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QUANTITATIVE CLINICAL PHARMACOLOGY

Model-Based Development of a PPAR{gamma} Agonist, Rivoglitazone, to Aid Dose Selection and Optimize Clinical Trial Designs

Shashank Rohatagi, PhD, Timothy J. Carrothers, ScD, JinYan Jin, PhD, William J. Jusko, PhD, Tatiana Khariton, PhD, Joseph Walker, PharmD, Kenneth Truitt, MD and Daniel E. Salazar, PhD

From Daiichi Sankyo Pharma Development, Edison, New Jersey (Dr Rohatagi, Dr Walker, Dr Truitt, Dr Salazar); Pharsight Corporation, Mountain View, California (Dr Carrothers, Dr Khariton); and Department of Pharmaceutical Sciences, SUNY/Buffalo, Buffalo, New York (Dr Jin, Dr Jusko).

A model-based approach was implemented for the development of the proliferator-activated receptor gamma (PPAR{gamma}) agonist rivoglitazone. Population pharmacokinetic and pharmacodynamic models were developed using data collected from 2 phase I and 2 phase II studies in healthy volunteers and participants with type 2 diabetes mellitus. A 2-compartment model with first-order absorption and elimination and an absorption time lag best described rivoglitazone pharmacokinetics. Modified indirect-response models were used to characterize changes in fasting plasma glucose, HbA1c, and hemodilution as a function of rivoglitazone plasma concentrations. In addition, differences in hemodilution among participants correlated with the incidence of edema. Current use of oral antidiabetic medication was a significant covariate for the fasting plasma glucose-HbA1c exposure-response model. Using a learn-and-confirm process, models developed prior to the second phase II study were able to make valid predictions for exposures and response variables in that study. In future studies, seamless designs can be supported by models such as those developed here.

Key Words: Population pharmacokinetics • rivoglitazone • pharmacodynamics • learn and confirm • exposure response

Address for reprints: Shashank Rohatagi, PhD, MBA, Fellow FCP, Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837; e-mail: Srohatagi{at}dsus.com.


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