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Clinical Pharmacokinetics

Erschienen in:

01.05.2014 | Original Research Article

Population Pharmacokinetic Modeling of Veliparib (ABT-888) in Patients with Non-Hematologic Malignancies

verfasst von: Ahmed Hamed Salem, Vincent L. Giranda, Nael M. Mostafa

Erschienen in: Clinical Pharmacokinetics | Ausgabe 5/2014

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Abstract

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 (CL_CR), 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 CL_CR 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 CL_CR of 100 mL/min) and 173 L (for an LBM of 56 kg), respectively.

Conclusion

Only LBM and CL_CR 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.

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Titel: Population Pharmacokinetic Modeling of Veliparib (ABT-888) in Patients with Non-Hematologic Malignancies
verfasst von: Ahmed Hamed Salem
Vincent L. Giranda
Nael M. Mostafa
Publikationsdatum: 01.05.2014
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 5/2014
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-013-0130-1

Springer Medizin

Abstract

Background and Objective

Methods

Results

Conclusion

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