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 has been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics 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 (PBMC). Seventy-one subjects contributed with veliparib plasma concentrations, M8 plasma concentrations, and PAR levels in PBMC. Veliparib and M8 concentrations were modeled simultaneously using a population PK approach. A two-compartment model with delayed first-order absorption and the elimination parameterized as renal (CLR/F) and non-renal clearance (CLNR/F) adequately described veliparib pharmacokinetics. The pharmacokinetics of the M8 metabolite was described with a two-compartment model. Creatinine clearance and lean body mass 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), 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.

Population pharmacokinetics and exposure–response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias

“…Our data demonstrate that the pharmacokinetics of veliparib in a population of older patients with advanced myeloid leukemias is similar to that reported earlier in other cancer patient populations [8, 24, 25]. In addition, exposure–response analysis shows that, in the trial patient population, a lower dose of veliparib can be efficacious in combination with temozolomide.…”

“…The pharmacokinetics of veliparib alone and in combination with cytotoxic DNA-damaging agents has been described in patients with various malignancies [8, 23]. While early studies described veliparib PK using a one-compartment model [8, 23], a two-compartment model described their data better than a one-compartment model in recently published studies [24, 25]. Analysis of data from this trial agrees with the findings of Mehrotra et al and Niu et al showing that a two-compartment model appropriately describes veliparib pharmacokinetics [24, 25].…”

Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia

“…In the population PK analysis data set, individual eGFR values were calculated using the Modification of Diet in Renal Disease study equation 20 and ranged up to 379 mL/min/1.73 m 2 . Because such a high eGFR value might not be physiologically relevant, a sensitivity analysis was conducted by rerunning the final quizartinib population PK model with the original eGFR values (ie, individual values up to 379 mL/min/1.73 m 2 ) or eGFR values capped at 120 mL/min/1.73 m 2 21 . The NONMEM objective function value decreases from these runs were 0.326 ( P = .568) and 2.37 ( P = .124), respectively, thereby confirming no effect of eGFR on quizartinib clearance.…”

Steady‐state population pharmacokinetics of terizidone and its metabolite cycloserine in patients with drug‐resistant tuberculosis

“…This decision allows Fm to be identified and to distinguish between terizidone clearance via biotransformation and other routes . It is worth noting that Fm is not the true fraction but apparent fraction . Another way of dealing with parameter identifiability problem is to set the volume of the parent drug equal to metabolite volume, fixing metabolite volume equal to 1 or fixing Fm to any value between zero and 1.…”

“…24,25 It is worth noting that Fm is not the true fraction but apparent fraction. 26 Another way of dealing with parameter identifiability problem is to set the volume of the parent drug equal to metabolite volume, fixing metabolite volume equal to 1 or fixing Fm to any value between zero and 1. However, we chose not to undertake these options.…”