title: Parent-Metabolite Pharmacokinetic Modeling and Pharmacodynamics of Veliparib (ABT-888), a PARP Inhibitor, in Patients With BRCA 1/2-Mutated Cancer or PARP-Sensitive Tumor Types.
abstract: Veliparib (ABT-888) is a novel oral poly-ADP-ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib have been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics (PK) of chronically dosed single-agent veliparib in patients with either BRCA 1/2-mutated cancer or PARP-sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly-ADP-ribose (PAR) level observed in peripheral blood mononuclear cells (PBMCs). Seventy-one subjects contributed with veliparib plasma concentrations, M8 plasma concentrations, and PAR levels in PBMCs. Veliparib and M8 concentrations were modeled simultaneously using a population PK approach. A 2-compartment model with delayed first-order absorption and the elimination parameterized as renal (CLR/F) and nonrenal clearance (CLNR/F) adequately described veliparib pharmacokinetics. The pharmacokinetics of the M8 metabolite was described with a 2-compartment model. Creatinine clearance(CLCR) and lean body mass (LBM) were identified as significant predictors of veliparib CLR/F and central volume of distribution, respectively. For a typical subject (LBM, 48 kg; CLCR, 95 mL/min), total clearance (CLR/F + CLNR/F), and central and peripheral volume of distribution for veliparib were estimated as 17.3 L/h, 98.7 L, and 48.3 L, respectively. At least 50% inhibition of PAR levels in PBMCs was observed at dose levels ranging from 50 to 500 mg.
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Niu
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Christie
authors.initials: C
authors.lastname: Scheuerell
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Shailly
authors.initials: S
authors.lastname: Mehrotra
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Karan
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Puhalla
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Kiesel
authors.affiliation: Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Mathangi
authors.initials: M
authors.lastname: Gopalakrishnan
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ivaturi
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Jogarao
authors.initials: J
authors.lastname: Gobburu
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.|Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000097:blood
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D011065:Poly(ADP-ribose) Polymerases
keywords: BRCA; PARP inhibitor; parent-metabolite modeling; population pharmacokinetics; veliparib