1. Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours.
- Author
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Plummer, Ruth, Swaisland, Helen, Leunen, Karin, Herpen, Carla, Jerusalem, Guy, Grève, Jacques, Lolkema, Martijn, Soetekouw, Patricia, Mau-Sørensen, Morten, Nielsen, Dorte, Spicer, James, Fielding, Anitra, So, Karen, Bannister, Wendy, Molife, L. Rhoda, van Herpen, Carla M L, De Grève, Jacques, Lolkema, Martijn P, and Mau-Sørensen, Morten
- Subjects
DRUG tablets ,DRUG formularies ,ORAL medication ,PHARMACOKINETICS ,BRCA genes ,GENETIC mutation ,CANCER patients ,ANTINEOPLASTIC agents ,BIOTRANSFORMATION (Metabolism) ,CLINICAL trials ,COMPARATIVE studies ,CROSSOVER trials ,DIET ,DRUG-food interactions ,DRUG administration ,HETEROCYCLIC compounds ,INTESTINAL absorption ,RESEARCH methodology ,MEDICAL cooperation ,METASTASIS ,PHARMACEUTICAL chemistry ,RESEARCH ,RESEARCH funding ,TIME ,TUMORS ,EVALUATION research - Abstract
Background: The oral PARP inhibitor olaparib has shown efficacy in patients with BRCA-mutated cancer. This Phase I, open-label, three-part study (Parts A-C) in patients with advanced solid tumours evaluated the effect of food on the pharmacokinetics (PK) of olaparib when administered in tablet formulation.Methods: PK data were obtained in Part A using a two-treatment period crossover design; single-dose olaparib 300 mg (two 150 mg tablets) was administered in two prandial states: fasted and fed. In Part B, patients received olaparib tablets (300 mg bid) for 5 days under fasting conditions; in Part C, patients were allowed continued access to olaparib. Safety was assessed throughout, with data reported for Parts A and B.Results: A total of 60 and 56 patients were evaluable for safety and PK analyses, respectively; 57 patients entered Part B. Rate of olaparib absorption was slower in the presence of food (t max delayed by 2.5 h), resulting in a statistically significant ~21 % decrease in peak plasma exposure (C max) [ratio of geometric means (90 % CI), 0.79 (0.72, 0.86)] but only a marginal increase in olaparib absorption (AUC0-∞) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC0-∞ treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib.Conclusions: Results of this study showed that a high-fat meal decreases the rate of absorption and peak exposure to olaparib 300 mg tablets, although in the absence of an effect on the extent of olaparib absorption. [ABSTRACT FROM AUTHOR]- Published
- 2015
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