Anti‐Human Immunodeficiency Virus (HIV) Activity, Safety, and Pharmacokinetics of Adefovir Dipivoxil (9‐[2‐(bis‐pivaloyloxymethyl)‐phosphonylmethoxyethyl]adenine) in HIV‐Infected Patients

Abstract

A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .02), 25% (P = .31), and 30% (P = .01) occurred in each drug-treated group, respectively, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups (P = .03), compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at the lowest dosage studied, 125 mg daily.

Ultra sensitive method for the determination of 9-(2-phosphonylmethoxyethyl)adenine in human serum by liquid chromatography–tandem mass spectrometry

“…Adefovir dipivoxil was readily absorbed after oral administration to mice [13], rats [15], dogs [16] and man [17]. Adefovir dipivoxil and its monoester (mono-POM PMEA) were not observed in plasma, suggesting rapid hydrolysis of the prodrug to adefovir (PMEA) before reaching the systemic circulation.…”

Acyclic Nucleoside Phosphonates in the Chemotherapy of DNA Virus and Retrovirus Infections

“…at 3 dose lev els (125, 250 or 500 mg once daily), was found to effect a significant decrease in serum p24 antigen and HIV RNA copies. Adefovir dipovoxil was best tolerated at the lowest dose (125 mg daily) studied, and its anti-HIV activity was already evident after 8 days of dosing [53]. In another randomized, double-blind, placebo-controlled study [54], adefovir dipixovil.…”

“…The first case of an hypopharyngeal/esophageal papilloma (due to HPV type 16) that showed complete regression under topical cidofovir therapy was reported three years ago [47], In a randomized, double-blind, placebo-controlled, dose-escala tion study [53], bis(POM)-PMEA (adefovir dipivoxil). at 3 dose lev els (125, 250 or 500 mg once daily), was found to effect a significant decrease in serum p24 antigen and HIV RNA copies.…”

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“…However, although adefovir shows significant in vitro antiviral activity against poxviruses, its efficacy as a therapeutic agent for smallpox is currently uncertain. In addition to its activity against VACV replication in tissue culture, it has a good oral availability and has been approved for treatment of Hepatitis B [45], making it a serious candidate. This compound needs to be evaluated further for its activity against monkeypox and variola viruses before its real potential is known [46].…”