A prospective phase I multicentre randomized cross-over pharmacokinetic study to determine the effect of food on abiraterone pharmacokinetics

Floor J E Lubberman, Guillemette E Benoist, Winald Gerritsen, David M Burger, Niven Mehra, Paul Hamberg, Inge van Oort, Nielka P van Erp, Floor J E Lubberman, Guillemette E Benoist, Winald Gerritsen, David M Burger, Niven Mehra, Paul Hamberg, Inge van Oort, Nielka P van Erp

Abstract

Purpose: Abiraterone acetate is used at a fixed oral dose of 1000 mg once daily (OD) taken fasted. By administering abiraterone acetate with food, a reduced dose can potentially be given while maintaining equivalent abiraterone exposure. Moreover, administering abiraterone acetate with a breakfast is considered more patient friendly. The aim of this study was to establish the bio-equivalent lower dose of abiraterone when taken with a continental breakfast (CB) compared to the standard intake of 1000 mg OD fasted.

Methods: In this phase I, randomized cross-over, multi-center study, abiraterone pharmacokinetics (PK) were evaluated in patients with metastatic castration-resistant prostate cancer who were treated for 14 days with 1000 mg abiraterone acetate taken fasted, followed by 14 days of treatment with 500 mg taken with a CB.

Results: 14 patients were enrolled into the study, of whom 12 were eligible for PK analysis. The geometric mean ratio (GMR) (fed/fasted) was 0.88 (90% CI 0.73-1.07) for area-under-the-curve (AUC0-24h), 1.03 (90% CI 0.79-1.34) for Cmax and 0.81 (90% CI 0.60-1.10) for Ctrough, respectively. High inter-patient variability (> 50%) was found for all PK parameters under both intake conditions. Patients seemed to be slightly more satisfied about the intake of 500 mg abiraterone acetate when taken with a CB compared to 1000 mg fasted.

Conclusion: In conclusion, a bioequivalent lower dose of abiraterone taken with food could not be established in our study. Although based on the absence of a exposure-toxicity relationship, the strict bioequivalence margins as defined by the FDA guidelines could be applied more flexible for abiraterone. Information on the effect of food on abiraterone pharmacokinetics as presented in our study can be used for patients with difficulties taken their medication fasted.

Keywords: Abiraterone; Bioequivalence; Food; Pharmacokinetics; Prostate cancer.

Conflict of interest statement

NvE received grants from Novartis, Astellas, AstraZeneca, Bristol-Meyers Squibb, Gilead, Ipsen, Janssen, Pfizer and Roche. IvO received grants from Astellas, Janssen, Sanofi, Beyer and Roche. The other authors declare to have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Concentration time curve of 1000 mg abiraterone acetate taken fasted and 500 mg abiraterone acetate taken with a continental breakfast
Fig. 3
Fig. 3
Geometric mean ratio including their confidence interval. Vertical lines represent the threshold of 0.8 and 1.25 as defined by the FDA

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