Improved absorption profile by forcing volume of the central compartment

Dear NM-users, Currently I am working on the PK data of a drug that is taken twice daily orally. I have full AUC data from 45 individuals with 10 samples per individual over a 12-hour period and abbreviated AUC data from 99 individuals with 5 samples per individual over a 2-hour period. Individual plots and literature demonstrate that a 2-compartment PK model with first order absorption and elimination and with a lagtime should adequately describe the data. To model the data I used ADVAN4 TRANS4 with FO and a combined error model. Problems occur with fitting the absorption phase of the drug, which results in a structural underestimation of the peak concentration. Plots of predicted versus observed concentration showed deviations from the line of unity. Application of transit-compartments (Erlang) and more flexible absorption profiles (eg Weibull) did not solve this problem. However the fit could be improved by forcing the volume of the central compartment to higher values, which resulted in higher Ka values, higher peak concentrations, better individual plots in Xpose, but an increase of the objective function. What could be the possible reasons for these observations? Is it appropriate to fix the distribution volume to higher values which produce better goodness-of-fit plots but higher minimum objective function values? Thanks in advance for your time. Brenda de Winter -- /B.C.M. de Winter Erasmus Medical Center Department Hospital Pharmacy Unit Clinical Pharmacology Room L-056 's-Gravendijkwal 230 3015CE Rotterdam the Netherlands T +31 (0)10 46 33202 F +31 (0)10 43 66605 [EMAIL PROTECTED] /