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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 2/2019

01-02-2019 | Original Article

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

Authors: Renu Singh, Shailly Mehrotra, Mathangi Gopalakrishnan, Ivana Gojo, Judith E. Karp, Jacqueline M. Greer, Alice Chen, Richard Piekarz, Brian F. Kiesel, Jogarao Gobburu, Michelle A. Rudek, Jan H. Beumer, on behalf of the ETCTN-6745 study team

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2019

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Abstract

Purpose

Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design.

Methods

Population pharmacokinetic analysis was performed using Phoenix® NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival.

Results

A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure.

Conclusions

Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure–safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure–efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit–risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.
Appendix
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Metadata
Title
Population pharmacokinetics and exposure–response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias
Authors
Renu Singh
Shailly Mehrotra
Mathangi Gopalakrishnan
Ivana Gojo
Judith E. Karp
Jacqueline M. Greer
Alice Chen
Richard Piekarz
Brian F. Kiesel
Jogarao Gobburu
Michelle A. Rudek
Jan H. Beumer
on behalf of the ETCTN-6745 study team
Publication date
01-02-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 2/2019
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3731-4

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