Population pharmacokinetic modeling of veliparib (ABT-888) in patients with non-hematologic malignancies.

BACKGROUND AND OBJECTIVE

Veliparib (ABT-888) is a potent oral inhibitor of Poly(ADP-ribose) polymerase enzyme that is currently in development for the treatment of non-hematologic and hematologic malignancies. This analysis characterizes the population pharmacokinetics of veliparib, including developing a structural pharmacokinetic model and testing patient demographics and covariates for potential influence on veliparib pharmacokinetics in patients with non-hematologic malignancies.

METHODS

The analysis dataset included 3,542 veliparib concentration values from 325 patients with non-hematologic malignancies enrolled in three phase I and one phase II studies. Population pharmacokinetic modeling was performed using NONMEM. The likelihood ratio test was used for comparison of nested models, and visual predictive check was employed for model qualification. Covariates tested included body size measures, creatinine clearance (CLCR), formulation, age, sex, race, liver function tests, and coadministration with temozolomide.

RESULTS

A one-compartment model with first-order absorption and elimination adequately described veliparib pharmacokinetics. The final model included fixed effects for CLCR on veliparib oral clearance (CL/F) and lean body mass (LBM) on volume of distribution (V d/F). CL/F and V d/F were 20.9 L/h (for a CLCR of 100 mL/min) and 173 L (for an LBM of 56 kg), respectively.

CONCLUSION

Only LBM and CLCR were found to be determinants of veliparib V d/F and CL/F, respectively. Dosage adjustments of veliparib on the basis of body size, age, sex, race, liver function, and temozolomide coadministration are not necessary in patients with non-hematologic malignancies. This is the first study to characterize the population pharmacokinetics of veliparib, and the developed model will be used to conduct simulations and evaluate veliparib exposure-response relationships.