Abstract
Purpose To support future dosing recommendations, the effect of food on the pharmacokinetics of adavosertib, a first-in-class, small-molecule reversible inhibitor of WEE1 kinase, was assessed in patients with advanced solid tumors. Methods In this Phase I, open-label, randomized, two-period, two-sequence crossover study, the pharmacokinetics of a single 300 mg adavosertib dose were investigated in fed versus fasted states. Results Compared with the fasted state, a high-fat, high-calorie meal (fed state) decreased adavosertib maximum plasma concentration (C-max) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC(0-t)decreased by 7% and time to maximum plasma concentration was delayed by 1.97 h (P = 0.0009). The 90% confidence interval of the geometric least-squares mean treatment ratio for AUC and AUC(0-t)was contained within the no-effect limits (0.8-1.25), while that ofC(max)crossed the lower bound of the no-effect limits. Adverse events (AEs) related to adavosertib treatment were reported by 20 (64.5%) of the 31 patients treated in this study. Grade >= 3 AEs were reported by four (12.9%) patients (one in the fed state, three in the fasted state); two of these AEs were considered treatment-related by the investigator. Three serious AEs were reported in three (9.7%) patients; these were not considered treatment-related. No patients discontinued because of treatment-related AEs, and no new safety signals were reported. Conclusion A high-fat meal did not have a clinically relevant effect on the systemic exposure of adavosertib, suggesting that adavosertib can be administered without regard to meals.
Original language | English |
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Pages (from-to) | 97-108 |
Number of pages | 12 |
Journal | Cancer Chemotherapy and Pharmacology |
Volume | 86 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jul 2020 |
Keywords
- adavosertib
- carboplatin
- combination
- food effect
- kinase
- mk-1775
- oncology
- pharmacokinetics
- phase-i
- wee1
- CARBOPLATIN
- Food effect
- KINASE
- Oncology
- COMBINATION
- WEE1
- Adavosertib
- Pharmacokinetics
- PHASE-I
- MK-1775