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Effect of food on the pharmacokinetics of the WEE1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors.
- Source :
- Cancer Chemotherapy & Pharmacology; Jul2020, Vol. 86 Issue 1, p97-108, 12p
- Publication Year :
- 2020
-
Abstract
- <bold>Purpose: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- PHARMACOKINETICS
TUMORS
CONFIDENCE intervals
KINASE inhibitors
FOOD
PEMETREXED
ANTINEOPLASTIC agents
BIOAVAILABILITY
COMPARATIVE studies
CROSSOVER trials
DIET
DRUG-food interactions
HETEROCYCLIC compounds
RESEARCH methodology
MEDICAL cooperation
ORAL drug administration
PROTEIN-tyrosine kinases
RESEARCH
EVALUATION research
PROTEIN kinase inhibitors
CELL cycle proteins
CHEMICAL inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 03445704
- Volume :
- 86
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Cancer Chemotherapy & Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 144404616
- Full Text :
- https://doi.org/10.1007/s00280-020-04101-4