Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours

被引:49
作者
Plummer, Ruth [1 ]
Swaisland, Helen [2 ]
Leunen, Karin [3 ]
van Herpen, Carla M. L. [4 ]
Jerusalem, Guy [5 ]
De Greve, Jacques [6 ]
Lolkema, Martijn P. [7 ]
Soetekouw, Patricia [8 ]
Mau-Sorensen, Morten [9 ]
Nielsen, Dorte [10 ]
Spicer, James [11 ]
Fielding, Anitra [12 ]
So, Karen [12 ]
Bannister, Wendy [13 ]
Molife, L. Rhoda [14 ]
机构
[1] Northern Ctr Canc Care, Newcastle Upon Tyne, Tyne & Wear, England
[2] Therakin Consulting, Sandbach, Cheshire, England
[3] UZ Leuven, Leuven, Belgium
[4] Radboud Univ Nijmegen, Med Ctr, NL-6525 ED Nijmegen, Netherlands
[5] CHU Sart Tilman, B-4000 Liege, Belgium
[6] Univ Ziekenhuis Brussel, Brussels, Belgium
[7] Univ Med Ctr Utrecht, Utrecht, Netherlands
[8] Maastricht Univ Med Ctr, Maastricht, Netherlands
[9] Rigshosp, DK-2100 Copenhagen, Denmark
[10] Herlev Hosp, DK-2730 Herlev, Denmark
[11] Guys Hosp, Kings Coll London, London SE1 9RT, England
[12] AstraZeneca, Macclesfield, Cheshire, England
[13] PHASTAR, London, England
[14] Royal Marsden Inst Canc Res, Drug Dev Unit, Sutton, Surrey, England
关键词
Olaparib; Food effect; Tablet; PARP inhibition; PK; MAINTENANCE THERAPY; OVARIAN-CANCER; PHASE-2; INHIBITION; AZD2281;
D O I
10.1007/s00280-015-2836-2
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. 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. 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 similar to 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 (AUC(0-a)) [ratio of geometric means (90 % CI), 1.08 (1.01, 1.16)]. The point estimate and 90 % CI for the AUC(0-a) treatment ratio were within pre-defined bioequivalence limits (0.80-1.25). Adverse event data were consistent with the known safety profile of olaparib. 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.
引用
收藏
页码:723 / 729
页数:7
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