RE: Absorption

-----Original Message----- From: [EMAIL PROTECTED] on behalf of Adithya Muralidharan Sent: Tue 04/09/2007 15:25 To: [EMAIL PROTECTED]; [email protected] Subject: Re: [NMusers] Absorption Dear Justin, I did look into dose normalized concentrations-time curve and i do not see any nonlinearity in PK except for a couple of subjects who appear to be outliers. I did try to run transit model with FOCE in NM6 but it runs for a long time and results in terminated message. I did look into Rada's previous abstarct and tried to use it for single dose but had no luck. I have around 8 observations in the absorption phase and 6 in the elimination phase.I have mailed you the code i used for my model Dear Malaz, Thanks for your tips, i did look into the dose linearity early on the drug appears to be dose proportional on both AUC and Cmax. There is definitely a shift in Tmax from 1 hour in lower doses to 6 hours in higher doses but this drug has low solubility so i assumed that this was inherent characteristic of the drug so i used a combination Zero-First order model to address this issue but that was not good enough. At higher doses i have 3 subjects who have much higher concentrations leading to Cmax unlike other subjects in the same dose group. I tried to remove these three subjects to see whether they were impacting the model but it appears that they have no effect on the model. I tried fixing volume but even that doesnot answer the anomaly of the model at higher doses. This drug is a 3A4 substrate so i am assuming that may be there is a saturable first pass effect observed at higher doses. In trying to address this i used a dose varying absorption model as KA=KAMAX*DOSE/KA(50)+DOSE. when i run with this NONMEM returns to me the same set of intial conditions in other words the same intial condition value is returned as final estimate. Could anyone please advice on how to model saturable first pass effect. Thanks to all Adithya On 9/4/07, [EMAIL PROTECTED] <[EMAIL PROTECTED]> wrote: > > > Dear Adithya, > > Your problem has attracted some good advice from the list, but if you are > still interested in trying out the transit model, perhaps we could help, if > you were able to furnish some more details about what exactly went wrong > with your implementation of it in NONMEM V - posted code snippets and > precise error messages would be of particular use. > > It ought to be possible to make it work under NMV, although the richer the > data, the better, and NMV is known to be less robust at working with > differential equations than NMVI. Problems can often be resolved with some > minor tweaking, given sufficient information in the data to support the > model - how many observations per individual are you working with, and how > well covered is the absorption phase? You might also try hard-coding the > transit compartments, i.e. not estimating the number as a model parameter, > but fixing it to different values until you find an optimum. > > You might also want to take a look at some previous work on the subject, > in which the method was established for single dosing: > > Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13 (2004) Abstr 513 [ > www.page-meeting.org/?abstract=513] > > Have you tried normalizing the concentrations by dose and plotting them on > the same axes? That should give you information with respect to whether you > have any dose-related nonlinearity - if the curves for each dose levels are > roughly superimposed, kinetics are linear, and if not, the relative > positions of the curves should provide some useful clues about what is going > on. > > Best regards > Justin > *Justin Wilkins > Novartis Pharma AG** > PH346, MODELING & SIMULATION* > CHBS, WSJ-027.1.084 > Novartis Pharma AG > Lichtstrasse 35 > CH-4056 Basel > Switzerland > Phone: +41 61 324 6549 > Fax: +41 61 324 3039 > Mobile: +41 76 561 0949 > Email : [EMAIL PROTECTED] <[EMAIL PROTECTED]> > > > > *"Adithya Muralidharan" <[EMAIL PROTECTED]>* > Sent by: [EMAIL PROTECTED] > > 03.09.2007 19:10 > To > [email protected] cc > Subject > [NMusers] Absorption > > > > > Dear nmusers, > > I am working on a rising single dose study, with 5 cohorts (10, 25, > 50, 100 and 200 mg dose groups). This is a oral drug. There are a > total of 45 subjects in the study, 9 subjects in each cohort. > > The data fits well to a two compartment model, but at higher doses 100 > and 200mg dose groups the concentrations leading to Cmax is > overpredicted significantly that the model seems to be completely > ineffecient in explaining the absorption phase at higher doses. > > I have tried using a > > Mixture model assuming that there is a sub population with a totally > different absorption, this seemed to work but visual predictive check > failed. > > Used a cobination zero and first order absorption model which couldn't > fix the issue at higher doses > > Transit compartment model (A flexible approach to modeling variable > absorption in the context of repeated dosing: illustrated with > rifampicin, J. Wilkins, Page 2007). This approach did not work with > NONMEM V. > > i assumed that the drug at higher doses has saturable absorption but > even that does not help much. > > Can someone please comment on this. > > Thanks > Adithya > >