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

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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.

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Acknowledgments

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. This study was sponsored by AstraZeneca. Medical writing assistance was provided by Claire Routley Ph.D. from Mudskipper Business Ltd, funded by AstraZeneca. The UK Centres participating in this research receive funding from Cancer Research UK (CRUK) and the Department of Health as Experimental Cancer Medicine Centres.

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Authors and Affiliations

  1. Northern Centre for Cancer Care, Newcastle upon Tyne, UK

    Ruth Plummer

  2. Therakin Consulting, Sandbach, UK

    Helen Swaisland

  3. UZ Leuven, Leuven, Belgium

    Karin Leunen

  4. Radboud University Medical Center, Nijmegen, The Netherlands

    Carla M. L. van Herpen

  5. CHU Sart-Tilman, Liege, Belgium

    Guy Jerusalem

  6. Universitair Ziekenhuis Brussel, Brussels, Belgium

    Jacques De Grève

  7. University Medical Center Utrecht, Utrecht, The Netherlands

    Martijn P. Lolkema

  8. Maastricht University Medical Center, Maastricht, The Netherlands

    Patricia Soetekouw

  9. Rigshospitalet, Copenhagen, Denmark

    Morten Mau-Sørensen

  10. Herlev Hospital, Herlev, Denmark

    Dorte Nielsen

  11. King’s College London at Guy’s Hospital, London, UK

    James Spicer

  12. AstraZeneca, Macclesfield, UK

    Anitra Fielding & Karen So

  13. PHASTAR, London, UK

    Wendy Bannister

  14. Drug Development Unit, The Royal Marsden/Institute of Cancer Research, Sutton, UK

    L. Rhoda Molife

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  1. Ruth Plummer
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  2. Helen Swaisland
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  3. Karin Leunen
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  4. Carla M. L. van Herpen
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  11. James Spicer
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  12. Anitra Fielding
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  15. L. Rhoda Molife
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Corresponding author

Correspondence to Ruth Plummer.

Ethics declarations

Conflict of interest

RP has received institutional remuneration from AstraZeneca and has received funding from AstraZeneca for chairing an advisory board. GJ has received remuneration from Novartis, Celgene, and Roche, funding from Novartis, MSD, and Roche, and has consulted/had an advisory role for Novartis and Celgene. LRM has received funding from AstraZeneca. JDG has received funding from AstraZeneca for attendance at a national advisory board. AF is an employee of, and owns stock in, AstraZeneca. HS was formally an employee of AstraZeneca and owns stock in AstraZeneca. KS is a contractor for AstraZeneca. KL, CvH, DN, ML, JS, MMS, PS, and WB have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

HS was an employee of AstraZeneca while the study was conducted.

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Plummer, R., Swaisland, H., Leunen, K. et al. Olaparib tablet formulation: effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours. Cancer Chemother Pharmacol 76, 723–729 (2015). https://doi.org/10.1007/s00280-015-2836-2

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  • DOI: https://doi.org/10.1007/s00280-015-2836-2

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