Clinical Pharmacokinetics and Mass Balance of Veliparib in Combination with Temozolomide in Subjects with Nonhematologic Malignancies.

ABSTRACT

BACKGROUND AND OBJECTIVES: Veliparib is an orally active potent poly(ADP-ribose) polymerase (PARP) inhibitor currently in phase III clinical trials in solid tumors. This phase I study evaluated the pharmacokinetics and mass balance of veliparib administered alone and in combination with temozolomide, and assessed any potential pharmacokinetic drug-drug interaction between veliparib and temozolomide. METHODS: This was an open-label, dose-escalation study of veliparib in combination with temozolomide in 42 subjects with nonhematologic malignancies. Veliparib was administered orally at doses ranging from 10 to 80 mg twice daily on days 1-7, and temozolomide was administered orally at 150-200 mg/m2 once daily on days 1-5 of each 28-day cycle. The pharmacokinetics of veliparib, its M8 metabolite, and temozolomide, as well as urinary excretion of unchanged veliparib and its M8 metabolite, were determined. RESULTS: Mean veliparib maximum observed plasma concentration (C max) and area under the plasma concentration-time curve for the first 6 h postdose (AUC6) values increased dose proportionally in the veliparib 10-80 mg twice-daily dose range. The urinary recovery of veliparib dose as the unchanged parent compound alone and together with the M8 metabolite was 73 ± 18 and 90 ± 22%, respectively, over a 12-h dosing interval on day 6 of Cycle 1. Veliparib and temozolomide pharmacokinetic exposures were not affected when administered together. CONCLUSIONS: Veliparib is a Biopharmaceutical Classification System (BCS) Class 1 compound, with no less than 90% of the dose absorbed and an oral bioavailability of at least 73%. Veliparib is primarily eliminated by renal excretion. Veliparib exhibited linear pharmacokinetics in the 10-80 mg twice-daily dose range. No pharmacokinetic interaction was observed when veliparib and temozolomide were administered together. CLINICAL TRIAL REGISTRATION NUMBER NCT00526617.