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Mechanism of Action
Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis activity. The mechanism of action against Pneumocystis jiroveci has not been fully elucidated. In Plasmodium species, the site of action appears to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are linked to the mitochondrial electron transport chain via ubiquinone. Inhibition of electron transport by atovaquone will result in indirect inhibition of these enzymes. The ultimate metabolic effects of such blockade may include inhibition of nucleic acid and ATP synthesis.
Activity In Vitro
Several laboratories, using different in vitro methodologies, have shown the IC50 (50% inhibitory concentration) of atovaquone against rat P. jiroveci to be in the range of 0.1 to 3.0 mcg/mL.
Phenotypic resistance to atovaquone in vitro has not been demonstrated for P. jiroveci. However, in 2 patients who developed Pneumocystis carinii pneumonia (PCP) after prophylaxis with atovaquone, DNA sequence analysis identified mutations in the predicted amino acid sequence of P. jiroveci cytochrome b (a likely target site for atovaquone). The clinical significance of this is unknown.
Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The suspension formulation provides an approximately 2-fold increase in atovaquone bioavailability in the fasting or fed state compared to the previously marketed tablet formulation. The absolute bioavailability of a 750-mg dose of MEPRON Suspension administered under fed conditions in 9 HIV-infected (CD4 > 100 cells/mm³) volunteers was 47% ± 15%. In the same study, the bioavailability of a 750-mg dose of the previously marketed tablet formulation was 23% ± 11%.
Administering atovaquone with food enhances its absorption by approximately 2 fold. In one study, 16 healthy volunteers received a single dose of 750 mg MEPRON Suspension after an overnight fast and following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area under the concentration-time curve (AUC) values were 324 ± 115 and 801 ± 320 hr•mcg/mL under fasting and fed conditions, respectively, representing a 2.6 ± 1.0-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone concentrations was also evaluated in a multiple-dose, randomized, crossover study in 19 HIV-infected volunteers (CD4 < 200 cells/mm³) receiving daily doses of 500 mg MEPRON Suspension. AUC was 280 ± 114 hr•mcg/mL when atovaquone was administered with food as compared to 169 ± 77 hr•mcg/mL under fasting conditions. Maximum plasma atovaquone concentration (Cmax) was 15.1 ± 6.1 and 8.8 ± 3.7 mcg/mL when atovaquone was administered with food and under fasting conditions, respectively.
Plasma atovaquone concentrations do not increase proportionally with dose. When MEPRON Suspension was administered with food at dosage regimens of 500 mg once daily, 750 mg once daily, and 1,000 mg once daily, average steady-state plasma atovaquone concentrations were 11.7 ± 4.8, 12.5 ± 5.8, and 13.5 ± 5.1 mcg/mL, respectively. The corresponding Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL. When MEPRON Suspension was administered to 5 HIV-infected volunteers at a dose of 750 mg twice daily, the average steady-state plasma atovaquone concentration was 21.0 ± 4.9 mcg/mL and Cmax was 24.0 ± 5.7 mcg/mL. The minimum plasma atovaquone concentration (Cmin) associated with the 750-mg twice-daily regimen was 16.7 ± 4.6 mcg/mL.
Following the intravenous administration of atovaquone, the 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-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.
The plasma clearance of atovaquone following intravenous (IV) administration in 9 HIV-infected volunteers was 10.4 ± 5.5 mL/min (0.15 ± 0.09 mL/min/kg). The half-life of atovaquone was 62.5 ± 35.3 hours after IV administration and ranged from 67.0 ± 33.4 to 77.6 ± 23.1 hours across studies following administration of MEPRON Suspension. The half-life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. In a study where 14C-labelled atovaquone was administered to healthy volunteers, greater than 94% of the dose was recovered as unchanged atovaquone in the feces over 21 days. There was little or no excretion of atovaquone in the urine (less than 0.6%). There is indirect evidence that atovaquone may undergo limited metabolism; however, a specific metabolite has not been identified.
In a study of MEPRON Suspension in 27 HIV-infected, asymptomatic infants and children between 1 month and 13 years of age, the pharmacokinetics of atovaquone were age dependent. These patients were dosed once daily with food for 12 days. The average steady-state plasma atovaquone concentrations in the 24 patients with available concentration data are shown in Table 1.
Table 1: Average Steady-State Plasma Atovaquone
Concentrations in Pediatric Patients
|Age||Dose of MEPRON Suspension|
|10 mg/kg||30 mg/kg||45 mg/kg|
|Average Css in mcg/mL (mean ± SD)|
(n = 1)
|27.8 ± 5.8
(n = 4)
|> 3-24 months||5.7 ± 5.1
(n = 4)
|9.8 ± 3.2
(n = 4)
|15.4 ± 6.6
(n = 4)
|> 2-13 years||16.8 ± 6.4
(n = 4)
|37.1 ± 10.9
(n = 3)
The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment.
In a study with 13 HIV-infected volunteers, the oral administration of rifampin 600 mg every 24 hours with MEPRON Suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the average steady-state plasma atovaquone concentration and a 37% ± 42% increase in the average 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.
Rifabutin, another rifamycin, is structurally similar to rifampin and may possibly have some of the same drug interactions as rifampin. No interaction trials have been conducted with MEPRON and rifabutin.
The possible interaction between atovaquone and TMP-SMX was evaluated in 6 HIV-infected adult volunteers as part of a larger multiple-dose, dose-escalation, and chronic dosing study of MEPRON Suspension. In this crossover study, MEPRON Suspension 500 mg once daily, or TMP-SMX tablets (160 mg trimethoprim and 800 mg sulfamethoxazole) twice daily, or the combination were administered with food to achieve steady state. No difference was observed in the average steady-state plasma atovaquone concentration after coadministration with TMP-SMX. Coadministration of MEPRON with TMP-SMX resulted in a 17% and 8% decrease in average steady-state concentrations of trimethoprim and sulfamethoxazole in plasma, respectively. This effect is minor and would not be expected to produce clinically significant events.
Data from 14 HIV-infected volunteers who were given atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every 8 hours showed 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.
Relationship Between Plasma Atovaquone Concentration and Clinical Outcome
In a comparative study of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate PCP (see INDICATIONS AND USAGE), where AIDS patients received 750 mg atovaquone tablets 3 times daily for 21 days, the mean steady-state atovaquone concentration was 13.9 ± 6.9 mcg/mL (n = 133). Analysis of these data established a relationship between plasma atovaquone concentration and successful treatment. This is shown in Table 2.
Table 2: Relationship Between Plasma Atovaquone
Concentration and Successful Treatment
|Steady-State Plasma Atovaquone Concentrations (mcg/mL)||Successful Treatmenta
No. Successes/No. in Group (%)
|0 to < 5||0/6||(0)||1.5/6||(25)|
|5 to < 10||18/26||(69)||14.7/26||(57)|
|10 to < 15||30/38||(79)||31.9/38||(84)|
|15 to < 20||18/19||(95)||18.1/19||(95)|
|20 to < 25||18/18||(100)||17.8/18||(99)|
|aSuccessful treatment was defined as improvement in clinical
and respiratory measures persisting at least 4 weeks after cessation of
therapy. This was based on data from patients for which both outcome and
steady-state plasma atovaquone concentration data are available.
bBased on logistic regression analysis.
A dosing regimen of MEPRON Suspension for the treatment of mild-to-moderate PCP has been selected to achieve average plasma atovaquone concentrations of approximately 20 mcg/mL, because this plasma concentration was previously shown to be well tolerated and associated with the highest treatment success rates (Table 2). In an open-label PCP treatment study with MEPRON Suspension, dosing regimens of 1,000 mg once daily, 750 mg twice daily, 1,500 mg once daily, and 1,000 mg twice daily were explored. The average steady-state plasma atovaquone concentration achieved at the 750-mg twice-daily dose given with meals was 22.0 ± 10.1 mcg/mL (n = 18).
Last reviewed on RxList: 3/21/2013
This monograph has been modified to include the generic and brand name in many instances.
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