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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

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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 hydroxy-propyl-β-cyclodextrin (HPBCD) complex, a PEG based cosolvent solution, and an aqueous 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.

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Authors and Affiliations

  1. Gilead Sciences, Inc., 353 Lakeside Drive, Foster City, California, 94404

    Kenneth C. Cundy, James A. Fishback, Jeng-Pyng Shaw, Min L. Lee, Gary C. Visor & William A. Lee

  2. Tulane University Medical Center, Covington, Louisiana, 70433

    Kenneth F. Soike

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  1. Kenneth C. Cundy
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  2. James A. Fishback
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  3. Jeng-Pyng Shaw
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  4. Min L. Lee
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  5. Kenneth F. Soike
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  6. Gary C. Visor
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  7. William A. Lee
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Cundy, K.C., Fishback, J.A., Shaw, JP. et al. 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. Pharm Res 11, 839–843 (1994). https://doi.org/10.1023/A:1018925723889

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  • DOI: https://doi.org/10.1023/A:1018925723889

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