Comparison of a Novel Formulation of Abiraterone Acetate vs. the Originator Formulation in Healthy Male Subjects: Two Randomized, Open-Label, Crossover Studies

Abstract

Background and ObjectiveAbiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer. The originator abiraterone acetate (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure. Abiraterone acetate fine particle (AAFP) is a proprietary formulation (using SoluMatrix Fine Particle Technology™) designed to increase the oral bioavailability of abiraterone acetate. Here, we report on two phase I studies in healthy male subjects aged 18–50 years.MethodsIn Study 101, 20 subjects were randomized in a crossover design to single doses of AAFP 100, 200, or 400 mg or OAA 1000 mg taken orally under fasting conditions. Results suggested that AAFP 500 mg would be bioequivalent to OAA 1000 mg in the fasted state. To confirm the bioequivalence hypothesis and to further expand the AAFP dose range, in Study 102, 36 subjects were randomized in a crossover design to single doses of AAFP 125, 500, or 625 mg or OAA 1000 mg. Both studies included a 7-day washout period between administrations.ResultsDose-dependent increases in the area under the plasma concentration–time curve and maximum plasma concentration with AAFP were observed in both studies. The AAFP 500-mg bioavailability relative to OAA 1000 mg measured by the geometric mean ratio for area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration was 93.4% (90% confidence interval 85.3–102.4), area under the plasma concentration–time curve from time zero to infinity was 91.0% (90% confidence interval 83.3–99.4), and maximum plasma concentration was 99.8% (90% confidence interval 86.3–115.5). Dose proportionality was seen across all AAFP dose levels (100–625 mg). Abiraterone acetate fine particle was found to be safe and well tolerated in this study.ConclusionAbiraterone acetate fine particle 500 mg was demonstrated to be bioequivalent to OAA 1000 mg in healthy volunteers under fasted conditions.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0536-2) contains supplementary material, which is available to authorized users.

Improved Oral Bioavailability and Variability Control in Pharmacokinetic Data – Role of Formulations

“…The recently published work of Goldwater et al confirmed that a single 500 mg dose of AAFP prepared using SoluMatrix Fine Particle Technology ™ was bioequivalent with the 1000 mg Zytiga dose under fasted conditions [9]. The geometric mean of test: reference (90% confidence interval limits) were 91 (83.3 to 99.4) and 99.8 (86.3 to 115.5) for AUC inf and C max , respectively [9].…”

“…Because there was the addition of methylprednisolone (4 mg twice daily) to AAFP or prednisone (5 mg twice daily) to the Zytiga tablets, there was the need of a single dose bioequivalence study to confirm the existence of bioequivalence of 500 mg AAFP versus 1000 mg Zytiga tablets [8]. The recently published work of Goldwater et al confirmed that a single 500 mg dose of AAFP prepared using SoluMatrix Fine Particle Technology ™ was bioequivalent with the 1000 mg Zytiga dose under fasted conditions [9]. The geometric mean of test: reference (90% confidence interval limits) were 91 (83.3 to 99.4) and 99.8 (86.3 to 115.5) for AUC inf and C max , respectively [9].…”

“…In addition, there would be an opportunity to dose abiraterone acetate without regard to food intake. In this context, there are data that support 50% dose reduction of abiraterone acetate using fine particle technology [8,9].…”

The Effect of Food on the Absorption of Abiraterone Acetate from a Fine Particle Dosage Form: A Randomized Crossover Trial in Healthy Volunteers

“…The higher surface area--to-mass ratio can increase the in vivo dissolution rate of lipophilic, poorly water-soluble, active pharmaceutical ingredients such as AA that often have dissolution rate-limited oral bioavailability. In a previous companion study of healthy male subjects, AAFP 500 mg was shown to be bioequivalent to OAA 1000 mg (within 80-125% of C max and AUC) when taken under fasted conditions [13]. The present study investigates the effect of a high-fat meal on AAFP pharmacokinetic parameters and bioavailability.…”

“…Based on a previous companion study, a sample size of 22 subjects was deemed sufficient to provide statistical power to detect a 20% difference in the reference mean between fed and fasted conditions [13]. Assuming a screen failure/dropout rate of 15%, enrollment of 26 subjects was planned.…”