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

Summary 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.

Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions

“…For elderly patients with AML considered unfit for conventional chemotherapy, the combination therapy with MLN4924 and azacitidine was generally well tolerated (ClinicalTrials.gov Identifier: NCT01814826) [ 208 ]. In addition, six clinical trials at phase I of MLN4924 in patients with nonhematologic malignancies or solid tumors (ClinicalTrials.gov Identifier: NCT00677170, NCT01862328, NCT02122770, NCT03057366, NCT03330106 and NCT03486314) have also been completed [ 209 – 212 ]. For pediatric patients with recurrent or refractory solid tumors, MLN4924 in combination with temozolomide and irinotecan is well tolerated (ClinicalTrials.gov Identifier: NCT03323034) [ 213 ].…”

An open‐label study to explore the optimal design of CYP3A drug–drug interaction clinical trials in healthy Chinese people

“… 1 , 10 According to recently published research, pre‐dosing of rifampin at 600 mg QD varied from 7 to 14 days in NME DDI studies. 7 , 12 , 13 To provide further evidence for standardizing the design of clinical DDI studies and reducing variability, we conducted this real‐world clinical trial to compare the two most widely used rifampin dosing regimens (600 mg QD for 7 days vs. 600 mg QD for 14 days) in DDI studies.…”

Effect of Pevonedistat, an Investigational NEDD8‐Activating Enzyme Inhibitor, on the QTc Interval in Patients With Advanced Solid Tumors

“…However, co-administration with the strong CYP3A inhibitor itraconazole or metabolic enzyme inducer rifampin did not result in clinically meaningful changes in pevonedistat systemic exposures. 14,15 A physiologically based PK model for pevonedistat suggested that systemic exposure of pevonedistat was not sensitive to the modulations of enzyme activity if hepatic uptake was the rate-determining step of pevonedistat clearance. 15 Prolongation of the heart-rate corrected QT (QTc) interval is a potential drug side effect associated with an increased risk of cardiac arrhythmias, particularly tor-sades de pointes (TdP), which may spontaneously lead to ventricular fibrillation and sudden death.…”

“…14,15 A physiologically based PK model for pevonedistat suggested that systemic exposure of pevonedistat was not sensitive to the modulations of enzyme activity if hepatic uptake was the rate-determining step of pevonedistat clearance. 15 Prolongation of the heart-rate corrected QT (QTc) interval is a potential drug side effect associated with an increased risk of cardiac arrhythmias, particularly tor-sades de pointes (TdP), which may spontaneously lead to ventricular fibrillation and sudden death. 16 Blockade of the human cardiac K+ ether-à-go-go related gene (hERG) channel is usually associated with these clinical findings.…”

“…In vitro metabolism (Takeda data on file) and clinical mass balance studies suggested that CYP3A played a major role in pevonedistat elimination pathways. However, co‐administration with the strong CYP3A inhibitor itraconazole or metabolic enzyme inducer rifampin did not result in clinically meaningful changes in pevonedistat systemic exposures 14,15 . A physiologically based PK model for pevonedistat suggested that systemic exposure of pevonedistat was not sensitive to the modulations of enzyme activity if hepatic uptake was the rate‐determining step of pevonedistat clearance 15 …”