Effect of Food on the Pharmacokinetics of Olaparib after Oral Dosing of the Capsule Formulation in Patients with Advanced Solid Tumors
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The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of ≤400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer.
This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5–14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID.
32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02–1.20] for standard and 1.00 [0.92–1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10–1.33] for standard and 1.19 [1.08–1.31] for high-fat meal).
The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib.
KeywordsFood effect Olaparib Olaparib capsule PARP inhibition Pharmacokinetics PK Poly(ADP-ribose) polymerase (PARP) inhibitor
The authors would like to thank all patients who consented to participate in this study. We also acknowledge Gil Morrison (Covance®) for analysis of the PK data, and Quintiles® for conducting the study and associated data management activities. Dr Dean would like to acknowledge The University of Manchester and Experimental Cancer Medicine Centre for supporting clinical trial research in Manchester. Sponsorship and article processing charges for this study were funded by AstraZeneca, and medical writing assistance was provided by Claire Routley from Mudskipper Business Ltd and funded by AstraZeneca. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
Conflicts of interest
C. Rolfo, K. Leunen, A. Rutten, P. Soetekouw, S. Slater, H. Verheul, W. Bannister and E. Dean declare no conflict of interest. H. Swaisland was an employee of AstraZeneca at the time of the design, conduct and interpretation of the study and is an AstraZeneca shareholder. A. Fielding is an employee of AstraZeneca and has stock ownership. K So is an employee of AstraZeneca.
Compliance with ethics guidelines
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study.
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