Prescription Drug Information: Atovaquone (Page 3 of 5)

12.3 Pharmacokinetics

Plasma atovaquone concentrations do not increase proportionally with dose following ascending repeat-dose administration of atovaquone oral suspension in healthy subjects. When atovaquone oral suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily, and 1,000 mg once daily, mean (±SD) steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8, and 13.5 ± 5.1 mcg/mL, respectively. The corresponding mean (±SD) Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL.

Absorption

Atovaquone is a highly lipophilic compound with low aqueous solubility. The mean (±SD) absolute bioavailability of atovaquone from a 750-mg dose of atovaquone oral suspension administered under fed conditions in 9 HIV-1-infected (CD4 >100 cells/mm3) volunteers was 47% ± 15%.

Effect of Food: Administering atovaquone oral suspension with food enhances atovaquone bioavailability. Sixteen healthy subjects received a single 750 mg- dose of atovaquone oral suspension after an overnight fast and following a meal (23 g fat: 610 kCal). The mean (SD) atovaquone AUC under fasting and fed conditions were 324  115 and 801  320 h●mcg/mL, respectively, representing a 2.6  1-fold increase.

Distribution

Following IV administration of atovaquone, the mean (±SD) volume of distribution at steady state (Vdss ) was 0.60 ± 0.17 L/kg (n = 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the concentration range of 1 to 90 mcg/mL. In 3 HIV-1-infected children who received 750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal fluid concentrations of atovaquone were 0.04, 0.14, and 0.26 mcg/mL, representing less than 1% of the plasma concentration.

Elimination

The mean (SD) half-life of atovaquone was 62.5  35.3 hours after IV administration and ranged from 67  33.4 to 77.6  23.1 hours following administration of atovaquone oral suspension.

Metabolism: The metabolism of atovaquone is unknown.

Excretion: Following oral administration of 14 C-labelled atovaquone was administered to healthy subjects, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days.

Specific Populations

Patients with Hepatic or Renal Impairment: The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment.

HIV-Infected Subjects: When atovaquone oral suspension was administered to 5 HIV-1–infected subjects at a dose of 750 mg twice daily, the mean (±SD) steady-state plasma atovaquone concentration was 21 ± 4.9 mcg/mL and mean (±SD) Cmax was 24 ± 5.7 mcg/mL. The mean (±SD) minimum plasma atovaquone concentration (Cmin ) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL.

In an open-label PCP trial in 18 HIV-1–infected subjects, administration of atovaquone oral suspension 750 mg twice daily with meals resulted in a mean (±SD) steady-state plasma atovaquone concentration of 22 ± 10.1 mcg/mL.

The mean (±SD) plasma clearance of atovaquone following IV administration in 9 HIV-1–infected subjects was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg).

Drug Interaction Studies

Rifampin/Rifabutin: In a trial with 13 HIV-1-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with atovaquone oral suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the mean (±SD) steady‑state plasma atovaquone concentration and a 37% ± 42% increase in the mean (±SD) steady‑state plasma rifampin concentration. The half‑life of atovaquone decreased from 82 ± 36 hours when administered without rifampin to 50 ± 16 hours with rifampin. In a trial of 24 healthy volunteers, the oral administration of rifabutin 300 mg once daily with atovaquone oral suspension 750 mg twice daily resulted in a 34% decrease in the mean steady‑state plasma atovaquone concentration and a 19% decrease in the mean steady‑state plasma rifabutin concentration.

Tetracycline: Concomitant treatment with tetracycline has been associated with a 40% reduction in plasma concentrations of atovaquone.

Metoclopramide: Concomitant treatment with metoclopramide has been associated with a 50% reduction in steady-state atovaquone plasma concentrations.

Indinavir: Concomitant administration of atovaquone (750 mg twice daily with food for 14 days) and indinavir (800 mg three times daily without food for 14 days) did not result in any change in the steady‑state AUC and Cmax of indinavir, but resulted in a decrease in the Ctrough of indinavir (23% decrease [90% CI: 8%, 35%]).

Trimethoprim/Sulfamethoxazole: Concomitant administration of atovaquone oral suspension 500 mg once daily (not the approved dosage) and TMP-SMX in 6 HIV-infected adult subjects did not result in significant changes in either atovaquone or TMP-SMX exposure.

Zidovudine: The administration of atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every 8 hours to 14 HIV-1 infected subjects resulted in a 24% ± 12% decrease in zidovudine apparent oral clearance, leading to a 35% ± 23% increase in plasma zidovudine AUC. The glucuronide metabolite: parent ratio decreased from a mean of 4.5 when zidovudine was administered alone to 3.1 when zidovudine was administered with atovaquone tablets. This effect is minor and would not be expected to produce clinically significant events. Zidovudine had no effect on atovaquone pharmacokinetics.

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.

Antimicrobial Activity

Atovaquone is active against P. jirovecii [see Clinical Studies (14)].

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.

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.

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 6. 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

0.77

1.47

1.14

(CI)c

(0.57, 1.04)

(0.86, 2.50)

(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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