Population Modeling to Guide Phase 3 Dose Selection for AC2993 (Synthetic Exendin-4)
Introduction. AC2993 is a novel glucose lowering agent for the treatment of patients with type 2 diabetes.
Methods. Population PK and PK/PD models were developed for AC2993 using subject data from four Phase 2 trials evaluating subcutaneous injections of 0.02-0.4 µg/kg administered QD, BID, or QID. The models simulated the relationship between plasma glucose and drug exposure (AUC0-5hr) to select a fixed dose (not normalized to bodyweight) that balances efficacy and dose-related nausea.
Results. The resultant PK model was a one-compartment model with dose-dependent first-order absorption. Clearance was related to weight and bilirubin, although the latter relationship was based on few subjects. Weight explained 5.5% of the inter-individual variability of clearance. The PK/PD model was an inhibitory Emax model, with the maximum reduction in glucose AUC expressed as % of the placebo glucose AUC. For the simulations, the target range for AC2993 exposure was 600-950 pg*hr/mL, to balance glucose-lowering effects with dose-related nausea. The glucose response target was at least a 20% reduction in glucose AUC0-5hr. Simulations of 10 clinical trials (100 subjects; 50-
120kg bodyweight) using 5, 9, 10, and 12 µg doses predicted the % of subjects above the target exposure range (associated with increased nausea) to be 0, 15, 23, and 51, respectively. The % of subjects under/above 20% glucose reduction were predicted to be 39/61, 24/76, 23/77, and 20/80, respectively.
Conclusion. Overall, these results support the selection of a 5 µg and 10 µg dose for Phase 3 evaluation.
American Society for Clinical Pharmacology and Therapeutics (ASCPT); Atlanta, Georgia; March 2002
By Luann Phillips, M. Fineman, K. Taylor, A. Baron, Elizabeth Ludwig, Thaddeus H Grasela