Phase 1 study to evaluate the effects of rifampin on pharmacokinetics of pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

Abstract

Pevonedistat (TAK-924/MLN4924) is an investigational small molecule inhibitor of the NEDD8-activating enzyme that has demonstrated clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase 1 study evaluating the effect of rifampin, a strong CYP3A inducer, on the pharmacokinetics (PK) of pevonedistat in patients with advanced solid tumors (NCT03486314). Patients received a single 50 mg/m2 pevonedistat dose via a 1-h infusion on Days 1 (in the absence of rifampin) and 10 (in the presence of rifampin), and daily oral dosing of rifampin 600 mg on Days 3-11. Twenty patients were enrolled and were evaluable for PK and safety. Following a single dose of pevonedistat at 50 mg/m2, the mean terminal half-life of pevonedistat was 5.7 and 7.4 h in the presence and in the absence of rifampin, respectively. The geometric mean AUC0-inf of pevonedistat in the presence of rifampin was 79% of that without rifampin (90% CI: 69.2%-90.2%). The geometric mean Cmax of pevonedistat in the presence of rifampin was similar to that in the absence of rifampin (96.2%; 90% CI: 79.2%-117%). Coadministration of pevonedistat with rifampin, a strong metabolic enzyme inducer, did not result in clinically meaningful decreases in systemic exposures of pevonedistat. The study results support the recommendation that no pevonedistat dose adjustment is needed for patients receiving concomitant CYP3A inducers. CLINICALTRIALS.GOV IDENTIFIER: NCT03486314.

Keywords: Advanced malignancies; Pevonedistat; Pharmacokinetics [4 to 6 max]; Rifampin.

Conflict of interest statement

XZ is employed by Takeda Development Center Americas, Inc. (TDCA), Lexington, MA, USA. UV has received honoraria from Sanofi, Exelixis, Pfizer, Bayer; consulting fees from BMS, Merck, Exelixis, Bayer, Aveo; and grants/funds from Merck. DM has received honoraria from Amgen, BMS, Exelixis, Eisai; consulting fees from Qurient, OncoOne; and grants/funds from Amgen, Merck, Oncolytics. RDH has received research funding to their institution that supports their salary from: Abbisko, AbbVie, Actuate, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boston Biomedical, Genmab, GlaxoSmithKline, Infinity, InhibRx, Janssen, Merck, Mersana, Meryx, Nektar, Novartis, Pfizer, Regeneron, Sanofi, Sutro, Takeda, Turning Point Therapeutics, Xencor; and reports consultancy for: Amgen, GlaxoSmithKline. KYC has nothing to disclose. FS is employed by Takeda. CD is employed by Takeda; and has ownership of stock/shares in Takeda and Settle Genetics. DVF is employed by Takeda; has ownership of stock/shares in Viracta Therapeutics, Briacell Therapeutics, Phoenicia Biosciences, R2ccouncil, LLC; was on the advisory council/committee for Viracta Therapeutics, Briacell Therapeutics; and owns multiple patents unrelated to this work. KV is a previous employee of Takeda; and a current employee of EMD Serono Research & Development Institute, Inc., Billerica, MA. NG is employed by Takeda; and has ownership of stock/shares in Takeda.

© 2022. The Author(s).

Figures

Fig. 1

Mean (+ SD) pevonedistat plasma concentration–time profiles in the absence (Day 1) or presence (Day 10) of rifampin (PK population) linear scale (Panel A), semi-log scale (Panel B)

Fig. 2

Individual comparisons of AUC∞ and Cmax for pevonedistat in the absence (Day 1) or presence (Day 10) of rifampin (PK population)