Mechanism of Action
Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jirovecii has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc 1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone results in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and adenosine triphosphate (ATP) synthesis.
Atovaquone is active against P. jirovecii [see CLINICAL STUDIES (14)].
Phenotypic resistance to atovaquone in vitro has not been demonstrated for P. jirovecii. However, in 2 subjects who developed PCP after prophylaxis with atovaquone, DNA sequence analysis identified mutations in the predicted amino acid sequence of P. jirovecii cytochrome b (a likely target site for atovaquone). The clinical significance of this is unknown.
Carcinogenicity studies in rats were negative; 24-month studies in mice (dosed with 50, 100, or 200 mg/kg/day), showed treatment-related increases in incidence of hepatocellular adenoma and hepatocellular carcinoma at all doses tested, which correlated with 1.4 to 3.6 times the average steady-state plasma concentrations in humans during acute treatment of PCP. Atovaquone was negative with or without metabolic activation in the Ames Salmonella mutagenicity assay, the mouse lymphoma mutagenesis assay, and the cultured human lymphocyte cytogenetic assay. No evidence of genotoxicity was observed in the in vivo mouse micronucleus assay.
Impairment of Fertility
Atovaquone administered by oral gavage in doses of 100, 300, or 1,000 mg/kg/day to adult male rats from 73 days prior to mating until 20 days after mating and to adult female rats from 14 days prior to mating until LD20 did not impair male or female fertility or early embryonic development at doses up to 1,000 mg/kg/day corresponding to plasma exposures of approximately 3 times the estimated human exposure based on steady-state plasma concentrations.
The indication for prevention of PCP is based on the results of 2 clinical trials comparing atovaquone oral suspension with dapsone or aerosolized pentamidine in HIV-1-infected adolescent (aged 13 to 18 years) and adult subjects at risk of PCP (CD4 count <200 cells/mm 3 or a prior episode of PCP) and unable to tolerate TMP-SMX.
Dapsone Comparative Trial
This open-label trial enrolled 1,057 subjects, randomized to receive atovaquone oral suspension 1,500 mg once daily (n = 536) or dapsone 100 mg once daily (n = 521). The majority of subjects were white (64%), male (88%), and receiving prophylaxis for PCP at randomization (73%); the mean age was 38 years. Median follow-up was 24 months. Subjects randomized to the dapsone arm who were seropositive for Toxoplasma gondii and had a CD4 count <100 cells/mm 3 also received pyrimethamine and folinic acid. PCP event rates are shown in Table 7. Mortality rates were similar.
Aerosolized Pentamidine Comparative Trial
This open-label trial enrolled 549 subjects, randomized to receive atovaquone oral suspension 1,500 mg once daily (n = 175), atovaquone oral suspension 750 mg once daily (n = 188), or aerosolized pentamidine 300 mg once monthly (n = 186). The majority of subjects were white (79%), male (92%), and were primary prophylaxis patients at enrollment (58%); the mean age was 38 years. Median follow-up was 11.3 months. The results of the PCP event rates appear in Table 7. Mortality rates were similar among the groups.
|Assessment||Trial 1||Trial 2|
|Atovaquone Oral Suspension 1,500 mg/day (n = 527)||Dapsone 100 mg/day (n = 510)||Atovaquone Oral Suspension 750 mg/day (n = 188)||Atovaquone Oral Suspension 1,500 mg/day (n = 172)||Aerosolized Pentamidine 300 mg/month (n = 169)|
|Relative Risk b (CI) c||0.77 (0.57, 1.04)||1.47 (0.86, 2.50)||1.14 (0.63, 2.06)|
a Those events occurring during or within 30 days of stopping assigned treatment.
b Relative risk <1 favors atovaquone and values >1 favor comparator. Trial results did not show superiority of atovaquone to the comparator. c The confidence level of the interval for the dapsone comparative trial was 95% and for the pentamidine comparative trial was 97.5%.
An analysis of all PCP events (intent-to-treat analysis) for both trials showed results similar to those shown in Table 7.
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