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15.09.2016 | Original Research Article | Ausgabe 5/2017

Clinical Pharmacokinetics 5/2017

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Zeitschrift:
Clinical Pharmacokinetics > Ausgabe 5/2017
Autoren:
Kevin J. Freise, Aksana K. Jones, Doerthe Eckert, Sven Mensing, Shekman L. Wong, Rod A. Humerickhouse, Walid M. Awni, Ahmed Hamed Salem
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s40262-016-0453-9) contains supplementary material, which is available to authorized users.

Abstract

Background

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies.

Objective

The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Methods

A total of 272 and 338 patients from four clinical studies were pooled for the exposure–efficacy and exposure–safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection).

Results

Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5–88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events.

Conclusions

The exposure–response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

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