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