NONLINEAR MIXED EFFECTS MODELING OF SINGLE-DOSE AND MULTIPLE-DOSE DATA FOR AN IMMEDIATE-RELEASE (IR) AND A CONTROLLED-RELEASE (CR) DOSAGE FORM OF ALPRAZOLAM

Purpose. NONMEM was applied to single dose and multiple dose bioavaila bility data for an immediate release (IR) and a controlled release (CR ) dosage form of alprazolam to acquire additional information from the data which are not easily obtainable by traditional means. Methods. T he objective function value (OBJ) and diagnostic plots were used as me asures of goodness of fit of the model to the data. A change in the OB J value of 7.9 was necessary to show statistical significance (p < 0.0 05) between two models when the two models differed by 1 parameter. Re sults. A two-compartment linear model with first-order absorption and elimination best describes the data. Including a lag time, two differe nt rates of absorption (KA(IR) and KA(CR)), and bioavailability for th e CR relative to the IR dosage form significantly improved the fit of the model to the data. Cigarette smoking was associated with a 100% in crease in clearance of alprazolam as compared to non-smokers. The high er residual variability observed in this study, where interoccasion va riability (IOV) was not initially modeled, could be explained to a lar ge extent by the presence of significant interoccasion variability (IO V). Conclusions. Since alprazolam has been suggested to be mainly meta bolized by the CYP3A4 isozyme in humans, it appears that tobacco could be an inducer of CYP3A4 and/or alprazolam may be metabolized by other isozyme(s) (specifically, CYP1A1/1A2) that are induced by cigarette s moke. The population pharmacokinetic model approach combined with expl oratory graphical data analysis is capable of identifying important co variates from well-controlled ''data rich'' Phase I studies early in d rug development.