RE: Absorption

Adithya, Let the data tell you what model to use/try. Below are things that I personally looked at before or I've seen colleagues of mine at SPRI try: Look at linearity of Cmax and AUC (from noncompartmental data). Based on your description, Cmax is ~ 3-6 folds less than what you expect from dose proportionality. Does AUC behave the same way? if yes, then your issue is in F (bioavailability) and may be also absorption rate (ka). If AUC is linear but Cmax is not then it's an absorption rate issue and not bioavailability. If the issue is with rates only, play with Ka (saturable absorption, different ka with dose (if not an issue), etc). If the issue is Cmax and AUC with the same magnitude, then you have to look for a model describing nonlinear F and may be V/F. If the nonlinearity issue is in Cmax and AUC at different magnitude, most likely you'll have to have nonlinear models on both F and ka. Look at tmax, does it shift from e.g. 1hr to 3hr going from lower to higher doses. Do the PK profiles (at higher doses) look like ones with a sustained release formulation? Do the peaks for those profiles look more "flat" compared to the ones at lower doses? If tmax shifts, you may have gastric emptying/GI transit time playing a role and you may have to add a time dependency in ka and/or F in addition to the combined zero/first order models. Simpler things to try include: Look at individual V and Cl values, sort by dose group, do you see a trend? if yes, then you know that NonMem is trying to force the nonlinearity on V and Cl instead of F and ka: One thing that a colleague of mine tried at SPRI and worked for him: Fix V and this will force nonmem to recognize the differences in F and/or ka between dose groups. Regards, Malaz