Abstract 3224: Preclinical PKPD modeling and human dose projection of PF-04691502, a PI3K/mTOR dual inhibitor

Abstract

Abstract PF-04691502 is a potent dual inhibitor of PI3K and mTOR, which are involved in regulating cell growth, proliferation and survival. The main objective of this work was to develop a preclinical pharmacokinetic-pharmacodynamic (PKPD) model for the compound and project the human efficacious dose. The PK of PF-04691502 in mouse obtained following oral dosing was described by a linear 2-compartment model which was used to drive two separate PD models: 1) an exponential growth model describing the tumor growth inhibition (TGI) and 2) an indirect-response model describing changes in intratumoral pAKT-S473/AKT in the U87MG xenograft mouse model. Based on the PK model, the half-life calculated from the linear elimination constant (k = 0.306 hr−1) was 2.3 hr and the plasma-compartment volume of distribution was 8.72 L/kg. The inter-compartmental distribution rate constants were 0.282 hr−1 and 0.212 hr−1 for k12 and k21, respectively. The model estimated in-vivo potency (IC50) for pAKT-S473/AKT suppression was 38.3 nM which was within the range of the IC50 (23 nM) for TGI (as parameterized by the model). The Imax estimated from the model was 0.975 (or 97.5%), which indicated nearly complete suppression of pAKT-S473/AKT production rate by PF-04691502. Based on the PKPD model and the scaled human PK, a clinical dose of 10 mg QD was determined to be adequate for maintaining the level of pAKT-S473/AKT below 50% of baseline. At steady-state PK this dose yielded a range of 50-80% human pAKT-S473/AKT suppression over the 24 hr dosing interval. In conclusion, PF-04691502 was determined to have a robust PKPD relationship in the preclinical animal model and was projected to have a clinically achievable efficacious dose of approximately 10 mg QD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3224.