A Population Pharmacokinetic Meta-Analysis of Veliparib, a PARP Inhibitor, Across Phase 1/2/3 Trials in Cancer Patients.

Abstract

Veliparib (ABT‐888) is a poly(ADP‐ribose) polymerase inhibitor in development for the treatment of high‐grade ovarian cancer or BRCA‐mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1‐compartment model with linear clearance and first‐order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc/F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc/F. Mild and moderate renal impairment increased veliparib median (95%CI) steady‐state AUC (AUCss) by 27.3% (23.7%‐30.9%) and 65.4% (56.0%‐75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%‐23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%‐20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P‐glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.