Abstract #5443: Pharmacokinetics (PK) of PF-04929113 (SNX5422), an orally bioavailable heat shock protein 90 (Hsp90) inhibitor after single and multiple dose administration in patients with refractory solid tumor malignancies

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Introduction: Hsp90 inhibitors have the potential for broad anti-cancer effects based on the spectrum of known client proteins and increased effect on mutations that drive malignant transformation and cancer growth. PF-04929113 (SNX5422; 113) is a novel, oral, non-antibiotic, selective Hsp90 inhibitor prodrug, with preclinical anti-tumor activity in multiple tumor models and is a potentially important cancer therapy. The objective of this analysis was to describe the PK of 113 and its active moiety (PF- 04928473 /SNX2112; 473) after oral administration in patients with refractory solid tumor malignancies. Methods: Twenty-two subjects were enrolled in a multi-center, Phase 1, open-label, dose-escalation study. Subjects were treated with113 QOD for 21 days at doses ranging from 4 to 56 mg/m2. Subjects at the 4 mg/m2 dose level received an additional single dose of 113, 7 days before beginning the 21-day cycle (PK from Day -7 in this cohort summarized with Day 1 data from other cohorts). Serial plasma concentrations of 113 and 473 were measured by LC-MS/MS after the first dose (Day 1) and after 11 doses (Day 21). PK parameters (mean ± standard deviation) were calculated using non-compartmental methods in WinNonLin (v.5.2, Pharsight, Mountain View, CA). Results: Concentrations of the prodrug (113) were <1 ng/ml at all timepoints. Concentrations of 473 were detectable immediately after administration (0.33 hr) and remained detectable through 48 h after administration. 473 reached maximal concentrations at a median of 2 h (range:0.33-6 h) after administration. . 473 terminal elimination half-life was 9.8 h on both Day 1 and Day 21 (±2.1 h and 1.5 h on Days 1 and 21, respectively). Area under the 473 plasma concentration versus time curve increased dose proportionally, with clearance estimated at 20 (±12) and 28 (±13) L/hr on Days 1 and 21, respectively. Maximal 473 concentrations did not display accumulation between Days 1 and 21, when normalized for dose, at 7.4 (±3.7) and 7.1 (±4.8) ng/mL/mg, respectively. Conclusions: The Hsp90 inhibitor prodrug 113 is orally bioavailable, rapidly converted to the active moiety (473), and displays linear PK. Maximal concentrations were observed 2 h after oral administration. The terminal elimination half-life was estimated at 9.8 h, consistent with the lack of significant drug accumulation after 21 days of QOD dosing. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5443.