Abstract
Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate (AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate drug administration for patients with late-stage prostate cancer. Two four-sequence, four-period randomized crossover investigations were undertaken to establish the pharmacokinetic profiles of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS (250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng × h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large pills.
Highlights
Abiraterone acetate is indicated for patients with metastatic castration resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer (CSPC) and included in the WHO’s List of Essential Medicines [1]
We report the results of a two-part clinical pharmacokinetic study that was designed to characterize the pharmacokinetic properties of tablet for oral suspension (TOS) and establish the novel formulation’s equivalency to 1000 mg reference AA (R-AA)
There were no other clinically significant changes reported in hematological, clinical chemistry or urinalysis laboratory values; vital signs’ measurements; physical examinations; or 12-lead ECGs in either study. The results of these two phase 1 clinical investigations show that the pharmacokinetic profile of the novel TOS formulation of abiraterone acetate, when given in fasted or fed state, falls between the lower and upper limits defined for R-AA in the fasted and modified fasting state, respectively
Summary
Abiraterone acetate is indicated for patients with metastatic castration resistant prostate cancer (mCRPC) and metastatic high-risk castration-sensitive prostate cancer (CSPC) and included in the WHO’s List of Essential Medicines [1]. It is a prodrug which is converted in vivo to abiraterone. Pharmaceutics 2021, 13, 2171 inhibiting 17α-hydroxylase/C17,20-lyase which catalyzes the conversion of pregnenolone and progesterone into testosterone precursors. Inhibition of androgen synthesis results in decreased proliferation of androgen sensitive prostate cancer cell lines and prolongs survival in patients with metastatic prostate cancer [2]. Each 250 mg tablet of R-AA weighs 0.72 g and measures 15.9 mm long
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