ORAL BIOAVAILABILITY OF THE ANTIRETROVIRAL AGENT 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE (PMEA) FROM 3-FORMULATIONS OF THE PRODRUG BIS(PIVALOYLOXYMETHYL)-PMEA IN FASTED MALE CYNOMOLGUS MONKEYS

The bioavailability of PMEA from three oral formulations of the prodru g bis(POM)-PMEA has been evaluated ia fasted male cynomolgus monkeys. The formulations examined included a hydroxypropyl-beta-cyclodextrin ( HPBCD) Complex, a PEG based cosolvents solution, and an-aqueous suspen sion. Oral formulations containing H-3 bis(POM)-PMEA. were compared to intravenous H-3-PMEA at 10.9 mg-eq/kg in a crossover study in four-mo nkeys, with a 7 day washout period. No intact bis(POM)-PMEA,or monoest er 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 b ioavailability of PMEA from bis(POM)-PMEA was not limited by dissoluti on rate of the prodrug. Data for the PEG cosolvent solution and suspen sion indicate that the prodrug could potentially be formulated as a so ft gelatin capsule or a tablet.