Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors
Thistlethwaite, Fiona H
Valkenburg-van Iersel, L
AffiliationClinical Pharmacology and Quantitative Pharmacology, R&D Clinical Pharmacology and Safety Sciences, AstraZeneca, Gaithersburg, MD, USA.
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AbstractPurpose: 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 (Cmax) by 16% and systemic exposure (area under the plasma concentration-time curve [AUC]) by 6%; AUC0-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 AUC0-t was contained within the no-effect limits (0.8-1.25), while that of Cmax 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. Keywords: Adavosertib; Food effect; Oncology; Pharmacokinetics; WEE1.
CitationNagard M, Ah-See ML, So K, Vermunt M, Thistlethwaite F, Labots M, et al. Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2020;86(1):97-108.
JournalCancer Chemotherapy and Pharmacology