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

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/m 2 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 (AUC 6 ) 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.