Abstract CT221: The effect of food on the oral bioavailability of the novel PARP 1/2 inhibitor BMN 673 in healthy male subjects
Authors: Henshaw Joshua , Zhou Huiyu , Musson Don , O'Neill Charles , Stoltz Randall , Dorr Andrew 
Published: May 2015

Introduction: BMN 673 is a novel, potent (IC50 &lt; 1.0 nM in vitro) inhibitor of Poly(ADP-ribose) polymerase (PARP) 1 and PARP 2 in clinical development for the treatment of genetically defined cancers.

Methods: The effect of food on the oral bioavailability of BMN 673 was evaluated in 18 healthy male subjects who received a single 0.5 mg dose of BMN 673 following an overnight fast (fasted condition) and a single 0.5 mg dose of BMN 673 following a high-fat, high-calorie meal (fed condition) in a randomized two-sequence, two-period crossover design. Serial blood samples were collected to determine plasma pharmacokinetic (PK) profiles out to 21 days postdose during each treatment period. Urine samples to determine BMN 673 urine concentrations were collected out to 48 hours postdose during each treatment period. The relative bioavailability under fed and fasted conditions was determined using a linear mixed effects model fitted to the log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞. A nonparametric Koch test was used to evaluate the effect of food on Tmax.

Results: Food delayed the absorption of orally-administered BMN 673, as indicated by a prolonged Tmax and reduced Cmax under fed compared to fasted conditions, but did not affect the overall extent of absorption, as indicated by similar AUC0-t and AUC0-∞ values under fed and fasted conditions. Comparing fed (test) to fasted (reference) conditions, the treatment difference median (90% CI) in Tmax was 2.63 hours (2.13 to 3.13 hours), the geometric least squares mean (GLSM) ratio (90% CI) in Cmax was 54% (48% to 60%), and the GLSM ratios (90% CI) in AUC0-t and AUC0-∞ were 98% (92% to 103%) and 98% (92% to 103%), respectively. Mean values of the amount of BMN 673 excreted in the urine were similar under fed and fasted conditions. There were no clinically significant findings in vital signs, clinical laboratory evaluations, ECGs, or physical examinations during the study. The incidence and types of adverse events (AEs) were similar following administration of BMN 673 in the fed and fasted conditions. Importantly, there were no SAEs and no withdrawals due to AEs.

Conclusions: A high-fat, high-calorie meal delayed the absorption of orally-administered BMN 673, but did not affect the overall extent of absorption. Single 0.5 mg doses of BMN 673 were safe and well tolerated in healthy male subjects in the fed and fasted conditions. Based on these results, BMN 673 can be administered with or without food.

Citation Format: Joshua Henshaw, Huiyu Zhou, Don Musson, Charles O'Neill, Randall Stoltz, Andrew Dorr. The effect of food on the oral bioavailability of the novel PARP 1/2 inhibitor BMN 673 in healthy male subjects. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT221. doi:10.1158/1538-7445.AM2014-CT221