From: "Vipul Gupta"
Subject: [NMusers] Multiple dose analysis using NONMEM
Date: Mon, 10 Jul 2006 00:40:55 -0400

Hi All,
I am trying to analyze a multiple dose oral PK data using NONMEM. The drug is given
on 12 h dosing interval for over 30-40 weeks. There are 10-12 sampling points
available in first 24 h and then one peak and one trough sample is available
until the last dose.  Following last dose, 10-12 data points are available for next 24 h.

A comparison of first and last dose PK profile indicates a one compartment model
with decrease in Cl.  The drug is known to cause auto inhibition of its metabolism
over time. Data is available only for the parent drug and no information on F is available.

My question is :
I am not aware of how the changing clearance with time can be modelled using
NONMEM ? Any inputs will be appreciated.

Thank you

Vipul Kumar
Post Doc Fellow
Department of Pharmaceutics
Univ of Florida, Gainesville.

From: "Anthe Zandvliet"
Subject: RE: [NMusers] Multiple dose analysis using NONMEM
Date: Mon, 10 Jul 2006 10:37:52 +0200

Dear Vipul,

Please take a look at the references below. Iphosphamide and
cyclophosphamide autoinduction have been modeled using an enzyme
turnover model. In these models, the elimination of the hypothetical
enzyme is decreased during exposure to iphosphamide or cyclophosphamide.
In order to model autoinhibition, you may consider using this model with
a decreased input of the enzyme during drug exposure. Various effect
functions are possible (e.g. iphosphamide: Emax,


Kerbusch T, Huitema ADR, Ouwerkerk J, et al: Evaluation of the
autoinduction of ifosfamide metabolism by a population pharmacokinetic
approach using NONMEM. Br J Clin Pharmacol 49:555-561, 2000
de Jonge ME, Huitema ADR, Rodenhuis S, et al: Integrated Population
Pharmacokinetic Model of both cyclophosphamide and thiotepa suggesting a
mutual drug-drug interaction. J Pharmacokinet Pharmacodyn 31:135-156,

Anthe Zandvliet
Slotervaart Hospital
Dept. Pharmacy and Pharmacology
Louwesweg 6
The Netherlands
Telephone +31 20 512  4657
FAX +  31  20 512 4753

From: Justin Wilkins
Subject: Re: [NMusers] Multiple dose analysis using NONMEM
Date: Mon, 10 Jul 2006 13:28:48 +0200

Dear Anthe & Vipul,

The original question related to autoinhibition rather than
autoinduction, I guess, but an enzyme turnover model could still be
adapted to work in the way suggested. One could also consider other
semi-mechanistic ways of dealing with the problem as well, such as a
competitive interaction model, for example - but I've never seen one in

There's another published example of an enzyme turnover model in

Hassan M, Svensson US, Ljungman P, Bjorkstrand B, Olsson H, Bielenstein
M, Abdel-Rehim M, Nilsson C, Johansson M, Karlsson MO. A mechanism-based
pharmacokinetic-enzyme model for cyclophosphamide autoinduction in
breast cancer patients. Br J Clin Pharmacol. 1999 Nov;48(5):669-77.

Here, amount of drug in the central compartment increases the rate of
production of enzyme in the enzyme compartment (rather than its rate of
elimination) while the amount of enzyme in the enzyme compartment, in
turn, increases clearance of the drug from the central compartment. This
seems, to me, to be more mechanistically appropriate than the approaches
mentioned earlier.


Justin Wilkins, PhD
Division of Pharmacokinetics and Drug Therapy
Department of Pharmaceutical Biosciences
Uppsala University
P.O. Box 591
SE-751 24 Uppsala
Work:   +46 18 471 4304
Mobile: +46 768 506 606
Fax:    +46 18 471 4003

Subject: Re: [NMusers] Multiple dose analysis using NONMEM
Date: Tue, 11 Jul 2006 20:02:56 -0400

Dear Vipul,

I would like to suggest a look at the following paper:

Gordi T, Xie R, Huong NV, Huong DX, Karlsson MO, Ashton M.: A
semiphysiological pharmacokinetic model for artemisinin in healthy
subjects incorporating autoinduction of metabolism and saturable
first-pass hepatic extraction. Br J Clin Pharmacol. 2005 Feb;59(2):189-98

where we modeled the autoinduction of artemisinin using saliva samples,
allowing drug liver amounts to increase the production rate of an enzyme
precursor compartment. Enzyme amounts were then correlated directly to
the CLin, which using a well-stirred model, resulted in increased
extraction degree (EH) of the compound. EH was then related to both
total CL and F. The model can be applied to other conditions, such as
autoinhibition or changes in f due to displacement. 

The model performed satisfactorily when applied to another set of
limited saliva data (Gordi T, Xie R, Jusko WJ. Br J Clin Pharmacol. 2005
Dec;60(6):594-604) and has done very well in describing the
autoinduction of artemisinin in plasma samples from 6 previous studies
(manuscript under way).  

Toufigh Gordi