Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-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 preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366.

Asia‐inclusive global development of pevonedistat: Clinical pharmacology and translational research enabling a phase 3 multiregional clinical trial

“…Pevonedistat undergoes oxidative metabolism primarily by CYP3A enzymes (Takeda data on file), although its PKs are not sensitive to CYP3A inhibition or induction based on results of clinical drug‐drug interaction studies 57,58 . A mass balance study has been recently completed and subsequent metabolite profiling analyses will shed further light on the clearance mechanisms of pevonedistat in humans 59 . Data from our population PK analysis demonstrated that systemic pevonedistat exposures were similar between East Asian and Western populations and across the major East Asian races after individualizing the pevonedistat dose based on BSA, a key covariate.…”

Autophagy Agents in Clinical Trials for Cancer Therapy: A Brief Review

“…Trial NCT02610777, involving Pevonedistat plus azacytidine vs. azacytidine alone, had promising OS, EFS, ORR, and OS, with similar patient side effect profiles [70]. All other phase I trials demonstrated generally well-tolerated side effects with Pevonedistat use [66][67][68][69]71]. Two trials had unavailable results-one due to termination and one with an inaccessible abstract.…”

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

“…Rifampin produced an approximately 20% decrease in pevonedistat systemic exposure. These results are not consistent with a major contribution of CYP3A-mediated metabolism to the overall clearance of pevonedistat based on in vitro, clinical mass balance and metabolite profiling [ 14 ]. Interestingly, itraconazole, a strong CYP3A/P-glycoprotein inhibitor had no clinically relevant effects on pevonedistat PK [ 16 ].…”

“…In a clinical mass balance study, pevonedistat was shown to undergo extensive biotransformation following intravenous administration [ 14 ], with preferential distribution in whole blood with a whole-blood-to-plasma ratio of 40. The presence of circulating metabolites, the minor contribution of renal clearance to pevonedistat disposition, and the predominantly urinary and fecal elimination of metabolites suggested that hepatic metabolism plays a major role in the overall clearance of pevonedistat.…”

“…CYP3A was indicated to play a major role in pevonedistat elimination pathways based on in vitro metabolism (Takeda data on file) and the clinical mass balance study [ 14 ]. However, co-administration with the strong CYP3A inhibitor itraconazole did not result in clinically meaningful increase in pevonedistat systemic exposure [ 16 ].…”