Atovaquone (Page 3 of 4)

12.4 Microbiology

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.
Activity In Vitro
Several laboratories, using different in vitro methodologies, have shown the IC50 (50% inhibitory concentration) of atovaquone against P. jirovecii to be 0.1 to 3 mcg/mL.
Drug Resistance
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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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.

14 CLINICAL STUDIES

14.1 Prevention of PCP

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/mm3 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/mm3 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.Table 7. Confirmed or Presumed/Probable PCP Events (As-Treated Analysis)a

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)

%

15

19

23

18

17

Relative Riskb (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.

14.2 Treatment of PCP

The indication for treatment of mild-to-moderate PCP is based on the results of 2 efficacy trials: a randomized, double-blind trial comparing atovaquone tablets with TMP-SMX in subjects with HIV/AIDS and mild-to-moderate PCP (defined in the protocol as [(A-a)DO2 ] ≤45 mm Hg and PaO2 ≥60 mm Hg on room air) and a randomized open-label trial comparing atovaquone tablets with IV pentamidine isethionate in subjects with mild-to-moderate PCP who could not tolerate trimethoprim or sulfa antimicrobials. Both trials were conducted with the tablet formulation using 750 mg three times daily. Results from these efficacy trials established a relationship between plasma atovaquone concentration and successful outcome. Successful outcome was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Comparative pharmacokinetic trials of the oral suspension and tablet formulations established the currently recommended oral suspension dose of 750 mg twice daily [see Clinical Pharmacology (12.3)].
TMP-SMX Comparative Trial
This double-blind, randomized trial compared the safety and efficacy of atovaquone tablets with that of TMP-SMX for the treatment of subjects with HIV/AIDS and histologically confirmed PCP. Only subjects with mild-to-moderate PCP were eligible for enrollment.
A total of 408 subjects were enrolled into the trial. The majority of subjects were white (66%) and male (95%); the mean age was 36 years. Eighty-six subjects without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 322 subjects with histologically confirmed PCP, 160 were randomized to receive 750 mg atovaquone (three 250-mg tablets) 3 times daily for 21 days and 162 were randomized to receive 320 mg TMP plus 1,600 mg SMX 3 times daily for 21 days. Therapy success was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy. Improvement in clinical and respiratory measures was assessed using a composite of parameters that included oral body temperature, respiratory rate, severity scores for cough, dyspnea, and chest pain/tightness. Therapy failures included lack of response, treatment discontinuation due to an adverse experience, and unevaluable.
There was a significant difference (P = 0.03) in mortality rates between the treatment groups favoring TMP-SMX. Among the 322 subjects with confirmed PCP, 13 of 160 (8%) subjects treated with atovaquone and 4 of 162 (2.5%) subjects receiving TMP-SMX died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all 408 randomized subjects, there were 16 (8%) deaths among subjects treated with atovaquone and 7 (3.4%) deaths among subjects treated with TMP-SMX (P = 0.051). Of the 13 subjects with confirmed PCP and treated with atovaquone who died, 4 died of PCP and 5 died with a combination of bacterial infections and PCP; bacterial infections did not appear to be a factor in any of the 4 deaths among TMP-SMX-treated subjects.
A correlation between plasma atovaquone concentrations and death demonstrated that subjects with lower plasma concentrations were more likely to die. For those subjects for whom Day 4 plasma atovaquone concentration data are available, 5 (63%) of 8 subjects with concentrations <5 mcg/mL died during participation in the trial. However, only 1 (2%) of the 49 subjects with Day 4 plasma atovaquone concentrations ≥5 mcg/mL died.
Sixty-two percent of subjects on atovaquone and 64% of subjects on TMP-SMX were classified as protocol-defined therapy successes (Table 8).Table 8. Outcome of Treatment for PCP-positive Subjects Enrolled in the TMP-SMX Comparative Trial

Outcome of Therapya

Number of Subjects (%)

Atovaquone Tablets (n = 160)

TMP-SMX (n = 162)

Therapy success

99

62%

103

64%

Therapy failure due to: -Lack of response -Adverse reaction -Unevaluable

281122

17%7%14%

103316

6%20%10%

Required alternate PCP therapy during trial

55

34%

55

34%

a As defined by the protocol and described in trial description above.
The failure rate due to lack of response was significantly higher for subjects receiving atovaquone, while the failure rate due to an adverse reaction was significantly higher for subjects receiving TMP-SMX.
Pentamidine Comparative Trial
This unblinded, randomized trial was designed to compare the safety and efficacy of atovaquone with that of pentamidine for the treatment of histologically-confirmed mild or moderate PCP in subjects with HIV/AIDS. Approximately 80% of the subjects either had a history of intolerance to trimethoprim or sulfa antimicrobials (the primary therapy group) or were experiencing intolerance to TMP-SMX with treatment of an episode of PCP at the time of enrollment in the trial (the salvage treatment group). A total of 174 subjects were enrolled into the trial. Subjects were randomized to receive atovaquone 750 mg (three 250-mg tablets) 3 times daily for 21 days or pentamidine isethionate 3-to 4-mg/kg single IV infusion daily for 21 days. The majority of subjects were white (72%) and male (97%); the mean age was approximately 37 years. Thirty-nine subjects without histologic confirmation of PCP were excluded from the efficacy analyses. Of the 135 subjects with histologically-confirmed PCP, 70 were randomized to receive atovaquone and 65 to pentamidine. One hundred and ten (110) of these were in the primary therapy group and 25 were in the salvage therapy group. One subject in the primary therapy group randomized to receive pentamidine did not receive trial medication.
There was no difference in mortality rates between the treatment groups. Among the 135 subjects with confirmed PCP, 10 of 70 (14%) subjects receiving atovaquone and 9 of 65 (14%) subjects receiving pentamidine died during the 21-day treatment course or 8-week follow-up period. In the intent-to-treat analysis for all subjects, there were 11 (12.5%) deaths among those treated with atovaquone and 12 (14%) deaths among those treated with pentamidine. Among subjects for whom Day 4 plasma atovaquone concentrations were available, 3 of 5 (60%) subjects with concentrations <5 mcg/mL died during participation in the trial. However, only 2 of 21 (9%) subjects with Day 4 plasma concentrations ≥5 mcg/mL died. The therapeutic outcomes for the 134 subjects who received trial medication in this trial are presented in Table 9.Table 9. Outcome of Treatment for PCP-positive Subjects (%) Enrolled in the Pentamidine Comparative Trial

Outcome of Therapy

Primary Treatment

Salvage Treatment

Atovaquone (n = 56)

Pentamidine (n = 53)

Atovaquone (n = 14)

Pentamidine (n = 11)

Therapy success

32

57%

21

40%

13

93%

7

64%

Therapy failure due to: -Lack of response -Adverse reaction -Unevaluable

1626

29%3.6%11%

9194

17%36%8%

001

7%

031

27%9%

Required alternate PCP therapy during trial

19

34%

29

55%

0

4

36%

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