Population PK Modeling of drugs exhibiting less than proportional increases in pharmacokinetics relative to increasing doses
Xuejun Chen, Suresh Mallikaarjun, Zhao Wang, Steven L. Bramer
Otsuka Maryland Research Institute, 2440 Research Blvd., Rockville, MD 20850
Purpose: To explore the approach to modeling drugs exhibiting less than proportional increases in pharmacokinetics relative to increasing doses.
Methods: Data from 11 studies in healthy volunteers, with doses ranging from 5mg to 240mg of compound X, were used for a population PK analysis using NONMEM. The PK of compound X appeared to be nonlinear with Cmax and AUC increasing less than proportionally with increasing of dose. In order to model the less than proportional increase in plasma concentrations, several approaches were attempted: 1) expressing ka as function of dose; 2) expressing ka as step function of dose; 3) determining the inflection point for nonlinearity. These were evaluated by examining the objective function and diagnostic plots.
Results: Objective functions are 34800 for expressing ka as function of dose, 33725 for expressing ka as step function of dose and 33620 for determining the inflection point of nonlinearity respectively. Splitting pharmacokinetic parameters by dose best described the nonlinear PK of compound X.
Conclusions: For drugs exhibiting less than proportional increases in pharmacokinetics, the best model describing compound X is to split pharmacokinetic parameters based upon the inflection point.