Brands, Medical Use, Clinical Data
- Antifungal Agents
- Antiprotozoal Agents
- Enzyme Inhibitors
Brands / Synonyms
Malarone; Malarone Pediatric; Mepron; Mepron
For the treatment or prevention of Pneumocystis carinii pneumonia in patients who are intolerant to trimethoprim-sulfamethoxazole (TMP-SMX). Also indicated for the acute oral treatment of mild to moderate PCP in patients who are intolerant to TMP-SMX.
Atovaquone is a highly lipophilic drug that closely resembles the structure ubiquinone. Its inhibitory effect being comparable to ubiquinone, in sensitive parasites atovaquone can act by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis. For illustration, cytochrome bc1 complex (complex III) seems to serve as a highly discriminating molecular target for atovaquone in Plasmodia
atovaquone has the advantage of not causing myelosuppression, which is an important issue in patients who have undergone bone marrow transplantation.
Mechanism of Action
Atovaquone is a hydroxy- 1, 4- naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis carinii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis. Atovaquone also has been shown to have good in vitro activity against Toxoplasma gondii.
The bioavailability of atovaquone is low and variable and is highly dependent on formulation and diet. Bioavailability of the suspension increases two-fold when administered with meals. When administered with food, bioavailability is approximately 47%. Without food, the bioavailability is 23%.
The median lethal dose is higher than the maximum oral dose tested in mice and rats (1825 mg/kg per day). Overdoses up to 31,500 mg of atovaquone have been reported. In one such patient who also took an unspecified dose of dapsone, methemoglobinemia occurred. Rash has also been reported after overdose.
Biotrnasformation / Drug Metabolism
Some evidence suggests limited metabolism (although no metabolites have been identified).
MEPRON Suspension is contraindicated for patients who develop or have a history of potentially life-threatening
allergic reactions to any of the components of the formulation.
Atovaquone is highly bound to plasma protein (99.9%). Therefore, caution should be used when administering MEPRON
concurrently with other highly plasma protein- bound drugs with narrow therapeutic indices, as competition for
binding sites may occur. The extent of plasma protein binding of atovaquone in human plasma is not affected by the
presence of therapeutic concentrations of phenytoin (15 mcg/ mL), nor is the binding of phenytoin affected by the
presence of atovaquone.
Rifampin: Coadministration of rifampin and MEPRON Suspension results in a significant decrease in
average steady- state plasma atovaquone concentrations. Alternatives to rifampin should be considered during the
course of PCP treatment with MEPRON.
Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug
interactions as rifampin. No interaction trials have been conducted with MEPRON and rifabutin.
Drug/ Laboratory Test Interactions: It is not known if MEPRON interferes with clinical laboratory
test or assay results.