B1 = ( Cp ) o

(EQ 10-28)

2

2.3 Obtaining Pharmacokinetic Parameters by “Feathering” By convention, α > β a. Plot C p against t on semilogarithmic paper

b. Find t 1 ⁄ 2 from the linear terminal phase: see “Intravenous Administration”, section A1.4a

c. Calculate the terminal hybrid rate constant ( β ) ; in reality it contains both distributive ( k 12 and k 21 ) and elimination ( k 10 ) factors.

0.693 β = -----------t1 ⁄ 2

(EQ 10-29)

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Multicompartment Modeling

d. Draw a straight line through the linear terminal elimination phase and extralpolate this line to t = 0. The intercept is equal to B1 .

e. Read estrapolated plasma concentrations ( C p ) from the plot at times equal to those given for values of C p which are prior to the terminal phase.

f. At each of these times calculate:

( C p )diff = C p – C p

g. Plot ( C p )diff against t (see Eq.8) on semilogarithmic paper. The is a “feathered” line and should decline linearly.

h. Find the half-life of the plot. It wil refer to the initial phase. Calculate,

0.693 α = -----------------------half – life

i. Measure the intercept of the “feathered” line; it will equal to A 1 (Note that usually A1 = B1 , even theoetically).

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Multicompartment Modeling

j. Calculate ( C p )o from Eq. 3

k. Calcultate V1 by Xo D V1 = ------------- = -----------------( Cp )o A1 + B 1

(EQ 10-30)

. Theory

When t is large, e

– αt

<e

– βt

. Hence, Eq. 2 becomes

Cp = B1 e

– βt

(EQ 10-31)

i.e., when t is large, the concentration of the drug in the plasma declines exponentilly with time.

**The extrapolated plasma concentrations are Cp = B1 e
**

– βt

(EQ 10-32)

Substituting from Eqs. 2 and 7a into Eq. 5,

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Multicompartment Modeling

( C p ) diff = A 1 e

– βt

(EQ 10-33)

i.e., the difference between observed and extrapolated drug concentrations in the plasma declines exponentially with time. Note (for reference only)

It is usually not informative to determine the “micro”rate constant; but see one use under the note on dosage regimens.

αB 1 + βA1 k 21 = ------------------------A 1 + B1

k 10 = αβ ⁄ k 21

k 12 = α + β – k 10 – k 21

2.4 Clearance and Volume

If model-independant equations can be used to define these terms, this is preferred.

a. Systemic Clearance (Cl) may be calculated by,

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Multicompartment Modeling

D Cl = ---------------------∞ ( AUC )o

(EQ 10-34)

b. The volume terms are complex than in a one-compartment open model. There are two terms of interest:

The apparent volume of distribution in compartment one ( V1 ) This is calculated using Eq. 6.

The apparent volume of distribution at pseudo-distribution equilibrium ( V β )

This volume may be defined only in relation to the terminal phase ( β phase), when initial distribution has been completed. D V β = -------------------------∞ β ( AUC )o

As Vβ requires calculation of the total area under the plasma concentration against time curve it is sometimes known as Varea .

c. Comparing Eqs. 9 and 10,

Cl = βV β

(EQ 10-35)

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Multicompartment Modeling

It may also be shown that,

Cl = k 10V 1

(EQ 10-36)

This follows as systemic clearance is always given by the elimination rate constant out of the body multiplied by the apparent volume of distribution in the compartment from which drug leaves the body. Comparing Eqs. 11 and 12,

k 10 V β = ------ V1 β

(EQ 10-37)

Note that k 10 (the elimination rate constant) is not the same as β (the terminal hybrid rate constant).

2.5 Bioavailability

Find ( AUC )0 using trapezoidal rule and, if necessary, the calculation for the terminal area.

∞

∞ t Cp ( AUC )o = ( AUC )o + ----β

(EQ 10-38)

This is a model-independent equation.

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Multicompartment Modeling

2.6 Dosage Regimens

The maintenance dose (D) is given by the same model-independent equation as before,

D = ( C p ) ss Cl • τ

Where ( C p )ss has its same previous definition.

The loading dose ( D L ) achieves a steady-state condition quite rapidly, but only after initial distribution has been completed. It is given by the previous equation.

D D L = --------------------------– 0.693N 1–e

(EQ 10-39)

As may be expected, equations relating ( C max )ss and ( C min ) ss to ( C p )ss are as before,

Note (reference only)

All dosage regimen equations strictly apply only when,

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Multicompartment Modeling

k 12 β- ------ 1 + ------ = 1 k 10 k 21

For digoxin Eq. 17 has a value of 0.947 For warfarin Eq. 17 has a value of 0.990 For cephalexin Eq. 17 has a value of 0.846

This is why, despite the fact that an open two-compartment model is better description of the pharmacokinetic of these drugs, a simple open-compartment model may often be assumed for dosage regimen purposes.

3. Intravenous Bolus Administration: Compartment Two

It is not normally possible to measure drug concentrations in compartment two. However, the mass of drug can be predicted based on the ddrug concentrations observed in compartment one.

2.6 Dosage Regimens

X2 = B2 ( e

– βt

–e

– αt

)

(EQ 10-40)

k 12D Where B2 = ----------------(α – β)

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Multicompartment Modeling

Note that the equations forms bears a similarity to that seen for plasma concentrations after oral administration inot a one compartment open model.

When t is large, e

– αt

<e

– βt

. Hence, Eq. 18 becomes,

X2= B2 e

– βt

(EQ 10-41)

**This is comparted to the mass modification of Eq. 7, X1= V1B1 e
**

– βt

(EQ 10-42)

Thus, when t is large the masses of drug in each compartment decline exponentially, and in parallel, with time. This indicates that initial distribution has been completed and equilibrium attained. If the value of X 2 reflects drug concentrations at the active site, the time of maximum concentration (and maximum pharmacological effect) is: ln ( α ⁄ β ) t max = --------------------α–β 4. Others Dosage Forms The equations become complex and it is therefore difficult to obtain useful parameter values without th eaid of a computer. Fortunately, because the complexity of the equations is greater than the experimental accuracy of the assays warrants, drugs that strictly require a mammillary model can be described adequately by an open one compartment for the purposes of calculating dosage regimens. 4.1 Intravenous Infusion The plasma concentrations at first rise faster than an open one compartment model profile would suggest. Later, the rise is slower. The decline, following the cessation of infusion, is biexponential. 4.2 Oral Administration

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Multicompartment Modeling

At a time just after t max the plasma concentration may exhibit a “nose”, when compared to the profile of an open one-compartment model.

SELECTED REFERENCES

Riegelman, S., Loo, J.C.K., and Rowland, M., Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single campartment, J. Pharm . Sci., 57, 117-123 (1968).

Riegelmen, S., Loo, J.C.k., and Rowland, M., Concept of a volume of distribution and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133 (l968).

Benet, L.Z. and Ronfeld, R.A., Volume terms in pharnacokinetics, J. Pharm. Sci., 58, 639-641 (l969).

Gibaldi, M Nagashima, R., ant Levy, G., Relationship between drug concentrations in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193197 (1969).

Metzler, C.M Usefulness of the two-compartent open model in pharmacokinetics, J. Amer. Stat. Assn., 66, 49-54 (1971).

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Multicompartment Modeling

Gibaldi, M. and Perrier, D., Drug eliminatin and apparent volume of distribution in multicompartment systems, J. Pharm. Sci., 61, 952-954 (1972).

Gillette, J.R., The importance of tissue distribution in pharmacokinetics, J. Pharmacokinetics. Biopharm., 1, 497-520 (1973).

DRUG DISPOSITION: VOLUME TERMS

As apparent volumes of distribution are proportionality constants, and not physiological volumes, more than one term is of value.

1. Apparent Volume of Sampled Compartment ( V1 )

This relates the concentration of drug in the sampled compartment with the mass of drug present in that compartment.

**It may be measured after an intravenous bolus dose: D V 1 = ------------( Cp )o
**

or

(EQ 10-44)

D V1 = --------------------------∞ K ( AUC )o

(EQ 10-45)

**It may be measured after an intravenous infusion by: ( X1 ) ss Q V 1 = -------------- = ------------------( C p ) ss K ( C p ) ss
**

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Multicompartment Modeling

2. Apparent Volume at Pseudo-Distribution Equilibrium ( Vβ )

This volume term (sometimes known as the apparent volume of distribution of the drug in the body) requires the assumption that the drug is evenly distributed throughout the body. The assumption is not true in practice. Thus Vβ can only be defined in relation to the terminal phase ( β -phase) when equilibrium has been attained; the equation is analogous to Eq. 2.

D Vβ = -------------------------∞ β ( AUC )o

(EQ 10-47)

3. Relationships Between Apparent Volumes By secondary alebraic definition, a clearance (Cl) is always given by the first-order rate constant for removal of drug from the body multiplied by the apparent volume of distribution on the drug in the compartment from which the drug leaves the body: Cl r = k u V 1 Cl m = k m V1 Cl s = KV 1

(EQ 10-48)

(EQ 10-49)

(EQ 10-50)

**However, systemic clearance is measured by D Cl s = ---------------------∞ ( AUC ) o
**

(EQ 10-51)

**Comparing Eqs. 4 and 8, and rearranging,
**

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Multicompartment Modeling

Cl s = βVβ Comparing Eqs. 7 and 9, K V β = --- V1 β Selected References

(EQ 10-52)

(EQ 10-53)

Riegelman, S., Loo, J.C.K., and Rowland, M., Concept of a volume of distribution and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133 (1968).

Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci., 58, 639-641 (1969).

Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentrations in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193197 (1969).

Perrier, D. and Gibaldi, M., Relationship between plasma or serum drug concentration and amount of drug in the body at steady state upon multiple dosing, J. Pharmacokin. Biopharm., 1, 17-22 (1973).

Oie, S. and Tozer, T.N., Effect of altered plasma protein binding on apparent volume of distribution, J. Pharm. Sci., 68, 1203-1205 (19793).

Li;vxrX LLrLLxLS

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Multicompartment Modeling

Drug is usuallo sampled from the centr->l compartment, designated compartment one.

1. Laplace Transforn for Compartment One

As,l

(in)(dS 1)

where As,l is Laplace Transform for mass of drug in comPartment one

s is the Laplace Operator in is the input function

dS,l is ehe disposition function for compartment one

2 InDut Functions . .

N ehat input need not necessarily be to compartment one.

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Multicompartment Modeling

2.1 IV Bolus

(in) - D where D is the dose

2.2 IV Infusion

Q (l-e sb)

where Q is the zero-order infusion rate, b-t when e<T, b-T when eiT, and T is the eime of cessation of infusion.

2-3 First-order Absorption

(in) . <

(s+ka)

where ka is first-order absorption rate constant, ant F is the fraction of D ultimately reaching the general circulation.

2-4 Dissolution and Absorpcion (type 1) (in) - krkaFD

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Multicompartment Modeling

(s+kr) (s+ka)

where kr is tirst-order dissolution rate constant.

2 5 Dissolution and Absorption (tvpe 2)

(la)

ka(l-e sb)

s(s+k>)

where ko is zero-order dissolution rate, ceasing at time T.

2-6 Others These may be formed by adtition of functions 2-1 through 2-5

e.g., (in) - D + Q(l-e~Sb)

This denotes the simultaneous commencement of an I.V. bolus and infusion.

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Multicompartment Modeling

3. Disposition Function for Comcartment One A driving force compartment has one or more exit rate constanes; for

.

instance, in compartment i, ehe sum of ehe first-order exit rate constants

is Ei.

As,~

n~

kca

‘a +

where q is the compartment into which input occurs, n is the number of driving force compartments,

i,j, and m are counters (maximum value of n),

kql is the first-order rate constant for transfer of drug from input compartment eo compartment one,

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Multicompartment Modeling

kl; and kjl are the first-order rate constants for drug transfer from compartment 1 to compartment j, ant vice-versa.

3-1 Using the disposition function (a) If q-l, ehen kqlsl

(b) Tr (Pi) and fT (Pm) are coneinued produces. ~e value of Pi (or Pm) equals one when thc counter i (or m) takes on a forbidden number. For example, i-l is forbidden in the numerator, ant m-l and m-j are forbidden in the denominaeor. 3-Z E.camples

(a) one-compartmene open model (n-l,q=l)

ds,l = 1

(Eq.l)

(b) Two-compart:.ent open models (n-2.q=1) (s+E~)

ds , 1

(s+El) (s+E2) - kl2kx

(c) Three-compartmene open models(n-3,q-2)

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Multicompartment Modeling

dS,l

k21 (s+E3)

(Eq.2)

(s+El) (s+E2) (s+E3) - kl2k21 (s+E3) - kl3t31 (5tk2)

(Eq.3)

3-3 Simplifying the Denominator The number of exponeneial terms in ehe final ineegrated equation will be equal eo the number of driving force compartments (n). This is also equal to the maximum power to which the Laplace operator (s) would nppear if

the denominator were multiplied out. Hence, the denominator is simplified n to become iXl (S+ki), where ki is a composite first-order rate constane.

(a) ds,l ‘

(b) d5 l

(c)

ts.l

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Multicompartment Modeling

(s+kl)

(s+E2)

(s+kl) ts I k2)

k21 (s+E3)

( s+kl ) ( s+k2 ) ( s+k3 )

(Eq.la)

(Eq.2a)

(Eq.3a)

The exact meaning of [i for any model depends on the equalities evident in the denominaeors. Example for (b):

(s+kl) (s+k2) - (s+El) (s+E2) - kl2k

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Multicompartment Modeling

4. Method of Partial Fractions Ihis method is used to solve (integrate) a Laplace Iransform providing there are no repeating factors in the denominator. Example: no 52 or (s+ki)2

‘l 1 Prepare che Laplace Transform Example: I.V. bolus into compartment one of two compartment model

( s+kl ) ( S+k2 )

4-2 Obtaining the Roots of Denominator Factors

If the factor is s, the rooc is zero

If ehe faceor is (s+ki), the root is

4-3 “Ridden-Hand” Method

(a) Deal with each factor of ehe tenominator in turn.

(b) Cover the factor with a finger, and remember its root.

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Multicompartment Modeling

(c) Wherever the Laplace operator(s) occurs in the uncovered transform, subseitute the root for s.

(d) Multiply the resule by eses again substituting ehe rooe for s

(e) After doing (b) through (d) for each factor, simplify.

Example:

X1 ‘ D(-kl+E2)e-klt - + D(-k2+E2)e~k2t

(-kl+k2)(-k7+kl )

or C1 - D (kl-Ez)e kl + D (E2-k2)e 2

V1 (kl k2 )

or

C1 - Ale 1 + A2e-k2t

In this example the meaning of A1, A2, kl, k2, and E2 depend on the form

of the two-compartmental model.

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Multicompartment Modeling

5. Laplace Transform for Peripheral Compartments

This is obtained by the following procedure, which is analogous eo that

employed when using the Laplace Transform table.

(a) Write the differential rate equation.

(b) Take the Laplace Transform of each side of the differential rate equation, using the table where necessary.

V1 (kl-k2)

(c) Algebraically manipulate the transformed equation until an equation having onlv one transformed dependent variable on the left-hand side is obtained.

(t) Substitute for anv known transformed dependent variables on tlle right-lland sidc of the equation.

(e) Solve (integrate) bv the method of partial fractions (tlle “hidden 1land”), and simplifv.

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Multicompartment Modeling

6. btethod if Denominator Contains the Factor 52 This may apply to terminal “compartments”, such as urine, following an I.V. infusion. The “hidden hand” method cannot be used for the factor 52 in the denominator as it has no simple root.

6-1 Example (n=2, q^l, exit from compartmenr one): aS,U - kloQ.(l-e~sb)(s+Es)

52(5+kl) (s+k2)

where klo is the first-order excretion rate constant from compartment one.

xu ~ kloQ.E2b + ...... klk2

where Xu is the cumulative mass of drug excreted into the urine. The other factors can be used as before in the “hidden-hand” method. 6-2 Example (n-3, q-l, exit from compartment one) aS u ‘ kloQ.(l-e 5b)(S+E2)ts+E3) s2(s+kl)(s+kv)(s+k3)

Xu t kloQ- E2Elb I

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Multicompartment Modeling

klk2k3

REFERENCES

L.Z. Benet, General treatment of linear mammillary models with elimination from any compartment as used in pharmacokinetics, J. Pharm. Sci., 61, 536-541 (1972)

D.P. Vaughan, D.J.H. Mallard, A. Trainor, and M. Mitchard, General pharmacokinetic equations for linear mammillary models with trug absorption into peripheral compartments, Europ. J. Clin. Pharmacol., 8, 141-148 (1975).

D.P. Vaughan and A. Trainor, Derivation of general equations for linear mammillary models when ehe drug is administered by different routes, J. Pharmacokin. Biopharm., 3, 203-218 (1975).

Two-Compartment Model-l

Prior inputs focuset on one-compartmcnt models, but many drugs arc charactetizet bettcr by multicompartmcnt motek. In the following three inputs, we shall bricfly tiscuss multico~_nt motek ant prcstnt a few apB plicadons. Multicompartnent motcis are not uset as fo quentlg u the one-compartment model in therapeutic trug monitonng, panly because they arc more tifficult to construct ant apply.

Gencially, muldeaw models arc appliet when th,e natural log of plasma drug consentration vcrsus time is not lincar afier an intravenous tose or when thc plasma concentration versus time psfilc cannot bc chu~ by a single cxpooential function (i.c., C, - CO e~~’). Wben the In of plasma concentration vcrsus timc is not a

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Multicompartment Modeling

stnight line, a multicompartmcnt model must bc constructet to tescribe the change in concentrations over time.

Of the mul

models, tbe two-compartment motel is tnost fxqucntly uset. lunis model usually

of thc weU-perfia

tissues ant • “penpbexal” compartment of less weU Erfuset dssues (such as muscle ant fat). hgure 23^ shows a diagram of thc two-compartmcnt model afir an intravenous bolus tose, where:

consists of a “central’

Xf—amount of diug in centnl comva XP s amount of drug in psipheral cowt

K,2—rate const nt for transfcr of drug from cd-compartment zo petipheral compartment rne subsaipt “12” irldicses tr nsfcr from thc first (cd) to the second (peripheral) compattments.

K2, - rate constant for tgansfcr of drugfrov peripheral computment to central comp rtment lbe subscript ‘’21” indicales tr nsfcr from Ulc second (periphaal) to the fint

Xo~

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Multicompartment Modeling

Kl2

K2l

+ Klo

•zgre23~ Gr phic reprtsentation of a zwbcompattment model.

(centri) compartments. (Nott h Kz2 and K2,—calkd micxnts.)

fintvder climinX aue consunt (similar to tbe Jr uxd paviously), i—”ting elimiXn of dmg out of tbe caul ~ into urine, feces,

esc~

A log plasma conscatration versus time curve for a two-compattment model shows a curvilinear profile—a atrved potoon followed by a straight li=. This “biexponential” curve c n bc described by two expoKntial tcrms (Flgure 23B). lEc phases of the curve may reprcstnt rapid d1stributioo to organs with high blood flow (central compuenent) and slower distnbution to organs with Ess blood flow (penphcnl compartmcnt).

Mer thc intovenous injection of a drug that follows a t_ model, thc drug consentrations in all fluids and dmms associated with tbc central compartmcnt declinc morc rapidly in tbc distributioo phasc thao during the post-diwibubon phasc. ARcr sornc

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Multicompartment Modeling

tirnc, a “pseudocquihEutn” is attained betwcen thc ccotral compartmcot and thc dssucs atid fluids of toc pc ipheral compO thc pl sma coocentration vcrsus timc ptnfile is thco chaserized by a linear pnmcess.

For many drugs, suco as aminoglycosides, thc distributdoo phast is vcry shott (e.g., 1920 mtn). If serum consentradons are measured after this phase is compited, toe ceotral compartmcot can be ignorcd and a one-compartrKnt model adequatcly repttsents the serum coocentratioos observed. However, for drugs such as vancomycin, thc-distribution phase lasts 1-2 hr after an intravenous dosc. If plasma concentrations of vancomycin are determined within the first hour after a dose is given, thc nonlincar (multiexponential) decline of vancomycin concentrations must bc considered.

REVIEW PROBLEMS

23.1. In the twocompartment model. Xt wpresents the

23.2. The log plasms concentration vcrsus time curve for a two-compartment model is reprcsented by a (bicxponential or monoexponential) cuNe. (Sclect one.)

23.3. The first portion of the log plasma concentration ver. sus timc cune. where the log concentration r;tpidly declincs. is lomwn as the

phasc.

23.4. The final. Iinear portion of the curve is the phase.

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Multicompartment Modeling

11- 1 ~1

I>Pur 2t 61

70 [ So

~i

~m

~.

F*wf 238 Four st ges of drug distribution nd eliminatioo following rapid intravenous injectiott. Points I, U, m, nd tv (ript) corrcspond to the points oo the plasmx concentntion curve (leR). Point 1: The injection has just becn compicted, and drug density io the cd compartment is hipcst. Drug distribution and elimination hve just begun. Poin~ 11: At midway through tbe distributioo process, the drug density in thc central compartment is falling r pidly, dulioly owing to rapid drug distributioo out of the centd ccrnpartment into the peripheral compartment. The density of drug io the peripheral compartment has not yet mched tht in the central compartmcnt. Poixt 111: Distribution equilibrium h s been attained, and drug densitics in the centd and periphed compartments arc appgoximately equal. Drug distribution in both directioos contioucs to talze place, but the ratio of drug quantitics in toe centel and peripheral compartments remains constant. At this point, the major determinant of drug disappearance from thc central compartmcnt becomes the elimination process; previously, drug disappearance W&S determined mainly by distribution. Poi/s : During this elimination phase, the drug is being ‘-drained” from both com-

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partmcnts out of the body (via the central companment) at approximatcly the same rate. (Reproduced, with permission, from Grecnblatt DJ &nd Shader Rl, Phrmacolsinetics in clinical practice, W.B. Saunders, Philadelphia. PA, 198S.)

TwoW M~

lo this input, wc soall apply mathematicaS principles to toe two-compartmcnt model to calculatc useful poarmacokinetic parameters.

horo tiscussioo of the ooe-comparaneot model, we koow that the climination zte coostant (J[) is estsmated fxm the slope of the lo pbsma coocentration vcrsus ame curve. However, in a two-canzrg tnodel, wose the lo plasma coocentration versus time curve is curvilinear, the slope varics, tepcndiog on waich porioo of toe curve is cxamined (Flgurc 24A).

In a two compartment model, the tenninal slope from the pos,t-digributive phase of the curve may bc backextrapolata~ to axnc zero (T). The oegative slope of this line is teferret-to as beta (O, aot ,B is the tennioal eliminatton tate coostant of the trug. The iotesept of this lioe on the In plasn coocentration axis is koown as B and is uset in vanous two~cotnpeneot equations.

Bc~ is similtr to K in to t it vsents the tsminal elim meion r te constant. From it, a half-life can be cal~ culS

T%, 0.693

is

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Multicompartment Modeling

which is refenet to as the “beta haSf-Ute. ‘

lEroughout the ame th_t trug is present in the boty, tistribuiion takes place between the central ant peripheral compartmenu. We can calculate a ratc of tistribuaion using the mct rcsidxals. This methot estim tes the cffect of distribution on the ovcrall plasma concentration curvc and uses thc diZfcrcncc between thc cffect of climination and thc actual plasma consentrations to determinc thc distribution rate. In the In concentration versus vime curvc in Flgure 24A, the slope of the initial portion is determined prim--arily by the distribution rate while thc tenninal portion is determined primarily by thc climination rate.

E <~

100

50

o S~

PodwDiattibutlon Ph~

Timo Figsot 24A Plasma druy concentralions with a two-compartment model atter an imravenous bolus do*c.

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Multicompartment Modeling

The methot of residuals may be used for calculating phamiacoMinctic parameters of thc two-compartmcnt model. FuSst, b cl:-extrapolate the terminal straight-line portion of tbe curve (Flgure 24B). If w, s. y, and 2 are actual, detennined concentration time points, let w’, ~’, y’, and 2’ xpresent points on the new (extopolated) line at the same times that tbe aaual points were obscrved. These newly generated points xpresent the cffect of clim~ ination alone, as if distribution had been instantaneous. Subtnction of the extrapolated points from the corresponding actual points (w—w’, X—~’, etc.) yields a new set of pbsma concenti-ation points for each time point. If we plot tbese new points with the appmpriate times, we generate a new line, the “residual” line (hgure 24C).

The slope of tbe xsidual line is—st, and alpha (a) is the distribution rate constant for the two-compartment system. The intrcept of the residual line is A. Therefore, witb the coocept of residuals, we attempt to separate the two pwocsscs of diseribution and climin~ jon.

Ist us now pn~cood through an exampic, applying thc metbot of xsidtis. Draw tbc plot for thc following cxampb on somilog gnph paper. A dosc of dnag is ad

10.0 50

‘ :!

Z c 10 —o fL Q

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Multicompartment Modeling

Tlmo F~—241R Mcthod of xsiduals.

E

100 5e

•

Y’

Bz

~’

\ Sbpo = a

s -R

Timo

F;

24C Dctermination of the rcsidual linc.

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Multicompartment Modeling

62

InPtJT 24 63

)

ministered by rapid intravenous injection, and the tollowing concentrations result:

Tkne afttr Dose (hr) 0.2S O.S 1.0 I.S 2.0 4.0 8.0 12.0 16 0

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Multicompartment Modeling

Plasms Concentration (u~/ml)

43 32 20 14 11 6.S 2.8 1.2 0.S2

A linc is trawn connecting the last four points and intcnecting the y-axis. Then, for the first five points, cxtrapolated values can be cstimated at cach time (0.2S, O.S, 1.0,’l.S, and 2.0 hr). If the extrapolated values from the actual plasma concentrations are subtracted, a new set of points is generated (resitual concentration points) as fts w~

Tlnse dir Doz (hr) 0.2S O.S

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Multicompartment Modeling

1.0 1.5 20

Pbsma Concentratlon (>g/ml)

^>e

Exupol ted Residud

14.S 13.S 12.3 1 1.0 !O.0

28.S 18.S 7.7 3.0 I.D

The zsidual concentrations are then plotted (on semilog paper) versus time, and the slope of that plot equals —1.8 hr~t. When the negative is dropped, this slope equals sx; we observe from the plot that the intercept (A) of the line is 4S Fg/ml. We also can estimate a from the slope of the terminal straight-line portion (equal to 0.21 hr~ ~) and 8 (equal to IS 1lg/ml).

Alpha (ex) must be greater than beta (a), indicating that drug removal from plasma by distribution into tissues proceeds at a greater rate than does drug removal from

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Multicompartment Modeling

plasma by eliminating organs (e.g., kidncys and liver). rhc initial portion of the plot is steeper than the terminal portion.

REVIEW PR08LEMS

24.1. Dnw a log pbsma concentntion versus timc profile for a drug Oinimed by the intravenous bolus nmute and best durizZ by a two-companrnent modeJ (Figure 24D).

242. Tbe slope of the tenninal phase of the above. plot equals

243. Tbe inucept of thc tenniial portion on tbe In pbsma concentstion axis is tenned

>.~ sca(g)~ tbe tenninal const nt of the dmg s it leaves the body.

24.S. One w y to calculatc a distnbution zate is to use tbe metbod of

24.C. Tbe fint step in the metaod of residuals is to.

- the telminal straight-line portioa of the curve. 24.7. The extryolatd points aw subtmed from tbe actuaJ observed at the correspoading times.

24.8. Tbe slope of the residual line equals

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Multicompartment Modeling

24.9. “A” is tbeof tbe In plasnu concenamtion axis by tbe line.

2410. Tbe coocept of residuals attempts to separate tbe two

processes ofand—

100

• 50

ca e

Z c 10 FQ

Fkwe 24D

Tim ljg

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Multicompartment Modeling

Two-Compartment Model-3

The estimations of A, 8, ss, ant t perforrned in tbe last input are useful for predicing plasrrs concentotions of dmg ch~nzi by a two-compartrnent model. For

• awrst rnodel (Flgureo2SA), we know th t thc plaSsma concentration (C) t any time (t) can be dessnbet by

Cf ^ Ce e t’

where CO is the initial concentration and g is ttne climination rate. Thae two-compartment rnodel (Flgure 2SB) is thc surn of two linear components, reprcsenting distnbution ant elimination (Flgurc 2SC).

In thc sarnc w y, we can dctrminc dnag consentration (C) at ny tinx (t) by iding thc two linear components. In cach casc, A or B i-s uset for CO, ant ex or z is used for XY. Therefe

C, s

‘ +- 8 e~*’

ThiSs equation is called a •’biexponential cquation” bccausc two cxponents rc iwaled. With thc onos

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Multicompartment Modeling

wrunt rnodcl (intravenous), wherc:

C. s Ce e ~’

2B

100 501 CO 10 S

Timo Fzwe 25A Pls dmg concentrations with a one com putment model aher an insvenous bolus dose (first order elimination).

100 50

,o

z -, 10 5

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Multicompartment Modeling

~c —o

Timc ft 25B Plasma drug concentrations with 3 two compartment model after an intnvenous boluXs dose sfirst-order elimination) .

100 50

E;

tO

Sz

Tlmo Fw 25C lOr azmpo~s of a twozxpo~ (>

t) model.

~nentid” becausc thc linc is t tnodel, diffcrcnt volume of

thc equation is

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Multicompartment Modeling

describet by onc exponents

E or thc twowrat dWibution psramctrs cxist thc centol volurnc {V¢), thc cxtrapolated volunc (V,~ ,), tbc volunc by arca (V,,, also lcnown as V~|), ant thc stcadystatc vohunc of diwibuX (V,,). Each of thcsc voluncs rclste to diffcrcat undertying assumptioos.

As in thc onc-cornpenent rnotcl, a volunc can bc calculated by

V dose dox ¢ ,~ + B Co

For thc two-compartrnent model, this volurne would bc cquivalent to thc volumc of the central compartment (V¢). Thc Ve rclates the amount of drug in thc-central compartmcnt to the concentration in the central compartment. In thc two-compartrnent model, CO is determined by cxtrapolating back to thc y-axis from the upper or initial straight-line portioo of the plot.

When we calculate the extrapolated volume of distribution (V,x,,,p), we assume that instantaneous distribution has occurred. The effect of the iniial distribubon phase is ignored:

da B

V_

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Multicompartment Modeling

wherc B is the w-intetcept of thc line extrapolated from the terminal portion of the curve. This volume of distribution determination may not provide a useful volume term since it ovcrsimplifics the two-compartmcnt model and disregards thc distribution phasc.

Another volumc (V,,O or V~) is detcrmined from the area under the plasma concentration vcrsus time curvc and thc tcrminal climination rate constant. This volumc is related as follows:

114

lNvts S 65

vffi

dox =

CL —

ffi x AUC3

va

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Multicompartment Modeling

This calculation is not subject to thc ovcrsimplification of V,S,,p, but it is affected by changes in clearance. The V,,,, relates the amount of drug in the body to the concentration of drug in plasrna in the post-absorpion and postwdisttibuiion phase.

A ffnal volume tenn is the volume of disttibution at steady state (V,,). Although it is not affected by changes in drug eliminadoo or ckarance, it is more difficult to calculate. One way to estimate Vs, is to use the two compartment microconstants:

V,—Ve + ~’2vf

21

or it may be estimated by more complicated methods using AUC.

Since-different methods can be used to calculate the various volumes of distribution of a two-compartment model, you should always specify the metbod used. When reading a pharrnacolcinetic study, pay particular attenion to the method for calculating thc volume of distribution.

REVIEW PROBLEMS

2S.1. The terminal eliniination rate constant tn a twoaconF putment model is

2S.2. For the two-compurtment model. complete the equo tion describing the relazionship of plasma concentration with time: C, - •

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Multicompartment Modeling

25.3. (True or False) The equation describing elimination afer an intravenous bolus dose of a drug charauerized by a two-compartment model lequires two exponential terms.

2!;.4. A patient is given a 500-mg dose of drug by intravenous injection and the following plasma concentrations result:

Plssms Time snerConcentrstion Dese (hr)ItsSml)

Oo ss 0.7S lS

3 ,6

72.0 46.0 33.0 26.3 20.0

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Multicompartment Modeling

16.6 1r.2 9.0 5.0 _.7 n Rr

Plot the points on semilog paper Ithree cycle) and deterTnine the following: a. ~. b. B. c. Residual concentrations for the first five points. d. A.

. t.

£ Prodictod Dlssma concentration at 1.2 hr after the

dose.

S- V,.

h. V,, (if AUC = 131.S mg/L x hr and dose SOO mg). ~ A#=W{~ SGS 2

PRi4CTlCE SET 2

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Multicompartment Modeling

The following pxbiems are for your xview. Dcfinitions of symbols ant Icey equations = pxvitet hc~:

k

~w climinton nte cowt

C, s pbSllk tn~ _—jUSt Aher a single inuvenous injectioQ

e

- bese for the nxl log f~|eion - 2@71S

4

- nte of tose ~ion (msy be cxptesset as milligsams per bour in the sense of a coQtinuous infusion or u trug tose divitot by itifusion tune for intemtittent infusions)

V

• voluxne of tistribution

C_t - pcalc p1ssfu a ocentntis

C_ • tnmugn plsCOOCCD

a steaty state

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Multicompartment Modeling

a stcady st te t —duFn of intsvenous inAlsion

For muldpk dose, intennittent, intnvenous bolus injeciiOQ g stF st~

—k V (I - e~t’) C_—Cw e~t’

For muletplffbse~ intctmiu, intnvenow itafi~ioo

C - t° (I ~ e t~) —~ VK (I—e~tD

C_ - Cp e~tt~4

Fot contitiuous infusion before stee st te is reacbed: C - V^°r (I - C-t’)

For continuous infusion t stcaty stac

C.4. 4 Vt Ws

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Multicompartment Modeling

PS2*1. A 60-kg patient is begun on a continuous intravenous infusion of theophylline at 40 mgtbr. a Forty-eight hours after beginning ttte infusion, the plasma concentniion is 12 ~/ml (12 mg/L). If we assume that tbis COncentRtiOD is tbe stcady state, wb t is the tbeoobylline clearansc?

b. If the volume of distribution is cstimated to be 30 L, what are the X and halflife?

c. Since we kww V and t. what would the concentntion bc 10 hr aftcr beginning the infusion?

d. ff the idision i continuet for 3 days ant then discondauet, what woult tD plamS consentm tion be 12 hr ~r stopping the infwiont

e. If tne infusion is continuct for 3 d ys at 40 mg/ hr ant the stcaty-statc pluma concenttation is 12 Fg/tnl, WDat rate of trug infusion would liltely xsult sn a concentradon of 18 ~/ml?

f. ARcr the iocosed infusion nte above is begun, how bog would it tic to tuch a plu coo~ cenudon of 18 Fgiml?

PS2< A 60-log p ekat is st rted on 80 mS of gentunicin ewety 6 br in • I*br infusiagL

L If this pSt is us led to have an “avenge” V of 15 L ult a normal half-life of 3 hr, wtuat will be the pealc plm coœcenttadon at stcady stuc?

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Multicompartment Modeling

b. After thc fifth tese. a peak plasma concentratlon (dsawn at thc ent of thc infusion) is S Ag/ml ant thc ttnugh consentration (drawn right befott thc sixth tosc) is 0.9 Ag/ml. What is thc patient’s xtual gentamicin half-life? What is thc xtual volume of disvribution?

c. For this patient, what dosc should bc administen:d to reach a new steady-state peak gentamicin concentration of 8 Fgiml? At this dosc. what will bc thc steadystate trouQh concentration!

II_q

tFoD~ sU

~ Tvo-ConPart-ent Open Hodel

tatlente •ufferln~ chronle tenal fellure often require h _ odiolyele. Drug~ •cy be ~dxinletered by Injeetlon Into the wenoue •lde of the he odtcl~ser •~chine

Such e rituetlon vax ~ecerlbed by L tourneeu-Scheb •t •1 (Int. J. Clln. tharv col IS 116-120 {1972)) for •lx pctlente vho received •n introvenoue done ot gent _ letn (90 ng). The neen etru- concentrctleno et sent~nicin (C~) •hovvd • blexponenttel deellne vith tl t (t).

Ce

t

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Multicompartment Modeling

(-~lllter)(oln) o 60 5 75 5 25 4 80 • 50 3 95 3 40 3 10 2 90 2 55 10 20 lO 40 50 90 150 180 240 28S

(

o. Caleelete the ter lnal half-llfe (t~) the hybrid rete eonetento

•nd O •nd the coefflelente (~1 • 3 Sl) for gent- leln to theeo he-odlulyal~ putlente

b. tor •ubJecte vith noreel renal functlon. the •yete-le elearence (Cl~) of gentanletn le •pproalaetel1 0.041 llter/ In. Sec uee 98X ef Cl~ le due to excretlon of unchanged drug. renel tciluro utll ~rkedly effect ~ent~lcin clecr~nce.

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Multicompartment Modeling

Show vhether the petlent~ undergoinfS he odlelyele •xhlbit o nor-ol gentcnicln •yett-le elexr~nce.

Calculete the two •pperent volune ot dletrtbut10n terwe (V •nd V )

•nd the ell fnetlon rete eonetont. Uhet frectton of tho gt ted eln ln the body •fter 3 hr nlght be la the peripherel ee part~ent7 At vh t tbae doee the gent _ Icin in the peripherel ee pert~ent rench

~t

4. Under the eondittons of h odSxlyxte. coleulete the doxe tD) of

sentcoleln •tlSch vould be •dolaletered •very S hr {1) In order to ~alnteln •n everogew •teady-ctete •erus concentretlon of 4 •g/llter.

•. Wlthout the hc odielyrer two ~ale petlente •ach •xhlbited • creetinine eleorence (Cle ) of 5 •llwin; the norx~l velue le 117 t 20 •I/nin. A~using that the deereFeed Clcr {e due to • decresce In glo-eruler filtretloo rcte vhst vould h-ve beeD the renel clecrxnce (Clr) of gent~elcia In there two patlentn hed they rz cined vithout the heodlolysert Uhct done vould then need to be dsinletered every • hr to n Intoin (C~ •t 4 tert Co pcro your •eouer wStb tho thy~telea e Deek Refer neo.

Vancomycin is an antibiotic used in the treatment of endocarditis in patients allergic to penicillin. It is poorly absorbed orally and acute pain is associated with intermuscular injection. I.V. is the route of choice. After a 1 gm I.V. dose the following data is observed:

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Multicompartment Modeling

Time (hours)Concentration (mcg/ml)

.5 1.0 1.5 2.0 3.0 4o 6.0 8.0 12.0

51 36 28 23 18.5 16 12.5 99 6.25

FIND: a) A1 ;

b) alpha c) Clearance ;

d) * of drug in peripheral compartment at equilibrium .

Clearance:

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Multicompartment Modeling

In normals, Erythromycin is cleared 90% by metabolism and 10% by the kidney. Also, it is 90% protein bound at therapeutic levels. Welling and Creig (JPS 67, 1057-9,1978) reported an increase in the half life from 2.0 to 2.3 hours while also reporting an increase in clearance from 275 to 485 ml/min and an increase in Vdss from 57 to 100 litres when comparing normals to uremic patients. (Uremic patients suffer from inveased concentration of urea as a result of severe renal failure.) A physician has just called you and asked you to explain how he could have seen an increase of 15% in the half life and a 75% increase in clearance at the same time and what is the impact of this on antibiotic therapy for his uremic patient. In clear concise English (not techno-bable), prepare a short written answer to this request. Keep in mind that the man who requested the information is a medical professionat intelligent, and very busy.

The following data was collected from a normal patient in the revious study (Welling, op. cit.) following an IV bolus injection of 500 mg of erythromycin (as lactobionate salt ).

time (hr)concentration (mcg/ml)timeconcentration

0 1 2

12 4 6.4 4.0

3 2.6 4 1.9 6 1.2 8 0.4

~.

Fmd the peak time in the peripheral compartment.the fraction of the drug in the peripheral compartment at four hours.

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Two compartment model

Spectinomycin (TROBICIN^TR^T) is an aminocyclitol antibiotic shown to be active against most strains of NEISSERIA GONORRHOEAE at a minimum inhibitory concentration of 20 mcg/ml. The usual adult dose is 2 g (4 g in areas of known resistance) given I.M. through a 20 gauge needle. Initial studies were done by the company to determine the pharmacokinetic parameters of the drug. The data from a single IV Bolus dose of 0.5 g is as follows.

Time (minutes)Concentration 10 20 30 45 60 120 240 360 63 51 43 35 30 183 7.6 3.2

FIND:

(5 points) a) A^V1^V = (5 points) b) B^V1^V = (5 points) c) Clearance =

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Multicompartment Modeling

(5 points) d) t max in the peripheral compartment = (10 points) e) % of drug in peripheral compartment at equilibrium =

Spectinomycin (TROBICINR) is an aminocyclitol antibiotic shown to be active against most strains of NEISSERIA GONORRHOEAE at a minimum inhibitory concentration of 20 mcg/ml. The usual adult dose is 2 g (4 g in areas of known resistance) given I.M. through a 20 gauge needle. Initial studies were done by the company to determine the pharmacokinetic parameters of the drug. The data from a single IV Bolus

dose of 0.5 g is as follows. Time (minutes)Concentration 10 20 30 45 60 120 240 360 63 51 43 35 30 18.3 7.6 3.2

b} B c) Ciearance d) t max in the peripheral compartment e) % of drug in peripheral compartment at equilibrium

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Multicompartment Modeling

The following information is offered from a 142 mg IV bolus dose of grisiofulvin given to a 73 Kg man.

Time mcg/ml 1 2 3 4 6 8 12 18 24 30 1.67 1.22 .97 .83 .66 .56 .42 .27 .17 .11

Find A1, B1, alpha, beta, K10, K12, K21, Peak time in the peripheral compartment, % in the peripheral compartment at equilibrium. Can you assume that this drug can be estimated by a one compartment model upon multiple dosing ?

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Multicompartment Modeling

Quinidine is current-ly used to treat ventricular and supraventricular arrythmias.- It is available as a sulfate, gluconate, and polygalactouronate which contain 83%, 62* and 60* by weight free base (pRa 8.6). Qunidino sulfate is available in 200, 260, 300 and 325 mg tablets, while quinidine gluconate is available in 325 mg tablets. The following pharnacokinetic parameters are reported by Ueda:

PARAMETER C1 renal (ml/min/kg)

C1 hepatic (ml/min/kg) V1 (L/kg)

V beta (L/kg) F (oral)

t 1/2 alpha (min) t 1/2 beta (hr)

MTC (mic/ml) NEC (mic/ml)

Population Ave (+ SD) 0.93 (0.52) 3.26 (1.74) 0.66 (0.38)

2.61 (1.10) 0.71 (0.16)

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Multicompartment Modeling

6.69 (4.03) 6.44 (1.63) 8.53 (0.81)

*

,

1.85

(0.19)

% bound to protein80.00(2.50)

During the last pharmacokinetic exam you noticed •ome cardiac problems. Wh n you ch-cked with your physician, He prescribes quinidine. What dose should you be on?

Later, he diagnoses mononucliosis from lack of sleep and poor •ating h bits •s weli as cardiac arrythmias. Your liver funcion has dropped to 60* of normal. He prescribes quinidine for you. What is the dose that you should be on ?

ie. -

ll-3

Quinidine is currently used to treat ventricular and supraventricular arrythmias. It is available as a sulfate, gluconate, and polygalactouronate which contain 83%, 62% and 60% by weight free base (pKa 8.6). Qunidine sulfate is available in 200,

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Multicompartment Modeling

260, 300 and 325 mg tablets, while quinidine gluconate is available in 325 mg tablets. The following pharmacokinetic parameters are reported by Ueda:

PARAMETERPopulation Ave (+ SD) C1 renal (ml/min/kg)0.93 (0.52) C1 hepatic (ml/min/kg)3.26 (1.74) V1 (L/kg)0.66 (0.38) V beta (L/kg)2.61 (1.10) F (oral)0.71 (0.16) t 1/2 alpha (min)6.69 (4.03) t 1/2 beta (hr)6.44 (1.63) MTC (mic/ml)8.53 (0.81) MEC (mic/ml)1.85 (0.19)

% bound to protein 80.00 (2.50)

During the last pharmacokinetic exam you noticed some cardiac problems. When you checked with your physician, He prescribes quinidine. What dose should you be on?

Later, he diagnoses mononucliosis from lack of sleep and poor eating habits as well as cardiac arrythmias. Your liver funcion has dropped to 60% of normal. He prescribes quinidine for you. What is the dose that you should be on ?

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Multicompartment Modeling

Methotrexate is a cytolytic used for the treatment of acute leukemia and other forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12 y/o boy.

Time (hours) 6 12 18 36 48 60 72 90

Concentration (mcg/ml) 360 70 15

2 1.2 0.46 0.36 0.15

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Multicompartment Modeling

bA) B c) Clearance d) % of drug in peripheral compartment at equilibrium

PROBLEM SET

zumper w~wFS t L) v , ~ s D fv

Patients suffering chronic renal failure often require hemodialysis. Drugs may be administered by injection into the venous side of the hemodialyzer machine.

Such a situation was described by L*tourneau-Saheb et al (Int. J. Clin. PKinmacol., 15, 116-120 (1977)) for six patients who receivet an intravenous dose 7 gentamicin (90 mg). The mean serum concentrations of gentamicin (Cs) showed a biexponential decline with time (t).

(~9cyml) 6.60 5-75 5.25 4.80 4.50 3.95 3.40

(mRn) 10 20 30 40 50 90 150

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Multicompartment Modeling

3.10 2.90 2.55 . .

180 240 285

(a) Calculate the values of t1/29 B, Bj, ~, A~, and V1. LFtourneau Saheb et al reported,

tl/2 = 5.50 t 0.77 hr (mean i SD) B s 0.0022 t 0.0004 min 1 B1 s 4.76 f 0.62 vg/ml

v • 0.053 t 0.009 min A1 a 3.47 s 1.01 pg/ml V1 s 11.3 ffi 2.0 litre

(b) Calculate C1 and VB LFtourneau-Sahleb et al reported,

C1 s 40.8 t 7.8 ml/min VB s 19.2 h 2.7 litre

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Multicompartment Modeling

_1

11-33

98X of the systemic clearance of gentamicin is composed of renal clearance-of unchanged drug, so that renal failure woult severely alter gentamRcin systemic clearance. In this case, the use of the hemodialyzer gave a systemic clearance close to the 41.0 ml/min seen in patients with normal renal function.

(c) Under the conditions of hemodialysis, calculate the dose (D) of gentamicin which would be administered every 8 hr (t) in order to maintain an Waverage” steady-state serum concentration of 4 ug/ml. What would be (Cmax)ss and (Cmin)ss?

(d) Without the hemodialyzer two male patients each exhibited a creatinine clearance (Clcr) of S ml/min; the noW l value is 117 + 20 ml/min. Assuming that the decreased ClCr is due to a decrease in glomerular filtration rate, what would have been the renal clearance (Clr) of gentamicin in these two patients had they remalned without the hemodialyzer? What dose would then need to be administered every 8 hr to maintajn (~s) at 4 ug/ml? Compare your answer with the Physician’s Desk Reference (5677).

Your third patient comes from Edelman et al (Clin Pbarmacol Therap 35:382-6 (1984)). He studied metotrexate is artbritic patients. The pharmacokinetic parameters gleened from the 10 mg IV data arc:

A1 (mg/L) 0.663 Alpha (hr-1) 059 B1 (mg/L) 0.073 Beta (hr-1) 0.097

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Multicompartment Modeling

15) What is the AUC (0 to inf) (mg / L * hr) ?

a) 0.75 b) 1.08 c) 1.12 d) 1.88e) 9.1

16) What is V1 (L) ? a) 13.6 b) 15.1 c) 253 d) 36.1e)103.1

17) What is the clearance (L/hr) ? a) 53 b) 8.9 c) 133 d) 15.4e) 17.2 18) What is V(beta) (L) ? a) 13.6 b) 253 c) 36.1 d) 45e 55

19) What is the t(max) in the perepheral compartment (hr) ? a) 0 b) 1.8 c) 3.7 d) 5.1 e)6.1

20) What percent of the drug is in the perepheral compartment at cquilibrium ? a) 25 b) 50 c) 75 d) 100 e) 125

Two compartment: It has been proposed (Ionescu et al. Clin Pkin 14:178186,1988) that morphine injectcd dirtctly into thc spioal chord would give significant analgesia. The following is a CSF concentration - time profile resulting from 05 mg/lcg IV bolus dose of Morphine:

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Multicompartment Modeling

time (min) (mg/L) 2 5 10 20 40 80

conc.

time (min) (mg/L)

conc.

251 181 142.5 1043 75.1 48.8 360 480 720

120 240 82 2.4 1.2

323 173

1 a) fraction of remaining drug contained in peripheral compartment at equilibrium. Lb) Can this drug be approximated by a one compartment model ? Support your contention with calculations. Lc) Calculate a rcasonable dosage regimen for the above patient to maintain the concentration within the therapeuticwindow of 50 to 5 mg/L.

Two compartment:

(1) It has been proposed that diazepam has anticonvulsant properties above 350 nanograms per milliliter. The following is a concentration - time profile resulting from 10 mg IV bolus dose of diazepam :

time (hrs) 0.25

conc. time (ng/ml)(hrs) 480 6.0

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Multicompartment Modeling

0-50 l.o 2.0 3.0 on

400 300 170 120 llo

8.0 10.0 16.0 24.0

l.a) fraction of remaining compartment at equilibrium.

n’

~_

conc. (ng/ml) 100 90 85 70 53

Dlezzewm

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Multicompartment Modeling

UA tD 20A Time

AD

drug contained in peripheral

k21 = (1.05 * 116.8) + (0.0325 * 487.6) / (487.6 + 116.8) = 138.5 / 604.4 = 0.239

klO = (1.05 * 0.0325) / 0.239 = n ls

kl2 = 1.05 + 0.0325 - 0.15 - 0.239 =n7

B2 = (0.7 * lOOOOmic) / (1.05 - 0.0325) = 6880

V1 = lOOOOmic / 604.4 mic/l = 16.55

X2 / total = 6880 / t6880 + (16.55 * 116.8mic/1)]

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Multicompartment Modeling

= 0.78

l.b) Can this drug be approximated by a one compartment model? Support your contention with calculations.

AUC = (487.6 / 1.05) + (116.8 / 0.0325) = 464.4 + 3594.8 = 4058.2

Since the beta phase contributes more than 80% of the total AUC, the model can be collapsed to a one compartment model.

3594.8 / 4058.2 = 0.886 = 89%

l.c) Calculate a reasonable dosage regimen for the above patient to maintain the concentration within the therapeutic window of 350 to 1100 nanograms per ml.

K = 1/MRT = 1 / (111007 / 4058.2) = 1/27.35 = 0.0253 per hr t 1/2 = 0.693 / 0.0253 = 27.39 hr 2^N^ = 1100 / 350 = 3.14 N = ln 3.14 / ln 2 = 1.65

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Multicompartment Modeling

Tau max = 27.39 * 1.65 = 45.19 hr drop the dosing interval to 24 hours now need to find a new N

N = 24 / 27.39 = 0.876

Vss = lOOOOmic / (4058.2mic*hr/1 * 0.0253/hr) = 97.25L

To find dose: l.lOOmg/L = (D / 97.25 L) * tl / (1 - 0.5^0.876^)] D = 49 mg daily (aggressive therapy)

0.350mg/L = (D / 97.25L) * t 1 / (1 - 0.5^0.876^)](0.5^0.876^) D = 29 mg daily (conseervative therapy)

Therefore, any dose between 30 and 50 mg a day can be given.

Two Compartment:

We have used theophylline as a test drug in many of our calculations in class. We assumed that it was a one compartment model. Look at the data from Mitenko (Clin Pharmacol and Ther,14p509 1974) for intravenous theophylline (Dose 5.6 mg/kg):

sos

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Multicompartment Modeling

theophylilne .

i ,_

1. OD 2D 4wD 6D8S Tlm~ tD

Time (hr.) 0.167 0.333 0.500 0.833 1.0 1.5 2.0 3.0 4.0 6.0

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Multicompartment Modeling

8.0

Conc. (mg./L.)

24.7 Estimates of Pharmacokinetic parameters

20.3 18.1 16.1 15.6 14.3

are as follows: A1 (mg/L)16.1 B1 (mg/L)17.9 Alpha (hr-l)4.8 Beta (hr-l)0.15

13.3 11.

AUC (O to inf) 122.7 AUMC (O to inf) 797.6

9.8

7.3 s.4

1) What is the volume of the central compartment (L/Kg) ?

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Multicompartment Modeling

*A) 0.165 B) 0.30 C) 0.35 D) 2.9 E) 6.1

2) What is the clearance of theophylline (L/Kg/hr) ?

A) 0.007 *B) 0.046C) 2.7 D) 22 E) 142.4

3) What is the Volume of

distribution in the beta phase (Vbeta)

(L/Kg) ? A) 0.165 *B) 0.30C) 0.35D) 2.9E) 6.1

4) What percent of the equilibrium ?

A) 12 B) 23

dose is in the peripheral compartment at

*C) 46 D) 69 E) 92 treated as a one compartment model for

5) Can theophylline be dosing purposes ?

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Multicompartment Modeling

A) No, a larger percentage of the drug is in the peripheral compartment.

B) NO, A1 and C) Yes, alpha D) Yes, the approximately

*E) Yes, the approximately

B1 are about the same value. is bigger than beta contribution of the alpha phase AUC is the total AUC. contribution of the beta the total AUC.

phase AUC is

6) What is the mean residence time (MRT) for the IV dose (hr) ?

A) 4.25 B) 5 C) 5.75*D) 6.5E) 7.25

For the same dose of an oral product information was obtained:

AUC (O to inf) AUMC (O to inf)

7) What is the MRT for the

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Multicompartment Modeling

A) 8.0 B) 8.75

122 1400

(TheoDur^TQ^T) the following

oral dose (hr) ?

C) 9.5 D) 10.25*E) 11.5

8) What is the mean absorption time (MAT) for the oral dose (hr)?

A) 1

B) 2

C) 3

D) 4

*E) 5

9) What is the absorption rate constant for theophylline in TheoDur

(hr^T-l^T) ?

A) 0.14 B) 0.17 *C) 0.2 D) 0.25 E) 0.3

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Multicompartment Modeling

Two compartment: The following pharmacokinetic information was obtained from EA, a

45 y/o, 70 kg, healthy male following an800 mg IV dose of vancomycin: A1 60 mg/L alpha 1.33 hr^-l B1 20 mg/L beta 0.129 hr^-l

AUC (mg/L * hr)200 AUMC (mg/L)1237

5) What is your patient’s vancomycin clearance(L/hr)?

a) 0.25 *b) 4 c) 24.74 d) 45.1 e) 155

6) What is your patient’s V(beta)(L)?

a) 10 b) 24.74 *c) 31 d) 45.1 e) 60

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Multicompartment Modeling

7) What is your patient’s V1(L)?

*a) 10 b) 24.74 c) 31 d) 45.1 e) 60

8) What is your patient’s MRT(iv) (hr)?

a) 0.112 b) 0.162 c) 1.39 d) 4.29 *e) 6.19

9) What is your patient’s effective rate of elimination (hr^-l)? a) 0.112 *b) 0.162 c) 0.5 d) 4.29 e) 6.19

10) What is your patient’s Vss (L)?

a) 10 *b) 24.74 c) 31 d) 45.1 e) 60

11) Following an IM dose of vancomycin, the MRT(im) was calculated to be 8.185 hr. What was the absorption half life (hr)? a) 0.112 b) 0.162 *c) 1.39 d) 2 e) 6.19

RP ‘s angina was controlled on 40 mg TID of propranolol. You calculated his pharmacokinetic parameters to be: Vd (L) = 125; T1/2 (hr) = 3.1; Qh (L/hr) = 33; Bioavailability (f) = .7; Bound(%) = 95. Propranolol is essen^_ tially 100% metabolized.

12) What is his Total body clearance (L/hr)? a) 1.4 b) 14 *c) 28 d) 33 e)40.3

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Multicompartment Modeling

13) What is his hepatic extraction ratio?

a) 0.042b) .42 *c) .85 d) 1

e) 1.22

14) Assuming propranolol to be rapidly absorbed, what is his Cpss

max free concentration (ng/mL)?

*a) 13.4 b) 19.2 c) 188 d) 268 e) 355

15) What is his Cpss max total(bound and free) (ng/mL)?

a) 13.4 b) 19.2 c) 188 *d) 268 e) 355

16) What is his Cpss min free (ng/mL)?

*a) 2.2 b) 3.2 c) 31.4 d) 44.8 e) 59.3

He is now suffering from renal failure. His half life went up to 3.8 hr while his binding went up to 98.3% because of an increase in AAG, a plasma protein to which propranolol binds.

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Multicompartment Modeling

17) What is his new clearance (L/hr)?

a) 14.4 *b) 21.7 c) 24 d) 28 e) 36.2

18) What is his new volume of distribution (L)?

a) 79 *b) 119 c) 132 d) 153 e) 199

19) What will his new Cpss max free be if we keep him on the same

regimen (ng/mL)?

*a) 5.26 b) 7.5 c) 310 d) 442 e) 554

20) What is his new Cpss max total(ng/ml) ? a) 5.26 b) 7.5 *c) 310 d) 442 e) 554

21) What is his new Cpss min free (ng/mL)?

*a) 1.23 b) 1.75 c) 72.3 d) 103 e) 129

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Multicompartment Modeling

22) The physician sees that the clearance has dropped and consequently the total plasma concentrations have gone up. He wants to decrease to dose to 40 mg / BID. What would you recommend? a) Sounds good to me. That will get the Cpss max total concentration back to it was before he was sick. b) His new clearance was marginally changed because the drug is cleared by the liver. I’d leave it alone. c) I think the change from TID to BID is a bit much. How about lowering it to 30 mg instead of 40 mg TID. *d) We need to increase the dose, not lower it. I’d recommend 40 mg QID. e) We need to increase the dose, not lower it. I’d recommend 80 mg QID.

Two compartment

Methotrexate is a cytolytic used for the treatment of acute leukemia and other forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12 y/o boy.

Time (hours)Concentration (mcg/ml) 6 12 18 36 48 60 72 Q(} 360 70 15 2 1.2 0.46 036 0.15

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Multicompartment Modeling

FIND: (5 points) a) A^V1^V = (5 points) b) B^V1^V = (5 points) c) Clearance = (5 points) d) % of drug in peripheral compartment at equilibrium =

Everything.

Primidone (Mysoline^T@^T) is an effective agent in the treatment of generalized and complex partial seizures. Although primidone has anticonmlsant activity of its own, much of the activity comes from the conversion to one of its metabolites, phenobarbital. For the purposes of this exam, an insignificant error will be introduced bytheuse of intermittent IV caSculations instead of oralformultipledose. Thefolloving information for primidone and phenobarbital is available:

Primiflnne. Phenabarbital

Therapeutic Range (mg/L)5 - 12 10 - 30 Bioavailabiliq (f)1 Salt factor (S)1 Vd (L/Kg) 0.6 0.9 09 0.7

T1/2

7 hr

5 days

% Excreted undhanged2520 % Metabolized75 80

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Multicompartment Modeling

% Metabolized to Phenobarbital25*~

% Metabolized (non Phenobarb-paths)50**

2.(20 pts) Please prepare a short consult for your M.D. in which you caSculate a dosage regimen for an 80 kg patient whidh would l~eep the plasma concentration within the therapeutic range. Prirnidone comes as 250 mg scored (can be broken in half) tablets. Indude your average, maximum and minimum primidone as well as phenobarbital steady-state concentrations in the consult.

3. (25 pts) The patient recently contracted mono. His liver function has been reduced to 50 % of normal.

Would you recommend a change in your therapy ? If you would, prepare a short consult for his M.D. as in question #2. Don’t forget that changes in hepatic clearance result in changes in both phenobarbital clearance 5~nfl fannation

4. (25 pts) Now that his mono has cleared up the doctor noticed that he has stenosis of the liver as a consequence of all t_e heavy parting that he did after the kinetics course. His liver plasma flow has been reduced to 50 % of normal. Would you recommend a dhange in therapy ? If you would, prepare a short consult for his M.D. as in question #2. Don’t forget that dhanges in hepatic dearance result in changes in both phenobarbital dearance and formation.

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Multicompartment Modeling

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Multicompartment Modeling

11.4 Begin

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Multicompartment Modeling

11.5 Problems

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11-91

Multicompartment Modeling

Aspirin

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 1)

Fu, C., Melethil, S., and Mason, W., "The pharmacokinetics of aspirin in rats and the effect of buffer", Journal of Pharmacokinetics and Biopharmaceutics, Vol. 19, (1991), p. 157 - 173.

Aspirin is an analgesic/ antipyretic commonly used to relieve minor pain and is used in such conditions as rheumatic fever, rheumatoid arthritis, and osteoarthritis. The major metabolite of aspirin is salicylic acid. The following set of data was collected using rats which weighed 250 - 300 g.

PROBLEM TABLE 11 - 1.

Aspirin

275 g 5 mg/kg IV 8.58 1.07 7.24 0.2 38.8 116.0

weight of rat Dose

A1

a

B1

b AUC AUMC

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

What is ? What is ? What is your patient's clearance? What is your patients MRT? What is your patient's ? What is your patient's V1? What is your patient's ? What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes? If this drug can be treated as a one-compartment model, what is K ?

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-92

Multicompartment Modeling

Buprenorphine

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 2)

Ohtani, M., et al., "Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbuprenorphine, in rats", Drug Metabolism and Disposition, Vol. 22, (1994), p. 2 - 7.

Buprenorphine is a morphine derivative which has twice the duration of action and 30 times the potency of morphine. Buprenorphine is partially metabolized to norbuprenorphine which is also active in the body. In this study, buprenorphine was given to rats weighing 280 - 300 g.

PROBLEM TABLE 11 - 2.

Buprenorphine

290 g 0.06 mg/kg IV 41 3.89 10 0.271 48.3 135.24

Weight of rat Dose

A1

a

B1

b AUC AUMC

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

What is the ? What is the ? What is the AUC? What is your patient's clearance? What is your patients MRT? What is your patient's ? What is your patient's V1? What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-93

Multicompartment Modeling

17.

If this drug can be treated as a one-compartment model, what is K ?

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-94

Multicompartment Modeling

Caffeine

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 3)

Shi, J., et al., "Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor effects", Clinical Pharmacology and Therapeutics, Vol. 53, (1993), p. 6 - 14.

This study looks at the cardiovascular effects of caffeine. Caffeine is known to increase blood pressure upon its withdrawl. This study looks at how tolerance to caffeine and its pressor effects develops and disappears with time.

PROBLEM TABLE 11 - 3.

Caffeine

80 kg 4 mg/kg oral 10.55 4.9 9.1 0.23 98.4 %

Patient weight Dose

A1

a

B1

b f

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ? What is your patient's V1? What is ? What is ? What is ? What is ? What is ? What is your patient's ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-95

Multicompartment Modeling

Cefazolin

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 4)

Nightingale, C., et al., "Changes in pharmacokinetics of cefazolin due to stress", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 712 - 714.

Cefazolin is a cephalosporin antibiotic used in the treatment of many types of infections. This study looks at the effect of stress on the pharmacokinetics of cefazolin. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 4.

Cefazolin

56.3 kg 1 g IV 206.48 4.832 122.96 0.573

Patient weight Dose

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ? What is your patient's V1? What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-96

Multicompartment Modeling

Ceftazidime

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 5)

Ackerman, B., et al., "Effect of decreased renal function on the pharmacokinetics of ceftazidime", Antimicrobial Agents and Chemotherapy, Vol. 25, (1984), p. 785 - 786.

Ceftazidime is a cephalosporin antibiotic. This study explores the effect of compromised renal function on the pharmacokinetics of ceftazidime. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 5.

Ceftazidime

1 g IV bolus 188 8.22 58.2 0.49

Dose

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ? What is your patient's V1? What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-97

Multicompartment Modeling

Clentiazem

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 6)

Shah, A., et al., "Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects", Journal of Clinical Pharmacology, Vol. 33, (1993), p. 354 - 359.

Clentiazem is an derivative of diltiazem which is under investigation for its use in the treatment of angina pectoris and hypertension. Clentiazem blocks calcium channels resulting in a decrease in peripheral vascular resistance which subsequently leads to a decrease in blood pressure.

PROBLEM TABLE 11 - 6.

Clentiazem

77 kg 20 mg IV bolus 37.52 2.7 16.17 0.078

Patient weight Dose

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ? What is your patient's V1? What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

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REV. 99.4.25

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11-98

Multicompartment Modeling

Cocaine

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 7)

Levine, B. and Tebbett, I., "Cocaine pharmacokinetics in ethanol-pretreated rats", Drug Metabolism and Disposition, Vol. 22, (1994), p. 498 - 500.

This study looks into several reports which claim that the euphoric effects of cocaine can be enhanced when taken in conjunction with alcohol. This effect may be the result of higher cocaine blood levels or a reduced elimination of cocaine or a combination of both.

PROBLEM TABLE 11 - 7.

Cocaine

300 g 2 mg/kg cocaine (also 1 g/ kg ethanol) 1172.6 0.362 462 0.045

Weight of rat Dose

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-99

Multicompartment Modeling

**1,2-Diethyl-3-Hydroxypyridine-4-One
**

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 8)

Epemolu, O., et al., "The pharmacokinetics of 1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) in rats, Drug Metabolism and Disposition, Vol. 20, (1992), p. 736 - 741.

1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) is an iron chelator which is orally active. It is being investigated for use in the treatment of hemoglobinopathic disorders. In this study, rats weighing 250 - 300 g were given doses 50 mg /kg intravenously and the following data was collected:

PROBLEM TABLE 11 - 8.

**1,2-Diethyl-3-Hydroxypyridine-4-One
**

275 g 50 mg/kg IV 30.9 2.03 8.13 0.38

Weight of rat Dose

A1

a

B1

b

Assume that the rat ( which weighs 275 g) is suffering from thalassemia and his iron levels are very high. The rat is prescribed CP94 to restore the iron levels to normal. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. What is ? What is ? What is ? What is your patient's clearance? What is your patient's ? What is your patient's V1? What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

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11-100

Multicompartment Modeling

2,2-dimethylaziridine

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 9)

Lalka, D., Jusko, W., and Bardos, T., "Reactions of 2,2-dimethylaziridine-type alkylating agents in biological systems II: Comparative pharmacokinetics in dogs", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 230 - 235.

The 2,2-dimethylaziridine alkylating agents are used for their antitumor capability as antineoplastic agents. In this study, male mongrel dogs, weighing 20 - 28 kg, were each given a dose of 12 mg/kg of ethyl bis (2,2-dimethylaziridinyl) phosphinate intraveneously.

PROBLEM TABLE 11 - 9.

2,2-dimethylaziridine

24 kg 12 mg/kg IV 42 0.409 8.5 0.095

Weight of dog Dose

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-101

Multicompartment Modeling

Flurbiprofen

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 10)

Menzel-Soglowek, S., et al., "Variability of inversion of (R)-flurbiprofen in different species", Journal of Pharmaceutical Sciences, Vol. 81, (1992), p. 888 - 891.

Flurbiprofen is an anti-inflammatory and analgesic agent. This study compares the pharmacokinetics of the (R)-isomer of flurbiprofen to the those of the (S)-isomer. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 10. Flurbiprofen

Weight of rat Dose

260 g 10 mg/kg IV 48.5 2.33 57.68 0.175

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-102

Multicompartment Modeling

Furosemide

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 11)

Tilsone, W., and Fine, A., "Furosemide kinetics in renal failure", Clinical Pharmacology and Therapeutics, Vol. 23, (1978), p. 644 - 650.

Furosemide is an agent which is used for its diuretic action to treat such conditions as renal and cardiac edema. In this study, normal subjects were given an intravenous bolus dose of 22 mg of furosemide. Blood samples were taken at various intervals and the following data was obtained:

PROBLEM TABLE 11 - 11. Furosemide

Dose

22 mg IV 2.1 6.9 0.77 0.96

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-103

Multicompartment Modeling

Glycyrrhizin

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 12)

Tsai, T., et al., "Pharmacokinetics of glycyrrhyzin after intravenous administration to rats", Journal of Pharmaceutical Sceinces, Vol. 81, (1992), p. 961- 963.

Glycyrrhizin is a component of licorice which is proposed to have anti-inflammatory, anti-hepatotoxic, interferoninducing, anti-viral, and anti-ulcer activity. It also causes pseudoaldosteronism. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 12. Glycyrrhizin

Weight of rat Dose

275 g 20 mg/kg 91.23 4.16 69.90 0.43

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-104

Multicompartment Modeling

Human Deoxyribonuclease

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 13)

Mohler, M., et al., "Altered pharmacokinetics of recominant human deoxyribonuclease in rats due to the presence of a binding protein", Drug Metabolism and Disposition, Vol. 21, (1993), p. 71 - 75.

Deoxyribonucleases are found in human serum, urine, and a variety of tissues. These endonucleases catalyze the hydrolysis of DNA to oligonucleotides. It has been suggested that increased levels of serum deoxyribonucleases may predict malignancies.

PROBLEM TABLE 11 - 13. Human

Deoxyribonuclease

260 g 1 mg/kg IV bolus 19250 8.61 4897 0.229

Patient weight Dose

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-105

Multicompartment Modeling

**Human Granulocyte Colony-Stimulating Factor
**

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 14)

Tanaka, H., and Kaneko, T., "Pharmacokinetic and pharmacodynamic comparisons between human granulocyte colony-stimulating factor purified from human bladder carcinoma cell line 5637 culture medium and recombinant human granulocyte colonystimulating factor produced in Escherichia coli", The Journal of Pharmacology and Experimental Therapeutics, Vol. 262, (1992), p. 439 - 444.

Human Granulocye Colony-Stimulating Factor (hG-CSF) is used to stimulate the proliferation of precursor cells and their subsequent differentiation in the bone marrow. This article compares the pharmacokinetics of hG-CSF produced by two different methods. In the first method, the hG-CSF was obtained from human bladder carcinoma cell line 5637 culture medium. In the second method, the hG-CSF was produced by Escherichia coli.

PROBLEM TABLE 11 - 14. Human

**Granulocyte Colony-Stimulating Factor
**

250 g 10 µg/kg IV 116.21 0.24 hours

Weight of rat Dose

A1 B1

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. What is ? What is ? What is ? What is your patient's clearance? What is your patient's ? What is your patient's V1? What is a? What is b? What is ? What is ? What is ? What is ? What is the in the peripheral compartment?

99.228 1.27 hours

What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

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11-106

Multicompartment Modeling

Hydrocortisone

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 15)

Derendorf, H., et al., "Pharmacokinetics and oral bioavailability of hydrocortisone", Journal of Clinical Pharmacology, Vol. 31, (1991), p. 473 - 476.

This study looks at both the two-compartment model pharmacokinetics and the oral bioavailability of hydrocortisone. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 15. Hydrocortisone

Dose

20 mg IV 430 13.1 439 0.445

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-107

Multicompartment Modeling

Levodopa

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 16)

Sasahara, K., et al., "Dosage form design for improvement of bioavailability of levodopa II: Bioavailability of marketed levodopa preparations in dogs and parkinsonian patients" Journal of Pharmaceutical Sciences, Vol. 69, (1980), p. 261 - 265.

Levodopa is an agent used in the treatment of Parkinson's disease. This study looks at various dosage forms of levodopa and compares the pharmacokinetic parameters of each. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 16. Levodopa

Dose

50 mg IV 8.63 13.3 2.97 1.14

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-108

Multicompartment Modeling

Meropenem

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 17)

Chimata, M., et al., "Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with end-stage renal disease", Antimicrobial Agents and Chemotherapy, Vol. 37, (1993), p. 229 - 233.

Meropenem is a carapenem antibiotic which has a broad spectrum of activity. It is used in the treatment of infections caused by both Gram-positive and Gam-negative bacteria and is active against Enterobacteriaceae and Pseudomonas aeruginosa. Meropenem is 60% renally and 40% hepatically eliminated.

PROBLEM TABLE 11 - 17. Meropenem

Dose

500 mg IV infusion over 40 minutes 21 1.85 20 0.503

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-109

Multicompartment Modeling

**N-Methylpyridinium-2-Carbaldoxime Chloride
**

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 18)

Bodor, N., and Brewster, M., "Problems of delivery of drus to the brain", International Encyclopedia of Pharmacology and Therapeutics, Vol. 120, (1975)

N-methylpyridinium-2-cabaldoxime chloride (2-PAM) is the drug of choice for the treatment of orgaonphosphate poisoning. It is mostly renally excreted. This article considers the fact that this agent is highly hydrophilic and thus has difficulty reaching the brain. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 18. N-Methylpyridinium-2-Carbaldoxime

Chloride

Weight of dog Dose

40 kg 7.0 mg/kg 5.356 0.28796 35.983 11.586

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-110

Multicompartment Modeling

Pyrazine Diazohydroxide

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 19)

Vogelzang, N., et al., "Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456)", Journal of Cancer Research , Vol. 54, (1994), p. 114 - 119.

Pyrazine diabhohydroxide is an agent which forms a reactive pyrazine dizonium ion in vivo which acts to destroy tumor cells. This study looks at the pharmacokinetic parameters of this agent in advanced cancer patients whose cancer was not curable by any other type of therapy. They were given a dose of 18 mg/m2/day for 5 days every 4 weeks. Most of the following data was collected for a 66 year old male subject. The remaining data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 19. Pyrazine

Diazohydroxide

Patient Body Surface Area Dose

1.82 m2 18 mg/ m2

8063 0.195 1186 0.0257

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-111

Multicompartment Modeling

Terbinafene

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 20)

Kovarik, J., et al., "Dose-proportional pharmacokinetics of terbinafine and its N-demethylated metabolite in healthy volunteers", British Hournal of Dermatology, Vol. 126, (1992), p. 8 - 13.

Terbinafene is an antifungal agent which acts by interfering with ergosterol biosynthesis. It is active against Trichophyton, Epidermophyton, and Microsporum. Approximately 70% of an oral dose is absorbed. Terbinafene has an Ndemethylated metabolite which is active. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 20. Terbinafene

Dose

750 mg 2398 0.511 102 0.0222 -

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-112

Multicompartment Modeling

Verrucarol

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 21)

Barel, S., Yagen, B., and Bailer, M., "Pharmacokinetics of the trichothecen mycotoxin verrucarol in dogs", Journal of Pharmacetuical Seciences, Vol. 79, (1990), p. 548 - 550.

Verrucarol is a toxin which is related to toxins which have anti-tumor activity. This study looks at the pharmacokinetics of verrucarol in dogs. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 21. Verrucarol

Weight of Dog Dose

22.5 kg 0.4 mg/ kg 126.05 0.0415 540.58 0.00946-

A1

a

B1

b

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

REV. 99.4.25

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11-113

Multicompartment Modeling

2-Chloro-2-deoxyadenosine

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 22)

Liliemark, J. and Juliusson, G., "On the pharmacokinetics of 2-Chloro-2-deoxy-adenosine in humans", Cancer Research, Vol. 51, (1991), p. 5570 - 5572.

Two-Chloro-2-deoxyadenosine is an antitumor agent used in the treatment of hairy cell leukemia and other lymphoproliferative diseases. Infusions of 0.14 mg/kg over 12 hours were administered to 12 patients with various lymphoproliferative diseases for 5 consecutive days. The following data was collected:

PROBLEM TABLE 11 - 22. 2-Chloro-2-deoxyadenosine

Patient weight Dose

65 kg 0.14 mg/kg over 12 hours 177.0 nM 1.04 21.0 nM 0.10

A1

a

B1

b

1. 2. 3. 4. 5.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ?

6.

7. 8. 9. 10. 11. 12. 13. 14. 15.

**What is your patient's V1?
**

What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

Basic Pharmacokinetics

Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

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11-114

Multicompartment Modeling

Felodipine

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 23)

Regardh, C., et al., "Pharmacokinetics of felodipine in patients with liver disease", Journal of Clinical Pharmacology, Vol. 36, (1989), p. 473 - 479.

The pharmacokinetic parameters of felodipine in patients with impaired liver function were investigated in this study. Felodipine blocks calcium channels resulting in a decrease in peripheral vascular resistance which subsequently leads to a decrease in blood pressure. Felodipine also works as a diuretic. The bioavailability of felodipine is 15%. It is highly (99.64%) protein bound and is eliminated almost exclusively by liver metabolism. The following data is for a patient with liver cirrhosis:

Weight of dog Dose kg mg/kg IV

A1

a

B1

b

1. 2. 3. 4. 5.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ?

6.

7. 8. 9. 10. 11. 12. 13. 14. 15.

**What is your patient's V1?
**

What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

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11-115

Multicompartment Modeling

Lorazepam

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 24)

Segal, J., et al., "Decreased systemic clearance of lorazepam in humans with spinal cord injury", Journal of Clinical Pharmacology, Vol. 31, (1991), p. 651 - 656.

**Lorazepam is a benzodiazepine which is used as an anxiolytic, an anti-convulsant, an anti-emetic, and a sedative-hypnotic agent.
**

PROBLEM TABLE 11 - 24. Lorazepam

Dose

2.0 mg infused intravenously over 1 - 2 minutes

A1

a

B1

b AUC AUMC

1. 2. 3. 4. 5.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ?

6.

7. 8. 9. 10. 11. 12. 13. 14. 15.

**What is your patient's V1?
**

What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

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11-116

Multicompartment Modeling

Metronidazole

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 25)

Uccellini, D., Morgan, D., and Raymond, K., "Relationships among duration of infusion, dose, dosing interval, and stedy-state plasma concentrations during intermittent intravenous infusions: studies with metronazole", Journal of Pharmacokinetics and Biopharmaceutics, Vol. 14, (1986), p. 95 - 106

PROBLEM TABLE 11 - 25. Metronidazole

Patient weight Dose

70 kg 1.5 g IV infusion

A1

a 2.11

B1

b AUC AUMC 0.09

1. 2. 3. 4. 5.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ?

6.

7. 8. 9. 10. 11. 12. 13. 14. 15.

**What is your patient's V1?
**

What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

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11-117

Multicompartment Modeling

Rhizoxin

Problem Submitted By: Maya Leicht Problem Reviewed By: Vicki Long AHFS 00:00.00 GPI: 0000000000

(Problem 11 - 26)

Graham, M., et al., "Preclinical and phase I studie with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme", Journal of the National Cancer Institute, (1991), p. 494 - 499.

Rhizoxin is a lactone which was obtained from the fungus, Rhizopus chinensis. It has anti-tumor activity against a broad spectrum of tumor types including LOX melanoma, A549 lung tumors, and MX-1 mammary tumors. This study looks at dosing of rhizoxin. Patients with nontreatable tumors who had a life expectancy of more than 12 weeks were given doses of 12 mg/ m2. The following data was approximated from the graph given in this article.

PROBLEM TABLE 11 - 26. Rhizoxin

Patient Body Surface Area Dose

1.82 m2 12 mg/ m2

1.55 4.00 0.12 0.116 -

A1

a

B1

b

1. 2. 3. 4. 5.

What is ? What is ? What is ? What is your patient's clearance? What is your patient's ?

6.

7. 8. 9. 10. 11. 12. 13. 14. 15.

**What is your patient's V1?
**

What is ? What is ? What is ? What is ? What is ? What is ? What is the in the peripheral compartment? What percent of the dose is in the peripheral compartment at equilibrium? Can this drug be treated as a one-compartment model for dosing purposes?

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11-118

Multicompartment Modeling

11.5.1

TWO-COMPARTMENT MODEL EQUATIONS

The following set of equations were used to solve the two-compartment model problem set. The problem sets for the first three drugs have been done for you. The others are done the same way. The answers for all of the problems are in the back of this packet. Aspirin 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Yes The weight of the rat is 275 g or 0.275 kg.

_____________________________________________________________________ Buprenorphine 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

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11-119

Multicompartment Modeling

12. 13. 14. 15. Yes

_____________________________________________________________________ Caffeine 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Yes

11.5.2

Aspirin 1. 2. 3. 4. 5. 6. 7.

ANSWERS

8.019 36.2 31.1 2.62 minutes 155.48 mL 86.92 mL 81.57 mL

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11-120

Multicompartment Modeling

8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

0.648 min 3.47 min 0.598 min-1 0.358min-1 0.314min-1 15.82 1.928 minutes 44.1% Yes 0.381 min-1

Buprenorphine 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 10.54 36.9 47.4 366.8 2.85 hours 1.35 L 0.34 L 0.178 hours 2.58 hours 0.981 h-1 1.075 h-1 2.11 h-1 51 0.736 hours 74.9% No Can't be calculated

Caffeine 1. 2. 3. 2.15 39.57 41.72

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11-121

Multicompartment Modeling

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

7.67 33.35 L 16.28 L 0.141 hours 3.014 hours 2.39 h-1 0.471 h-1 2.266 h-1 19.65 0.655 hours 51.2% Yes

Cefazolin 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 42.73 214.59 257.32 3.89 6.78 L 3.035 L 0.143 hours 1.21 hours 2.163 h-1 1.28 h-1 1.96 h-1 329.44 0.50 hours 55.2% Yes

Ceftazidime 1. 2. 22.87 118.78

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11-122

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

141.65 7.0598 14.41 L 4.06 L 0.0843 hours 1.415 hours 2.32 h-1 1.738 h-1 4.65 h-1 246.2 0.365 hours 39.2% Yes

Clentiazem 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Cocaine 1. 2. 3239.2 10266.7 13.9 207.3 221.2 90.4 1159.2 L 372.5 L 0.257 hours 8.89 hours 0.868 h-1 0.243 h-1 1.67 h-1 53.69 1.35 hours 47.4% Yes

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11-123

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

13505.89 44.43 987.2 mL 367.1 mL 1.91 minutes 15.4 minutes 0.1346 min-1 0.1210 min-1 0.1514 min-1 1634.6 8.35 minutes 59.2% No

1,2-Diethyl-3-hydroxpyridine-4-one 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 15.22 21.39 36.62 375.5 988.2 mL 352.3 mL 0.341 hours 1.824 hours 0.724 h-1 1.066 h-1 0.62 h-1 39.03 1.016 hours 55.4% No

2,2-dimethylaziridine 1. 2. 102.7 89.47

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11-124

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

192.16 1498.7 15.78 L 5.7 L 1.695 minutes 7.296 minutes 0.148 min-1 0.263 min-1 0.093 min-1 50.5 4.65 minutes 56.5% No

Flurbiprofen 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 20.82 329.6 350.42 7.42 42.4 mL 24.5 mL 0.297 hours 3.96 hours 1.35 h-1 0.303 h-1 0.856 h-1 106.18 1.2 hours 42.2% Yes

Furosemide 1. 2. 0.304 0.802

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11-125

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

1.106 19.88 20.71 L 7.67 L 0.1005 hours 0.722 hours 2.55 h-1 2.59 h-1 2.71 h-1 2.87 0.322 hours 62.99% No

Glycyrrhizin 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 21.93 162.56 184.5 29.8 69.33 mL 34.13 mL 0.167 hours 1.61 hours 2.048 h-1 0.873 h-1 1.67 h-1 161.13 0.61 hours 50.8% Yes

Human Deoxyribonuclease 1. 2. 2235.78 21384.3

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11-126

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

23620.1 11.01 48.07 mL 10.77 mL 0.0805 hours 3.027 hours 1.929 h-1 1.0223 h-1 5.89 h-1 24147 0.433 hours 28.9% Yes

Human Granulocyte Colony-Stimulating Factor 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 40.24 181.81 222.05 11.26 20.62 mL 11.6 mL 2.89 h-1 0.546 h-1 1.625 h-1 0.971 h-1 0.839 h-1 215.44 0.711 hours 43.8% Yes

Hydrocortisone 1. 2. 32.8 986.5

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11-127

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

1019.3 19.62 44.1 mL 23.01 mL 0.053 hours 1.56 hours 6.838 h-1 0.853 h-1 5.85 h-1 869 0.267 hours 47.8% Yes

Levodopa 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 0.649 2.61 3.25 15.37 13.48 L 4.31 L 0.052 hours 0.61 hours 4.25 h-1 3.56 h-1 6.62 h-1 11.6 hours 68.0% Yes

Meropenem 1. 2. 11.35 39.76

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11-128

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

51.11 9.78 19.45 L 12.20 L 0.375 hours 1.378 hours 1.16 h-1 0.802 h-1 0.391 h-1 41 0.967 hours 37.3% No

N-methylpyridinium-2-carbaldoxime chloride 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. ?14. 15. 18.6 3.106 21.71 12.9 1.11 L 6.77 L 2.41 hours 0.0598 hours 1.752 h-1 1.905 h-1 8.218 h-1 41.339 0.327hours 45.5% Yes

Pyrazine Diazohydroxide 1. 2. 41348.7 46147.9

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11-129

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

87496.6 0.3744 14.57 mL 3.542 mL 3.55 minutes 26.97 minutes 0.0474 min-1 0.106 min-1 0.0676 min-1 9249 11.97 minutes 75.7% No

Terbinafene 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 4692.8 4594.6 9287.4 80.75 3637.6 L 300 L 1.36 h 31.2 h 0.0421 h-1 0.2692 h-1 0.222 h-1 2500 6.42 hours 91.8% No

Verrucarol 1. 2. 3037.35 57143.8

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11-130

Multicompartment Modeling

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

60181.1 149.5 15.81 L 13.5 L 16.7 minutes 73.3 minutes 0.0155 min-1 0.0253 min-1 0.0101 min-1 666.63 46.15 minutes 28.1% Yes

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11-131

- 6. Pharmacokinetics and Pharmacodynamics
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