- On 3 Jun 2004 at 14:20:09, Guru Murthy (gurudasmurthy.aaa.yahoo.co.in) sent the message
Hello David and all,

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I am practically a novice to pharmacokinetics. Now suddenly I am

required to apply pharmacokinetic knowledge to a real life situation

and I am not sure whether i am getting it right. I have the

concentration-time profile of a drug after a 50 mg dose. 50 mg of the

drug is taken every 8 hrs. I have the half life reported and the AUC.I

need to find out the absorption rate constant and the volume of

distribution. For the Volume of distribution as I understand the

bioavalability factor( fraction of drug absorbed) is necessary but I

dont have it so I assumed it is 1. For the absoption rate constant I

tried Wagner nelson method and method of residuals but I am not getting

the correct fit lines. I suspect that the drug may not be behaving in a

one compartment model or it may have slow distribution rate. I

reproduce the concentration -time data. Please try to work out the Ka

and the Vd.

The data is as follows

Dose of drug: 50 mg

Dosing interval: 8 hrs

Half life reported: 6 hrs

AUC after 50 mg dose: 0.75 mcg.hr/ml

Conc-time data

Time (hr) Conc(mcg.ml)

0.25 0.048

0.5 0.269

1 0.216

20.111

4 0.044

6 0.025

8 0.017

12 0.011

24 Not detected

PLEASE HELP ME

Guru - On 3 Jun 2004 at 23:39:48, "Kazimierz H.Kozlowski" (khkoz.at.czd.waw.pl) sent the message
Dear Dr Guru,

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I hope that the data are after first test oral dose. I have used

2-compartment model with lag-time and exponential

error model (not multiple oral dose).

Objective function=-103.386 NONMEM (ADVAN8)

KA=9.61 (+/-0.938) 1/hr

ALPHA=0.761 (+/-0.035) 1/hr

BETA=0.106 (+-0.008) 1/hr

K10=0.448 (+-0.013) 1/hr

V1=151 (+-3) L

Tlag=0.234 (+- 0.012) hr

K12/K21=0.239/0.181

MODEL PREDICTION CP(MCG/ML)

fitted 0.048, 0.269, 0.212, 0.114, 0.044, 0.025, 0.018, 0.011

measured 0.048, 0.269, 0.216, 0.111, 0.044, 0.025, 0.017, 0.011

sincerely

Kazimierz H. Kozlowski

The Childrens Memorial Health Institute

Warsaw, Poland

E-mail: khkoz.-at-.czd.waw.pl - On 4 Jun 2004 at 09:18:59, "TRANCHAND Brigitte" (Brigitte.TRANCHAND.aaa.adm.univ-lyon1.fr) sent the message
Actually it is not a one comp model for the decreasing phase, but two

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comp. Moreover it is surprising to observe a conc of 0.011 at 12h when

the drug is delivered every 8 hours, and taking into account that I

found a lag-time of about 0.25h.

Please find in attachment a fit which looks not so bad, except for the

conc-time point of 12.

Hope this can help

Dr Brigitte Tranchand

Lab de Bact\0xC8riologie

Fac M\0xC8decine Lyon-Sud

BP12

69921 OULLINS Cedex

France

Tel 33 4 78 86 31 53

Fax 33 4 78 86 31 49

e-mail : Brigitte.Tranchand.-at-.adm.univ-lyon1.fr

[Sorry but attachments are not allowed in PharmPK messages - db] - On 4 Jun 2004 at 12:51:20, "Hans Proost" (j.h.proost.-a-.farm.rug.nl) sent the message
Dear Guru,

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From your data I calculated parameters almost similar to that reported

by

Kazimierz Kozlowski. The only relevant difference is in the standard

errors;

my own program (MultiFit) gives about two times higher values. This is

probably a result of the fact that my program uses a 'conservative'

estimate

for the residual error, taking into account the low degrees of freedom

of 2,

i.e. 8 measurements minus 6 parameters. I do not know how this is

handled in

NONMEM. I hope that others may comment upon this difference.

A further comment refers to the interpretation of the three rate

constants ka, alpha, and beta. Actually, the analyis results in two solutions with identical predicted plasma concentration profiles, but with different

parameter sets. In this case, the values of ka and alpha could be

interchanged (with corresponding changes in Vd, k10, k12, and k21; in

contrast, clearance is not affected). Without further knowledge it is

not possible to make a selection between both solutions. By convention, most

programs provide values where ka, alpha, and beta are have a decreasing

magnitude, but there is no obvious reason why this would be always the

case. The argument that absorption is usually fast compared to elimination is

reasonably, but this does not apply to distribution kinetics, so ka is

not necessarily larger than alpha.

In one-compartment kinetics this phenomenon is usually called

'flip-flop', and often regarded as a 'special case'. Please note, however, that

there are always 2 solutions for any concentration profile after extravascular

dosing, analysed with an exponential model with first-order absorption.

Best regards,

Hans Proost

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Antonius Deusinglaan 1

9713 AV Groningen, The Netherlands

tel. 31-50 363 3292

fax 31-50 363 3247

Email: j.h.proost.-a-.farm.rug.nl - On 6 Jun 2004 at 13:29:51, Walt Woltosz (walt.aaa.simulations-plus.com) sent the message
At 06:20 AM 6/3/2004, Guru Murthy wrote:

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"Please try to work out the Ka and the Vd."

Guru,

You have received several responses to your request. I hope they have

been helpful.

However, I cannot sit by and ignore that an underlying assumption is

being made that is incorrect.

Ka is a coefficient, not a constant. It changes with time, because it

changes in any one location with concentration difference across the

apical membrane and with location in the gut. Constant Ka is a

simplifying assumption that can be useful when a drug is absorbed

rapidly in the upper small intestine. It can also be misleading when a

compound is absorbed over a longer period of time and in the colon.

Our experience is that numerous compounds exhibit strong regional

dependence of permeability, in addition to the natural change in

absorption rate produced by changes in the concentration difference

across the apical membrane of the enterocytes. In GastroPlus, we

provide a calculation of the instantaneous Ka value that would be

needed to use the traditional relationship of absorption rate being

calculated as Ka * Mass in solution. The instantaneous "net Ka" can be

back-calculated from the more correct Fick's First Law absorption model

used in each of the 8 intestinal compartments, allowing for the

changing concentration in the enterocytes as well as the changing

concentration in the various gut compartments as transit, dissolution

and permeability combine to produce such changes.

The result is a net Ka that varies from zero at time zero (no

concentration gradient until the drug is introduced into the first

absorbing compartment), with a rapidly rising value to a peak typically

at 0.5-2 hours, then decreasing over the next 2-10 hours (depending on

the drug).

If all you want to predict is overall Fa, an average value can be

used. But it's like taking AUC/t to get an average concentration - it

can be very misleading when it comes to predicting the actual time

course of absorption, and hence plasma concentration-time.

Walt Woltosz

Chairman & CEO

Simulations Plus, Inc. (AMEX: SLP)

1220 W. Avenue J

Lancaster, CA 93534-2902

U.S.A.

http://www.simulations-plus.com

Phone: (661) 723-7723

FAX: (661) 723-5524

E-mail: walt.at.simulations-plus.com

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