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Re: target-mediate model: numerical difficulties

From: Jurgen Bulitta <jbulitta>
Date: Fri, 19 Sep 2008 22:18:45 +0200

Dear Pavel,

two initial thoughts:

1) Maybe run a sensitivity analysis in simulation
mode and assess if you really need to describe the
exact time course of the fast process. If not, then one
option might be to fix one of the non-influential parameters.

2) Try to find the steady-state solution for the fast
process and plug it in either directly as equation into
the differential equation block. NONMEM has also
special steady-state routines (see SS6 SS9 and ADVAN9
in the NONMEM help) which may be of help for you.

Below are two specific and two more general references
which seem very relevant.

All the best
Juergen


-----------------------------------------------
Jurgen Bulitta, PhD
Infectious Disease - Pharmacometrics
University at Buffalo, NY, USA
Phone: +1 716 645 2855 ext. 281
Fax: +1 716 645 3693
Email: jbulitta
-----------------------------------------------

References:

Mager DE, Krzyzanski W.
Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediat=
ed drug disposition.
Pharm Res. 2005 Oct;22(10):1589-96. Epub 2005 Sep 22.

Abraham AK, Krzyzanski W, Mager DE.
Partial derivative-based sensitivity analysis of models describing target-=
mediated drug disposition.
AAPS J. 2007 Jun 8;9(2):E181-9.


I am sure, you have those two:

Mager DE, Jusko WJ.
General pharmacokinetic model for drugs exhibiting target-mediated drug di=
sposition.
J Pharmacokinet Pharmacodyn. 2001 Dec;28(6):507-32.

Mager DE.
Target-mediated drug disposition and dynamics.
Biochem Pharmacol. 2006 Jun 28;72(1):1-10. Epub 2006 Feb 15. Review




-----Ursprüngliche Nachricht-----
Von: <nonmem
Gesendet: 19.09.08 21:40:46
An: nmusers
Betreff: [NMusers] target-mediate model: numerical difficulties



Hello NONMEM users,

 I am working on some target-mediated models. It is necessary to use
ADVAN8 because differential equations describe very fast and very
slow processes. The models run if I use option SLOW. If I do not use
SLOW, different models for different drugs fail. The message is

0PROGRAM TERMINATED BY OBJ
 ERROR IN NCONTR WITH INDIVIDUAL 4 ID=XXXXXXXX
 NUMERICAL HESSIAN OF OBJ. FUNC. FOR COMPUTING CONDITIONAL ESTIMATE
 IS NON POSITIVE DEFINITE
 MESSAGE ISSUED FROM ESTIMATION STEP
 AT 0TH ITERATION, UPON EVALUATION OF GRADIENT WITH RESPECT TO OMEGA
0TRY SUBSTANTIALLY INCREASING "INITIAL ESTIMATE OF SIGMA"
 OR DECREASING "INITIAL ESTIMATE OF OMEGA"

I tried to increase sigma, decrease omega, change the initial
estimates, use different data and models. Nothing works. Is there a
way around it? Option SLOW makes everything too slow.

Thanks!
Pavel



Received on Fri Sep 19 2008 - 16:18:45 EDT

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