Absolute bioavailability of PF-01367338 tablets following oral administration in cancer patients.

Abstract

e13615 Background: PF‐01367338 is a poly (ADP‐ribose) polymerase (PARP) inhibitor. The phosphate salt of PF‐01367338 (PF‐01367338‐09) was formerly known as AG‐014699. Its safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity following IV administration in combination with temozolomide has been previously evaluated in phase I and II studies. An oral formulation (the camphorsulfonic acid salt) is currently under study to allow for chronic/continuous dosing of PF-01367338 as single agent treatment or in combination with chemotherapeutic agents. One of the objectives of this study was to evaluate the absolute bioavailability of PF-01367338 following oral (PO) administration. Methods: In an ongoing phase I study of PF-01367338 in combination with several chemotherapeutic agents in adult patients (pts) with advanced solid tumors, a single IV dose and PO dose were administered on Day -10 and Day -5, respectively, during a lead-in phase of Cycle 1, to evaluate the bioavailability of PF-01367338. All PO doses were given under fasting conditions with 8 ounces of water. PK samples were collected at 0, 0.25, 0.5, 1, 1.5, 2.5, 4, 6, 10, 24, and 48 hours (h) after the start of the PF‐01367338 infusion or PO administration. The PK data were analyzed using Non-Compartmental Analysis (NCA). Results: To date, PK data from 6 pts at 12-18 mg IV dose and 12 to 48 mg PO dose have been analyzed. The key PK parameters are shown in the table below. The absolute bioavailability of the PF-01367338 immediate release tablet was estimated to be 34% and was independent of dose administered in the dose range studied. No DLTs occurred after single PO dosing. Conclusions: PF-01367337 was well tolerated after oral administration with an average absolute bioavailability of 34%. Preliminary summary of key plasma PF-01367338 PK parameters (N=6). CL (L/hr) Vdss (L) F (%) t1/2, IV (h) t1/2, Oral (h) Tmax, Oral (h) Mean* 18.1 230 34.1 16.6 20.1 1.0 CV (%) 8 77 23 26 19 0.5-2.5 * Geometric mean for all except: median (range) for Tmax, arithmetic mean (CV%) for t1/2.