Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors

M. Nagard, M.L. Ah-See, K. So, M. Vermunt, F. Thistlethwaite, M. Labots, P. Roxburgh, A. Ravaud, M. Campone, L. Valkenburg-van Iersel, L. Ottesen, Y. Li, G. Mugundu*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 languageEnglish
Pages (from-to)97-108
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume86
Issue number1
DOIs
Publication statusPublished - 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

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