Abstract
To review the chemistry, pharmacology, pharmacokinetics, clinical efficacy, and safety of atovaquone. An English-language literature search using MEDLINE (1984-1993), programs and abstracts of the 30th, 31st, and 32nd Interscience Conferences on Antimicrobial Agents and Chemotherapy, program and abstracts of the VIII International Conference on AIDS, and unpublished information from Burroughs Wellcome, the manufacturer of atovaquone. All available pharmacokinetic and clinical trials were reviewed. Study quality was assessed by a critical appraisal of study design and methods. Pharmacokinetic studies were evaluated for sampling, methods used to determine pharmacokinetic properties, and the presence of concentration-response and concentration-toxicity relationships. Clinical trials were assessed primarily for comparative efficacy and toxicity. Atovaquone is a novel hydroxynaphthoquinone with potent activity against Pneumocystis carinii and Toxoplasma gondii. Its pharmacokinetic properties are characterized by relatively poor bioavailability, excretion almost exclusively through the feces, lack of hepatic metabolism and urinary excretion, low steady-state plasma concentrations, high protein binding, and a long elimination half-life (50-70 h). Results from comparative clinical trials in AIDS patients with mild-to-moderate P. carinii pneumonia (PCP) reveal similar overall treatment success rates for atovaquone, trimethoprim/sulfamethoxazole (TMP/SMX), and pentamidine. Treatment failure because of lack of therapeutic response was significantly greater in patients who received atovaquone compared with those treated with TMP/SMX (p = 0.002). More atovaquone-patients experienced treatment failure compared with their pentamidine-treated counterparts, although statistical significance was not achieved. Treatment failure secondary to drug toxicity was significantly higher in the TMP/SMX- and pentamidine-treated patients (p < or = 0.01). Atovaquone has not been studied for PCP prophylaxis. Limited data exist on the use of atovaquone for toxoplasmic encephalitis (TE); however, results from an open trial reveal that the drug may be useful in treating this disorder. To date, atovaquone has been well tolerated by most patients administered the drug. The most common adverse effects include maculopapular rash, gastrointestinal disturbances, and fever. Atovaquone is considerably more costly than other oral agents used to treat PCP. Atovaquone appears to be better tolerated but less effective than TMP/SMX and pentamidine in the treatment of mild-to-moderate PCP. There is not enough information available on the use of atovaquone for PCP prophylaxis or the treatment of TE to definitively describe its efficacy. Comparative clinical trials are needed to assess its role in this clinical setting.
Published Version
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