Foods Atovaquone

Rolan, P.E., Mercer, A.J., Weatherly, B.C., Holdich, T., Meire, H., Peck, R.W., Ridout, G. and Posner, J. (1994). Examination of some factors responsible for a food-induced increase in absorption of atovaquone. Br. J. Clin. Pharmacol. 37 13-20. 

Failure to administer with food may result in lower atovaquone plasma concentrations and may limit response to therapy. 

Pharmacokinetics Absorption is enhanced approximately 2-fold when given with food. Atovaquone is extensively bound to plasma proteins (greater than 99.9%). 

Absorption Absorption of atovaquone is limited but can be significantly increased when the drug is taken with food. Plasma concentrations correlate with the likelihood of successful treatment and survival. Gl disorders may limit absorption of orally administered drugs. Patients with these disorders also may not achieve plasma concentrations of atovaquone associated with response to therapy in controlled trials. 

Drug/Food interactions Administering atovaquone with food enhances its absorption by approximately 2-fold. 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

Atovaquone is an alternative therapy for P jiroveci infection, although its efficacy is lower than that of trimethoprim-sulfamethoxazole. Standard dosing is 750 mg taken with food twice daily for 21 days. Adverse effects include fever, rash, nausea, vomiting, diarrhea, headache, and insomnia. Serious adverse effects appear to be minimal, although experience with the drug remains limited. Atovaquone has also been effective in small numbers of immunocompromised patients with toxoplasmosis unresponsive to other agents, although its role in this disease is not yet defined. 

Atovaquone is a hydroxynaphthaquinone that is effective in the prevention and treatment of murine Pneumocystis jiroveci pneumonitis. It also has effects against Toxoplasma gondii and Plasmodium falciparum. Food increases its absorption. The maximum serum concentration is dose-dependent, but absorption is reduced at doses above 750 mg. The maximum concentration occurs after 4-6 hours, with a second peak 24-96 hours later, suggesting enterohepatic cycling. The half-life is 77 hours. 

Mechanism and pharmacokinetics Atovaquone inhibits mitochondrial electron transport and probably folate metabolism. Used orally, it is poorly absorbed and should be given with food to maximize bioavailability. Most of the drug is eliminated in the feces in unchanged form. 

As part of a larger study, 6 HIV-positive subjects received atovaquone 500 mg once daily, co-trimoxazole 960 mg (trimethoprim/sulfamethoxa-zole 160/800 mg) twice daily, or the combination, taken with food. There was no change in steady-state atovaquone levels but there was a minor 17% decrease in steady-state trimethoprim levels and a minor 8% decrease in sulfamethoxazole levels when both drugs were given together. ... 

Atovaquone is a highly lipophilic compound, which shows considerable inter-individual variability in absorption. Dietary fat increases the rate and extent of atovaquone absorption from both the suspension and the tablets, probably by increasing its solubility in the gut. The suspension has about a twofold higher oral bioavailability than the tablets when given with food or when fasting. 

Established interactions of clinical importance. Atovaquone suspension used for the treatment or prevention of Pneumocystis pneumonia must be taken with food, since this is likely to increase the likelihood of successful treatment and survival. Alternatively, an enteral nutritional supplement with a high-fat content appears to be suitable. In the US, the manufacturer says that, for patients who have difficulty taking atovaquone suspension with food, parenteral therapy for Pneumocystis pneumonia should be considered. ... 

Similarly, atovaquone/proguanil tablets used for the treatment or prophylaxis of malaria should be taken with a milky drink or with food to maximise absorption. Be aware that if patients are unable to tolerate food, the systemic exposure to atovaquone will be reduced. In this situation, monitoring of parasitaemia to ensure efficacy would seem prudent. 

Rolan PE, Mercer AJ, Weatherley BC, Holdich T, Meire H, Peck RW, Ridout G, Posner J. Exam ination of some factoiB respcxisible for a food-induced increase in absoptiem of atovaquone. BrJ Clin Pharmacol (1994) 37, 13-20... 

Taking atovaquone with fatty food markedly increases its AUC by two to threefold. Atovaquone/proguanil tablets should be taken with food or a milky drink, and atovaquone suspension should be taken with food, to maximise absorption and efficacy. 

In a pharmacokinetic study in HIV-positive subjects designed to determine the dose of atovaquone suspension that would achieve specific steady-state plasma levels, administration with high-fat food increased the bioavailability of atovaquone by 1.4-fold when compared with the fasted state. In another similar study, administration of atovaquone suspension with food (23 g of fat) increased average steady-state levels by 1.3-fold to 1.7-fold with different dosage regimens (using 500 mg to 1.5 g of atovaquone. ... 

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