MEPRON Oral suspension Ref.[10869] Active ingredients: Atovaquone

Relationship between Plasma Atovaquone Concentrations and Clinical Outcome

In a comparative clinical trial, HIV/AIDS subjects received atovaquone tablets 750 mg 3 times daily or TMP‑SMX for treatment of mild‑to‑moderate PCP for 21 days [see Clinical Studies (14.2)]; the relationship between atovaquone plasma concentrations and successful treatment outcome from 113 of these subjects for whom both steady-state drug concentrations and outcome data were available is shown in Table 6.

Table 6. Relationship between Plasma Atovaquone Concentrations and Successful Treatment Outcome:

^a Successful treatment outcome 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, and severity scores for cough, dyspnea, and chest pain/tightness.

Cardiac Effects

The effect of MEPRON oral suspension on the QT interval is unknown in humans.

Plasma atovaquone concentrations do not increase proportionally with dose following ascending repeat-dose administration of MEPRON oral suspension in healthy subjects. When MEPRON 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) C_max 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 MEPRON oral suspension administered under fed conditions in 9 HIV-1–infected (CD4 >100 cells/mm ³) volunteers was 47% ± 15%.

Effect of Food

Administering MEPRON oral suspension with food enhances atovaquone bioavailability. Sixteen healthy subjects received a single 750-mg dose of MEPRON 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 ± 1.0-fold increase.

Distribution

Following IV administration of atovaquone, the mean (±SD) volume of distribution at steady state (Vd_ss) 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 67.0 ± 33.4 to 77.6 ± 23.1 hours following administration of MEPRON oral suspension.

Metabolism

The metabolism of atovaquone is unknown.

Excretion

Following oral administration of ¹⁴C-labelled atovaquone 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 MEPRON 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 21.0 ± 4.9 mcg/mL and mean (±SD) C_max was 24.0 ± 5.7 mcg/mL. The mean (±SD) minimum plasma atovaquone concentration (C_min) 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 MEPRON oral suspension 750 mg twice daily with meals resulted in a mean (±SD) steady‑state plasma atovaquone concentration of 22.0 ± 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 MEPRON 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 MEPRON 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 C_max of indinavir, but resulted in a decrease in the C_trough of indinavir (23% decrease [90% CI: 8%, 35%]).

Trimethoprim/Sulfamethoxazole (TMP-SMX)

Concomitant administration of MEPRON 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.

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 bc₁ 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.

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.

14.1 Prevention of PCP

The indication for prevention of PCP is based on the results of 2 clinical trials comparing MEPRON 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 MEPRON 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 MEPRON oral suspension 1,500 mg once daily (n=175), MEPRON 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:

^a Those events occurring during or within 30 days of stopping assigned treatment.
^b Relative risk <1 favors MEPRON and values >1 favor comparator. Trial results did not show superiority of MEPRON 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 MEPRON 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 MEPRON 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 3 times daily. Results from these efficacy trials established a relationship between plasma atovaquone concentrations and successful outcome. Successful outcome was defined as improvement in clinical and respiratory measures persisting at least 4 weeks after cessation of therapy [see Clinical Pharmacology (12.2)].

TMP-SMX Comparative Trial

This double-blind, randomized trial compared the safety and efficacy of MEPRON 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 MEPRON (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 MEPRON 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 MEPRON and 7 (3.4%) deaths among subjects treated with TMP-SMX (P=0.051). Of the 13 subjects with confirmed PCP and treated with MEPRON 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 (2.0%) of the 49 subjects with Day 4 plasma atovaquone concentrations ≥5 mcg/mL died.

Sixty-two percent of subjects on MEPRON 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:

^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 MEPRON, 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 MEPRON 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 MEPRON 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 MEPRON 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 MEPRON 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 MEPRON 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: