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Atovaquone

A Review of its Pharmacological Properties and Therapeutic Efficacy in Opportunistic Infections

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Abstract

Synopsis

Atovaquone has been investigated as an alternative agent for oral use in the treatment of both mild to moderate Pneumocystis carinii pneumonia (PCP) and toxoplasmosis, opportunistic infections commonly experienced by patients with AIDS. In patients with mild to moderate PCP, a dosage of 750mg 3 times daily (administered in tablet form) has similar overall therapeutic efficacy (defined as clinical response without a treatment-limiting adverse event) to the conventional therapies oral cotrimoxazole (trimethoprim-sulfamethoxazole) and intravenous pentamidine, respectively. Response rates to atovaquone are lower than those achieved with cotrimoxazole, but atovaquone has superior tolerability. Atovaquone recipients experienced significantly fewer treatment-limiting adverse effects than patients treated with cotrimoxazole (7 vs 20%) or pentamidine (4 vs 36%).

Mortality rates were higher among atovaquone-treated patients than in cotrimoxazole recipients (7 vs 0.6%) 4 weeks after completion of therapy in a large comparative trial, although most deaths were caused by bacterial infections. However, a similar rate of mortality was reported for atovaquone- and pentamidine-treated patients (16 vs 17% 8 weeks after discontinuation of therapy) in another study.

In predominantly small numbers of patients with toxoplasmosis, of whom most were unresponsive to conventional agents, atovaquone 750mg 4 times daily (administered as tablets) produced a complete or partial radiological response rate of 37 to 87.5%. 52% of patients achieved a complete or partial clinical response after 6 weeks of treatment in the largest trial (n = 87), although the incidence of toxoplasmosis-related death was 24% 18 weeks after therapy was initiated.

Thus, atovaquone will be a useful option for the treatment of patients with mild to moderate PCP who are intolerant or unresponsive to cotrimoxazole, especially if the increased plasma drug concentrations observed with the suspension further improve response rates. Atovaquone should also be considered a promising agent for the treatment of toxoplasmosis.

Pharmacodynamic Properties

Atovaquone is a hydroxynaphthoquinone which acts as an inhibitor of the mitochondrial respiratory chain. Atovaquone has intrinsic activity against Pneumocystis carinii; a median drug concentration of 1.4 μmol/L (0.513 mg/L) inhibited 50% of organisms (IC50) in vitro. The IC50 value of atovaquone was lower [about 0.05 μmol/L (0.018 mg/L)] when measured by oxygen consumption of isolated P. carinii from rat lungs. Atovaquone 100 mg/kg/day demonstrated activity as a prophylactic agent against, and as a treatment of, P. carinii pneumonia (PCP) in the corticosteroid-treated rat model. It had greater prophylactic activity than intravenous pentamidine or clindamycin plus primaquine, similar activity to dapsone plus trimethoprim, erythromycin plus sulfafurazole or pyrimethamine plus sulfadoxine, but lower activity than cotrimoxazole (trimethoprim-sulfamethoxazole), azithromycin plus sulfamethoxazole or clarithromycin plus sulfamethoxazole in this model. It was less effective than cotrimoxazole or pyrimethamine plus dapsone or in corticosteroid-treated rats with concomitant P. carinii and Toxoplasma gondii infection. The therapeutic and prophylactic activity of atovaquone is dose-proportional. Importantly, it appears that atovaquone may be microbicidal against P. carinii, in contrast with cotrimoxazole, which is microbistatic. No antagonistic effects were noted in mice given atovaquone in combination with other agents used in the treatment of opportunistic infections.

In a few patients with PCP, 42 days of therapy with atovaquone removed all signs of P. carinii in bronchoalveolar lavage fluid. The recommended regimen of 21 days’ therapy reduced this ratio by more than 50%, which is associated with a decreased risk of relapse within 6 months. Measurement of arterial blood gas (a measure of pneumonia resolution) showed that treatment with atovaquone 750mg 3 times daily improves oxygenation in patients with AIDS and PCP.

Atovaquone has activity against T gondii in in vitro models, with significant differences in susceptibility of different strains. Intracellular replication of 6 of 7 strains of T. gondii tachyzoites were inhibited by a drug concentration of 4.8 × 10−9 to 4.8 × 10−6 mol/L (0.00176 to 1.76 mg/L); the IC50 value of atovaquone against the virulent RH strain was 6.4 × 10−8 mol/L (0.0235 mg/L). Higher concentrations of atovaquone [2.8 × 10−4 mol/L (100 mg/L)] are required to kill bradyzoites within cysts, although it was the only agent, when compared with clindamycin, fluorouracil, pyrimethamine and sulfadiazine, to demonstrate cysticidal activity. Atovaquone was less effective when the time to initiation of treatment was increased or lower drug doses were administered. In mice with chronic T. gondii infection, treatment with atovaquone 100 or 200 mg/kg/day for 2 to 12 weeks resulted in a steady decline in the number of brain cysts compared with untreated controls.

Pharmacokinetic Properties

Atovaquone has slow and irregular absorption when administered orally in tablet form. Maximum plasma concentrations (Cmax) and area under the concentration-time curve at steady-state increased linearly over the dosage range 100 to 750 mg/day in volunteers with asymptomatic HIV infection. Mean Cmax at steady-state was lower in patients with AIDS and PCP than in volunteers with asymptomatic HIV infection; administration of atovaquone 750mg 3 times daily in tablet form resulted in a mean Cmax of 13.9 mg/L in patients with AIDS and PCP. Atovaquone has a long terminal plasma half-life (77 hours, when administered at a dosage of 750mg 3 then 2 times daily). Increased drug absorption (at least 3-fold) is observed when atovaquone is administered with or soon after meals, particularly a high fat meal, compared with the fasting state. Administration of atovaquone as an aqueous suspension, compared with as a tablet, also improves drug absorption approximately 2-fold. After undergoing enterohepatic cycling, atovaquone is predominantly excreted in the faeces in healthy volunteers. Less than 0.6% of the drug is renally excreted. Atovaquone is more than 99.9% protein bound and does not cross the blood-brain barrier to any appreciable extent.

Steady-state plasma atovaquone concentrations (Css) have been correlated with therapeutic response and survival and, in patients with toxoplasmosis, delay to disease progression. It appears that the incidence of some adverse events, particularly rash, is also correlated with Css in atovaquone-treated patients. The pharmacokinetic profile of atovaquone has not been evaluated in the elderly or in patients with renal or hepatic impairment, and only limited study has been performed in children.

Therapeutic Efficacy

In all clinical trials of atovaquone identified, the drug was administered orally, in tablet form.

Patients enrolled in trials assessing the efficacy of atovaquone against PCP generally had mild to moderate disease and all had AIDS. In noncomparative trials, treatment with atovaquone 750mg 2 to 4 times daily produced a clinical response in 77 to 83% of patients. In comparative trials, atovaquone 750mg 3 times daily demonstrated similar overall therapeutic efficacy (defined as clinical response without development of a treatment-limiting adverse event) to the conventional therapies, oral cotrimoxazole and intravenous pentamidine. Fewer atovaquone than cotrimoxazole recipients responded, although the incidence of treatment-limiting adverse effects was significantly lower in atovaquone-treated patients than in cotrimoxazole or pentamidine recipients. Mortality rates after completion of therapy were higher in atovaquone, than in cotrimoxazole, recipients (7 vs 0.6% at 4 weeks follow-up; most deaths were not PCP-related), but were similar in atovaquone- and pentamidine-treated patients (16 vs 17% 8 weeks after treatment was discontinued) in another trial.

Patients enrolled in a few trials evaluating atovaquone in the treatment of cerebral toxoplasmosis also had HIV infection and, in most studies, were unresponsive to, or unable to tolerate, previous standard therapy for T. gondii infection. Atovaquone 750mg 4 times daily showed radiological efficacy in all identified trials (complete or partial response in 37 to 87.5% of patients), although most trials enrolled small numbers of patients (n = 5 to 24). In the largest trial, 52% of 87 patients achieved a complete or partial clinical response and 12% had stable disease after 6 weeks of therapy. In this study, 40% of patients had died at 18 weeks’ follow-up, 24% because of toxoplasmosis. No patients in the remaining trials were reported to have died from toxoplasmosis. Atovaquone has also shown promise as an agent for maintenance therapy in patients with cerebral toxoplasmosis and as a treatment for ocular toxoplasmosis.

Tolerability

Atovaquone tablets, most commonly administered at a dosage of 750mg 3 times daily, have a superior tolerability profile in patients with AIDS and PCP, compared with cotrimoxazole or pentamidine. The incidence of treatment-limiting adverse effects was lower with atovaquone than with cotrimoxazole (7 vs 20%) or pentamidine (4 vs 36%). Rash, nausea, diarrhoea, headache, vomiting, fever and insomnia occurred in 10 to 23% of patients receiving atovaquone; rash and liver dysfunction were treatment-limiting in 4 and 3% of patients, respectively. Laboratory abnormalities were observed in up to 10% of patients with PCP receiving atovaquone in comparative trials, although abnormal hepatocellular function or elevated amylase levels tended to occur more frequently in cotrimoxazole recipients.

In trials of atovaquone conducted in patients with toxoplasmosis, few adverse events were reported. Documented events included headache, nausea and diarrhoea. Rash or liver toxicity were treatment-limiting in a small number of patients. Toxic epidermal necrolysis also caused discontinuation of atovaquone therapy in 1 patient and erythema multiforme in another. In an unspecified number of patients, neutrophil and platelet counts and transaminase levels fluctuated in abnormal ranges, but changes were not severe or clearly attributable to atovaquone.

The tolerability profile of atovaquone suspension appears to be similar to that of the tablet formulation.

Dosage and Administration

The recommended oral dosage of atovaquone, when administered in tablet form for treatment of mild to moderate PCP, is 750mg 3 times daily for 21 days. The suspension should be taken twice daily at a dose of 750mg. Atovaquone must be administered with meals as failure to do so may reduce therapeutic efficacy; alternative therapy should be considered in patients unable to take the drug with meals and in those with malabsorption conditions and/or severe diarrhoea. Rifampicin (rifampin) and atovaquone should not be administered concomitantly, as subtherapeutic atovaquone concentrations may result. Atovaquone tablets 750mg 4 times daily for 42 days, followed by maintenance therapy, in most instances with the same dosage or with a 3 times daily regimen, have been used for treating patients with toxoplasmosis in clinical trials.

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    Caroline M. Spencer & Karen L. Goa

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Various sections of the manuscript reviewed by: F. Derouin, Laboratoire de Parasitologie-Mycologie, Hôpital Saint-Louis, Paris, France; M.N. Dohn, Holmes Division, University of Cincinnati Medical Center, Cincinnati, Ohio, USA; B.G. Gazzard, Chelsea & Westminster Hospital, London, England; W. Hughes, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; S.R. Meshnick, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA; R. Murphy, AIDS Clinical Treatment Unit, Section of Infectious Diseases, Northwestern University Medical School, Chicago, Illinois, USA; J.K. Rockstroh, Allgemeine Innere Medizin, Medizinische Universitätsklinik, Bonn, Germany; T. Sauerbruch, Allgemeine Innere Medizin, Medizinische Universitätsklinik, Bonn, Germany; M.M.E. Schneider, Department of Internal Medicine, Immunology & Infectious Diseases, University Hospital, Utrecht, The Netherlands; N. Smith, Department of Genito-Urinary Medicine, St Thomas’ Hospital Trust, London, England.

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Spencer, C.M., Goa, K.L. Atovaquone. Drugs 50, 176–196 (1995). https://doi.org/10.2165/00003495-199550010-00011

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