Summary

• Food effect studies with AKEEGA have not been performed.¹
• Results from clinical studies evaluating the effect of food on niraparib and abiraterone acetate as individual agents have been published.^2-11
  • Food does not affect niraparib exposure.
  • Administration of food significantly increases the absorption of abiraterone acetate.
• No food should be consumed for at least 2 hours before and at least 1 hour after taking AKEEGA dual action tablet (DAT).¹²

CLINICAL DATA

AKEEGA

Food effect studies have not been conducted for AKEEGA. The lack of food effect on niraparib pharmacokinetics (PK) is anticipated to persist when niraparib is administered with abiraterone acetate. While abiraterone acetate is affected by fasted/fed conditions, the food effect on AKEEGA is anticipated to be similar to that of abiraterone acetate when administered alone.¹

In patients with metastatic castration-resistant prostate cancer (mCRPC), under fasted and modified fasted conditions, upon administration of multiple doses of AKEEGA DAT formulation, the maximum plasma concentration (C_max) was achieved within a median of 3 hours for niraparib and a median of 1.5 hours for abiraterone. The food effect of the individual components has been extensively characterized. Given the normal variation in the content and composition of meals, taking AKEEGA DAT with meals has the potential to result in increased and highly variable exposures of abiraterone.¹ No food should be consumed for at least 2 hours before and at least 1 hour after taking AKEEGA DAT.¹²

Niraparib

High-fat meal intake (defined as 800 to 1000 calories with approximately 50% of total caloric content of the meal derived from fat) prior to the time of dosing did not significantly affect the PK of niraparib in the capsule formulation. The area under the plasma concentrationtime curve (AUC) from time 0 to the last measurable concentration (AUC_0-last) and AUC from time 0 to infinite time (AUC_0-∞) for patients under fasted/fed conditions were bioequivalent based on the 90% confidence interval (CI) for these measures. There was a slight delay in time to reach maximum plasma concentration (t_max) and an approximate 20% decrease in C_max (least square mean [LSM] ratio of fed/fasted, 78.5; 90% CI,
69.5-88.6) following a high-fat meal; however, these changes were not clinically relevant.¹

Abiraterone Acetate

High inter- and intra-patient variability in abiraterone PK has been reported in the published literature.¹³ To control the potentially large differences in abiraterone systemic exposure deriving from inter-day differences in dietary intake, abiraterone acetate has been administered in a fasting state in phase 3 studies.^2-4 A summary of the studies examining the effect of food on abiraterone PK in healthy subjects and in patients with mCRPC is described below.

• Lubberman et al (2019)⁵ evaluated a phase 1 study that determined the PK of abiraterone acetate 1000 mg daily (fasting) followed by 500 mg with a continental breakfast in patients with mCRPC (N=14). Systemic exposure to abiraterone acetate 500 mg once daily with a continental breakfast did not meet the criteria for bioequivalence compared to abiraterone acetate 1000 mg administered in a fasted state due to the large variability in PK of abiraterone within and between patients. Due to the large variability in abiraterone exposure, the intake of abiraterone acetate with food could not be advised.
• Szmulewitz et al (2018)⁶ investigated a phase 2 study that determined the PK of a reduced-dose (250 mg) regimen of abiraterone acetate in combination with a low-fat breakfast in patients with progressive castration-resistant prostate cancer (CRPC; N=72). Administration of abiraterone acetate 250 mg once daily in combination with a low-fat breakfast (LOW arm) had similar effects on prostate-specific antigen (PSA) levels compared with abiraterone acetate 1000 mg once daily while fasting (STD arm). However, the average abiraterone trough concentrations were significantly higher in the STD arm than the LOW arm (P<0.001).
• Chi et al (2015)⁷investigated the short-term safety and PK profile of continuous dosing of abiraterone acetate in fasting and fed conditions in healthy subjects (study 1, n=36) and in patients with mCRPC (study 2, n=25). Administration of abiraterone acetate with low-fat meals and in a modified fasting state resulted in minimal difference in systemic exposure to abiraterone. In contrast, dosing with high-fat meals resulted in an approximate 2-fold increase in the AUC compared with dosing in a modified fasting state.
• Stuyckens et al (2014)⁸ evaluated a pooled PK analysis of 3 phase 1 studies, 1 phase 1b study, and 2 phase 3 studies that included healthy subjects and patients with mCRPC with and without prior chemotherapy (N=359). Administration of abiraterone acetate 1000 mg resulted in similar exposure regardless of prior chemotherapy status. The final model predicted that when healthy subjects were administered abiraterone acetate with a low- or high-fat meal, the bioavailability would be 3.8 times and 7.6 times higher, respectively, than abiraterone acetate taken under a fasting state.
• Acharya et al (2011)⁹ conducted a phase 1 study that evaluated the effect of high- and low-fat standardized meals on the PK of abiraterone acetate (N=36). Administration of abiraterone acetate in fed conditions resulted in increased exposure to abiraterone vs fasting. Exposure (C_max and AUC_0-∞) of abiraterone increased 7- and 5-fold, respectively, with a low-fat meal and 17- and 10-fold, respectively, with a high-fat meal.
• Ryan et al (2010)¹⁰ conducted a phase 1, dose-escalation study that evaluated the PK of abiraterone acetate in escalating doses of 250, 500, 750, and 1000 mg with fasted (overnight fast) or fed (800 to 1000 calorie breakfast) cohorts in patients with chemotherapy-naïve CRPC (N=33). Administration of a meal (800 to 1000 calorie breakfast) was associated with higher abiraterone exposure than after fasting.¹⁰
• Attard et al (2008)¹¹ conducted a phase 1, dose-escalation study that evaluated the food (high-fat food vs overnight fast) effect on the PK of 2 single doses of abiraterone acetate capsules in men with chemotherapy-naïve CRPC (N=21). In patients who received abiraterone acetate 1000 mg, abiraterone exposure was 4.4 times higher after administration with high-fat food than after fasting (P=0.49). Absorption was extended when abiraterone was taken with food, but no significant increase in the C_max was observed.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 12 June 2024. Summarized in this response are relevant data pertaining to this topic in patients with prostate cancer.