title: Oral bioavailability of the antiretroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from three formulations of the prodrug bis(pivaloyloxymethyl)-PMEA in fasted male cynomolgus monkeys.
abstract: The bioavailability of PMEA from three oral formulations of the prodrug bis(POM)-PMEA has been evaluated in fasted male cynomolgus monkeys. The formulations examined included a hydroxypropyl-beta-cyclodextrin (HPBCD) complex, a PEG based cosolvent solution, and an aqeous suspension. Oral formulations containing 3H-bis(POM)-PMEA were compared to intravenous 3H-PMEA at 10.9 mg-eq/kg in a crossover study in four monkeys, with a 7 day washout period. No intact bis(POM)-PMEA or monoester were detected in plasma. Bioavailabilities of PMEA from the prodrug were 24.7 +/- 6.5%, 27.3 +/- 12.3% and 22.2 +/- 15.6% for the HPBCD complex, PEG solution and aqueous suspension, respectively. The oral bioavailability of PMEA from bis(POM)-PMEA was not limited by dissolution rate of the prodrug. Data for the PEG cosolvent solution and suspension indicate that the prodrug could potentially be formulated as a soft gelatin capsule or a tablet.
authors.affiliation: Gilead Sciences, Inc., Foster City, California 94404.
authors.forename: K C
authors.initials: KC
authors.lastname: Cundy
authors.forename: J A
authors.initials: JA
authors.lastname: Fishback
authors.forename: J P
authors.initials: JP
authors.lastname: Shaw
authors.forename: M L
authors.initials: ML
authors.lastname: Lee
authors.forename: K F
authors.initials: KF
authors.lastname: Soike
authors.forename: G C
authors.initials: GC
authors.lastname: Visor
authors.forename: W A
authors.initials: WA
authors.lastname: Lee
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D003505:Cyclodextrins; D008252:Macaca fascicularis; D008297:Male; D063065:Organophosphonates; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011409:Propylene Glycols; D012190:Retroviridae / Q000187:drug effects; D013535:Suspensions; D047392:beta-Cyclodextrins
chemical_list: D000998:Antiviral Agents; D003505:Cyclodextrins; D063065:Organophosphonates; D011355:Prodrugs; D011409:Propylene Glycols; D013535:Suspensions; D047392:beta-Cyclodextrins; C089823:bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C053001:adefovir; D000225:Adenine