Abstract CT208: Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers

Abstract

Abstract Background: Dacomitinib (D) is a highly selective, irreversible small molecule inhibitor of the human epidermal growth factor receptor family of tyrosine kinases in clinical development for the treatment of non-small cell lung cancer (NSCLC). A 45-mg once daily oral dose is currently being evaluated in Phase 3 for NSCLC therapy in multiple settings. D has not previously been administered clinically as an intravenous dose. The absolute bioavailability (F%) of D in rats, dogs and monkeys was found to range from 56% to 100% at doses between 20 and 50 mg/kg. The current study was conducted to estimate the absolute bioavailability of D after oral administration (Test) relative to intravenous (IV, Reference) administration. Methods: A total of 14 healthy volunteers (HV) were enrolled in this Phase 1, open-label, 2-period, 2-treatment, fixed sequence study. Each HV received 2 treatments of D: Reference (20 mg IV infusion over 1 hour) and Test (45 mg oral), with a washout period of at least 16 days between each. Plasma samples to determine concentrations of D and its metabolite, PF-05199265, were collected at intervals up to 216 hours post-dose after IV or oral dose, and safety was assessed. F% was estimated as the ratio of dose-normalized adjusted geometric means of AUCinf for oral D and IV D using a mixed-effect model with treatment as a fixed effect and subject as a random effect. Corresponding 90% confidence intervals (CIs) were to be obtained from the same model. Results: The mean AUCinf, Cmax and CL/F for D after a single 45-mg oral dose were 1487 ng*hr/mL, 19.84 ng/mL and 30.27 L/hr, respectively. The mean AUCinf, Cmax and CL for D after a single 20-mg IV dose were 847 ng*hr/mL, 52 ng/mL and 23.61 L/hr, respectively. Mean pharmacokinetic parameters following a single oral dose in this study were similar to those observed in other single oral dose studies in HV. Conclusions: Assuming that clearance of D is similar via oral or IV administration at the administered doses, the absolute bioavailability of D was estimated to be 80.01% (90% CI: 74.90%, 85.47%). Single oral doses of D in both treatments were generally safe and well tolerated in the HV evaluated in this study. Citation Format: Nagdeep Giri, Robert R. LaBadie, Yali Liang, Tanya Boutros, Zelanna Goldberg, Carlo L. Bello. Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers. [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 CT208. doi:10.1158/1538-7445.AM2014-CT208