Re: Absorption

On 9/4/07, Abutarif, Malaz <[EMAIL PROTECTED]> wrote: > > Dear, > I may be missing something here. If the data is dose proportional for Cmax > and AUC, why are you trying to fit a nonlinear model in ka and/or F? > If you have much higher variability (higher CV%) at the higher doses, then > I would try using a different eta for the higher doses. > > A saturable first pass model will mean a nonlinear (higher than expected > concentrations/exposures) at larger doses. If your data says that you do not > have higher than dose proportional Cmax and AUC, I don't see why you would > think there is a satruable first pass? > Malaz > > > -----Original Message----- > *From:* [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] > *On Behalf Of *Adithya Muralidharan > *Sent:* Tuesday, September 04, 2007 3:26 PM > *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.Ihave > 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 > > > > > ********************************************************************* > This message and any attachments are solely for the > intended recipient. If you are not the intended recipient, > disclosure, copying, use or distribution of the information > included in this message is prohibited -- Please > immediately and permanently delete. > >