Abstract
The oral bioavailability of entecavir (EV), an anti-viral agent commonly prescribed to treat hepatitis B infections, is drastically reduced under a post-prandial state. This is primarily due to its low permeability in the gastrointestinal tract. To reduce the food effect on the intestinal absorption of the nucleotide analogue, four lipidic prodrugs were synthesized via the esterification of the primary alcohol of EV with fatty acids (hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid). EV-3-dodecanoate (or EV-C12) exhibited high solubility in a fed state simulated intestinal fluid (78.8 μg/mL), with the acceptable calculated logP value (3.62) and the lowest hydrolysis rate (22.5% for 12 h in simulated gastric fluid, pH 1.2). Therefore, it was chosen as a candidate to improve intestinal absorption of EV, especially under a fed state condition. Physical characterization using scanning electron microscopy, a differential scanning calorimeter, and X-ray powder diffraction revealed that EV-C12 had a rectangular-shaped crystalline form, with a melting point of about 170 °C. In a release test in biorelevant media, such as fasted and fed state-simulated intestinal and/or gastric fluid, more than 90% of the prodrug was released within 2 h in all media tested. These data suggest that this lipidic prodrug might have the potential to alleviate the negative food effect on the intestinal absorption of EV with increased therapeutic efficacy and patient compliance.
Highlights
Entecavir (2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-3H-purin-6-one, EV) has been frequently prescribed to treat infections caused by the hepatitis B virus (HBV) [1,2].This oral nucleotide analog can selectively hinder HBV by restraining three steps of viral replication procedures: Base priming, reverse transcription of the negative strand, and synthesis of the positive strand of HBV DNA [3]
In a release test in biorelevant media, such as fasted and fed state-simulated intestinal and/or gastric fluid, more than 90% of the prodrug was released within 2 h in all media tested
One of the hindrances in EV oral therapy is the food effect on intestinal absorption, in which oral absorption of this biopharmaceutics classification system (BCS) III compound is marked by reduced food consumption, especially after a high-fat meal
Summary
-6-one, EV) has been frequently prescribed to treat infections caused by the hepatitis B virus (HBV) [1,2]. This oral nucleotide analog can selectively hinder HBV by restraining three steps of viral replication procedures: Base priming, reverse transcription of the negative strand, and synthesis of the positive strand of HBV DNA [3]. One of the hindrances in EV oral therapy is the food effect on intestinal absorption, in which oral absorption of this biopharmaceutics classification system (BCS) III compound is marked by reduced food consumption, especially after a high-fat meal. Oral EV administration at a dose of 0.5 mg with a high-fat
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
