From: "atul" <>
Subject: Integrator options
Date: Sun, 14 Oct 2001 11:28:55 -0700

Hello All

Could everybody share their views on this?

I am using a regression program called SCIENTIST for analysis of PKPD data set. The software has interestingly six different integrator options:
1. Euler
2. Simple runge kutta
3. Error controlled runge-kutta
4. Burlisch-Stoer
5. Episode (Adams)
6. Episode (Stiff)

For a simple data set (Pharmacokinetics etc) the Eulers method works fine. But when I am analysing a PKPD model which is relatively complicated (disease progression/disease reversal) with effect of drug and indirect response model. I find that Eulers method is not working well. The estimates touch values as low as E-16 or as high as E+05. The simplex procedure works but the Least Squares Estimation which I suppose is based on these methods is behaving strangely with Eulers method. There is no problem with a simple PKPD model or a simple indirect response model with Eulers method but inclusion of a disease progression makes it behave strangely. I then tried the Simple runge Kutta option and it is working very well. The estimates make much meaning and although it is very slow it still converges. If I use a episode (stiff) the starting values do not change at all and the program terminates.

Can I use the runge kutta method? How can I decide if the estimates by this method are reliable in comparison to Eulers? I wish now to transfer my model to NONMEM. How can NONMEM be different here?

Thanks in advance for your time






From: "Sam Liao" <>
Subject: Re: Integrator options
Date: Sun, 14 Oct 2001 18:16:53 -0400

Hi Atul:

You will not have this knid of problem if you switch to NONMEM. This is typical problem when you are working with disease progression in which you have DE intgration over a long period of time. In my expereience, both NONMEM and WinNonMix can handle this very well.

"You can try ADVAN8 and/or ADVAN9 instead of ADVAN6; either of these is better able to handle stiff systems of differential equations." quoted from Alison (NONMEM usersnet archive)

Best regards,

Sam Liao, Ph.D.
PharMax Research
270 Kerry Lane,
Blue Bell, PA 19422
phone: 215-6541151
efax: 1-720-2946783