The Effect of Food on the Intraluminal Behavior of Abiraterone Acetate in Man

Abstract

To relate the reported positive effect of food on the oral bioavailability of abiraterone to the intraluminal behavior of abiraterone acetate, an in vivo experiment was performed, in which duodenal fluids and plasma samples were collected from healthy volunteers after the administration of abiraterone acetate in fasted and postprandial conditions. The plasma concentration-time profiles confirmed the positive food effect. Nevertheless, intraduodenal concentrations of abiraterone acetate and abiraterone did not fully reflect this observation. This apparent discrepancy was explored by performing several in vitro experiments including solubility, dissolution, and transfer studies. Gastrointestinal transfer studies illustrated a positive impact of gastric processing of the abiraterone acetate formulation on the duodenal concentrations in the fasted state, which could not be observed in the postprandial condition. As the influence of gastric dissolution on the intraluminal concentrations in the small intestine declines aborally, it is most likely the superior solubility of abiraterone acetate and abiraterone in intestinal fluids of the fed state that dictates the food effect. Furthermore, N-oxide abiraterone sulfate and abiraterone sulfate appeared in the duodenum at significantly later time points than abiraterone, suggesting biliary excretion of these abiraterone metabolites; this was confirmed by in situ biliary excretion experiments in rats.

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

“…They found that food effect was a statistically significant covariate on oral clearance for abiraterone [8]. Other studies have found substantial food effect in healthy subjects when AA was given following a meal, with plasma abiraterone exposure increasing by 2.9-to 10-fold [9,10,12]. For example, Chi et al reported that in healthy subjects administered the OAA formulation, the area under the plasma concentration-time curve (AUC) and maximum measured plasma concentration (C max ) of abiraterone, the active metabolite of AA, increased by 10-and 17-fold, respectively, when given shortly after a high-fat meal relative to the fasted state [10].…”

“…The AA tablets should be swallowed whole with water and should not be crushed or chewed [7]. Several studies have investigated the effect of food on AA absorption and bioavailability [8][9][10][11][12] and established that consumption of a high-fat meal before administration of the originator AA (OAA) formulation markedly increases abiraterone absorption [9,10,12].…”

“…For example, Chi et al reported that in healthy subjects administered the OAA formulation, the area under the plasma concentration-time curve (AUC) and maximum measured plasma concentration (C max ) of abiraterone, the active metabolite of AA, increased by 10-and 17-fold, respectively, when given shortly after a high-fat meal relative to the fasted state [10]. Biorelevant in vitro studies suggest that intestinal fluids, such as bile salt [6,10] produced during the fed state, may facilitate the absorption of abiraterone, thus producing the food effect observed in pharmacokinetic trials [9]. The large bioavailability changes recognized in the reference product with regard to meal fat content [10] may lead to differences in safety, tolerability, and efficacy.…”

Food for thought: formulating away the food effect – a PEARRL review

“…The principal cause of positive food effects is the increase in dissolution and solubilisation of poorly water‐soluble drugs (PWSD) in the fed state. The release of bile salts and the presence of exogenous solubilising species, such as ingested lipids and their digestion products serve to enhance solubilising capacity of gastrointestinal fluid . For drugs which are dissolution rate, rather than solubility limited, the increased gastric residence time also can improve bioavailability, while the increase in gastric pH may result in improved solubility and dissolution of weak acids.…”

The impact of food intake on the luminal environment and performance of oral drug products with a view to in vitro and in silico simulations: a PEARRL review

“…For BCS class IV drugs, the impact of extensive luminal solubilization in the fed state is even less straightforward as in this case transport through the mucosa may also be influenced by changes in the membrane fluidization (which may be induced by the interaction with surfactants) or the activity of membrane transport carriers . Geboers et al . observed a positive food effect on IR tablets containing 250 mg abiraterone acetate (Zytiga ® ), a BCS class IV drug, after administration with a liquid meal (Ensure ® plus).…”