Xuejun Chen, Suresh Mallikaarjun, Steven L. Bramer
Otsuka Maryland Research Institute, 2440 Research Blvd., Rockville, MD 20850
Purpose: The PK of compound X appeared to be nonlinear with Cmax increasing less than proportionally with increasing of dose. The goal of this study is to explore the approach to modeling drugs showing nonlinearity of Cmax to increasing doses.
Methods: 197 subjects dosed with 5-250 mg oral administration of compound X contributed to the 3775 data samples were analyzed. In order to model the less than proportional increase in plasma concentrations, several approaches were attempted: 1) absorption process consisting of first order of absorption and then zero-order of absorption after certain dose; 2) expressing ka as Michaelis-Menten function of dose; 3) determining the inflection point for nonlinearity. These methods were evaluated by examining the objective function and goodness of fit.
Results: The first two approaches provided physiological relevance to the pharmocokinetic interpretation of the nonlinear PK of compound X. However, the best model, splitting pharmacokinetic parameters by dose, provided best fit to the pooled data.
Conclusions: For drugs exhibiting less than proportional increases in Cmax, splitting pharmacokinetic parameters based upon the inflection point provides an alternative approach.
Reference: PAGE 12 () Abstr 434 [www.page-meeting.org/?abstract=434]
Poster: poster