Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: In vitro, rat in situ and human in vivo studies

Abstract

The aim of this study was to evaluate the intestinal disposition of abiraterone acetate, an ester prodrug of the anticancer agent abiraterone. Stability of the prodrug and solubility and dissolution characteristics of both abiraterone and abiraterone acetate were monitored in vitro. Moreover, the in vivo intraluminal concentrations of abiraterone and abiraterone acetate upon intake of one tablet of 250 mg abiraterone acetate were assessed in healthy volunteers. The intestinal absorption resulting from the intraluminal behavior of the ester prodrug was determined using the rat in situ intestinal perfusion technique with mesenteric blood sampling. Simulated and aspirated human intestinal fluids of the fasted state were used as solvent systems. Upon incubation of abiraterone acetate in human intestinal fluids in vitro, rapid hydrolysis of the prodrug was observed, generating abiraterone concentrations largely exceeding the apparent solubility of abiraterone, suggesting the existence of intestinal supersaturation. These findings were confirmed in vivo, by intraluminal sampling of duodenal fluids upon oral intake of an abiraterone acetate tablet by healthy volunteers. Rat in situ intestinal perfusion experiments performed with suspensions of abiraterone and abiraterone acetate in human intestinal fluids of the fasted state revealed significantly higher flux values upon perfusion with the prodrug than with abiraterone. Moreover, rat in situ intestinal perfusion with abiraterone acetate suspensions in simulated fluids of the fasted state in presence or absence of esterases demonstrated that increased hydrolytic activity of the perfusion medium was beneficial to the intestinal absorption of abiraterone. In conclusion, the rapid hydrolysis of abiraterone acetate in the intraluminal environment appears to result in fast and extensive generation of abiraterone supersaturation, creating a strong driving force for abiraterone absorption.

Exploring gastrointestinal variables affecting drug and formulation behavior: Methodologies, challenges and opportunities

“…Enabling formulations such as solid dispersions, nano-and microparticles and cyclodextrin/co-solvent based solutions are examples of methods used to increase solubilization or achieve supersaturated solution of the drug, with the ultimate goal of enhancing oral absorption. Aspiration of gastric and duodenal fluids in parallel with blood sampling resulted in new insights into how these enabling strategies behave after oral intake (Brouwers et al, 2006;Hens et al, 2015a;Stappaerts et al, 2015). Moreover, drug solubility measurements in these aspirated fluids can reveal whether the drug was supersaturated at the time of aspiration or directly started to precipitate (Hens et al, 2015b;Psachoulias et al, 2011;Van Den Abeele et al, 2015).…”

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

“…(Jarkko et al, 2008) It has been demonstrated, however, that premature intraluminal hydrolysis mediated by hydrolyzing enzymes present in the intestinal fluids may significantly alter the intestinal absorption of a prodrug. (Brouwers et al, 2007); (Stappaerts et al, 2015) It has for instance been shown that intraluminal degradation of the ester prodrug tenofovir disoproxil fumarate takes place in vivo, illustrating that the esterases present in the intestinal fluids may undermine the intended enhanced permeability. In another recently described study, the hydrolyzing capacity of intestinal fluids was revealed to be an effective trigger causing abiraterone supersaturation upon administration of the ester prodrug abiraterone acetate; esterase-mediated hydrolysis was shown to be beneficial for the intestinal absorption of abiraterone.…”

“…In another recently described study, the hydrolyzing capacity of intestinal fluids was revealed to be an effective trigger causing abiraterone supersaturation upon administration of the ester prodrug abiraterone acetate; esterase-mediated hydrolysis was shown to be beneficial for the intestinal absorption of abiraterone. (Stappaerts et al, 2015) It is clear that the intraluminal behavior of ester prodrugs can be diverse and may have significant repercussions on intestinal drug absorption. In vitro stability testing in biorelevant media containing hydrolyzing enzymes is clearly an important step in assessing the feasibility of a prodrug approach.…”

Physical chemistry of supersaturated solutions and implications for oral absorption

“…There is some evidence in the literature that lipolysis of a self-846 microemulsifying drug delivery system may lead to the formation of 847 an amorphous precipitate [81]. Both prodrug conversion [82] and 848 dissolution of cocrystals [83] can generate supersaturated solutions, 849 hence these are unexplored potential routes that could result in LLPS.…”