ly higher in the ZYTIGA group than in the placebo group (44% versus 27%, p=0.0002). A responder for pain palliation was defined as a patient who experienced at least a 30% reduction from baseline in the BPI-SF worst pain intensity score over the last 24 hours without any increase in analgesic usage score observed at two consecutive eva luations four weeks apart. Only patients with a baseline pain score of 4 and at least one post-baseline pain score were analysed (N=512) for pain palliation.
A lower proportion of patients treated with ZYTIGA had pain progression compared to patients taking placebo at 6 (22% versus 28%), 12 (30% versus 38%) and 18 months (35% versus 46%). Pain progression was defined as an increase from baseline of 30% in the BPI-SF worst pain intensity score over the previous 24 hours without a decrease in analgesic usage score observed at two consecutive visits, or an increase of 30% in analgesic usage score observed at two consecutive visits. The time to pain progression at the 25th percentile was 7.4 months in the ZYTIGA group, versus 4.7 months in the placebo group.
Skeletal-related events
A lower proportion of patients in the ZYTIGA group had skeletal-related events compared with the placebo group at 6 months (18% versus 28%), 12 months (30% versus 40%), and 18 months (35% versus 40%). The time to first skeletal-related event at the 25th percentile in the ZYTIGA group was twice that of the control group at 9.9 months versus 4.9 months. A skeletal-related event was defined as a pathological fracture, spinal cord compression, palliative radiation to bone, or surgery to bone.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with ZYTIGA in all subsets of the paediatric population in advanced prostate cancer (see section 4.2 for information on paediatric use)
5.2 Pharmacokinetic properties
Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects, patients with metastatic advanced prostate cancer and subjects without cancer with hepatic or renal impairment. Abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor (see section 5.1).
Absorption
Following oral administration of abiraterone acetate in the fasting state, the time to reach maximum plasma abiraterone concentration is approximately 2 hours.
Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (Cmax) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking ZYTIGA with meals has the potential to result in highly variable exposures. Therefore, ZYTIGA must not be taken with food. It should be taken at least two hours after eating and no food should be eaten for at least one hour after taking ZYTIGA. The tablets should be swallowed whole with water (see section 4.2).
Distribution
The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5,630 l, suggesting that abiraterone extensively distributes to peripheral tissues.
Biotransformation
Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed to abira
