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CLINICAL PHARMACOLOGY

Mechanism Of Action

Atovaquone is a quinone antimicrobial drug [see Microbiology].

Pharmacokinetics

Absorption

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

Administering atovaquone with food enhances its absorption by approximately 2-fold. In one trial, 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 under fasting and fed conditions were 324 ± 115 and 801 ± 320 h•mcg/mL, 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 trial in 19 HIV-1-infected volunteers (CD4 < 200 cells/mm³) receiving daily doses of 500 mg MEPRON suspension. AUC values under fasting and fed conditions were 169 ± 77 and 280 ± 114 h•mcg/mL, respectively. Maximum plasma atovaquone concentration (Cmax) values under fasting and fed conditions were 8.8 ± 3.7 and 15.1 ± 6.1 mcg/mL, respectively.

Dose Proportionality

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-1-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.

Distribution

Following IV 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-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 plasma clearance of atovaquone following IV administration in 9 HIV-1-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 trials following administration of MEPRON suspension. The half-life of atovaquone is due to presumed enterohepatic cycling and eventual fecal elimination. In a trial where 14Clabelled 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.

Hepatic/Renal Impairment

The pharmacokinetics of atovaquone have not been studied in patients with hepatic or renal impairment.

Relationship between Plasma Atovaquone Concentration and Clinical Outcome

In a comparative trial of atovaquone tablets with TMP-SMX for oral treatment of mild-to-moderate PCP [see Clinical Studies], where subjects with HIV/AIDS received atovaquone tablets 750 mg 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 (Table 6).

Table 6: Relationship between Plasma Atovaquone Concentration and Successful Treatment

Steady-state Plasma Atovaquone Concentrations (mcg/mL) Successful Treatmenta No. Successes/No. in Group (%)
Observed Predictedb
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%
25+ 6/6 100% 6/6 100%
aSuccessful treatment 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. This analysis was based on data from subjects for whom both outcome and steady-state plasma atovaquone concentration data were available.
bBased on logistic regression analysis.

A dosing regimen of MEPRON suspension for the treatment of mild-to-moderate PCP was 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 6). In an open-label PCP treatment trial 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).

Drug Interactions

Rifampin/Rifabutin: In a trial with 13 HIV-1-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. In a trial of 24 healthy volunteers, the oral administration of rifabutin 300 mg once daily with MEPRON suspension 750 mg twice daily resulted in a 34% decrease in the average steady-state plasma atovaquone concentration and a 19% decrease in the average 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 decreased bioavailability of atovaquone.

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: The possible interaction between atovaquone and TMP-SMX was evaluated in 6 HIV-1-infected adult volunteers as part of a larger multiple-dose, dose-escalation, and chronic dosing trial of MEPRON suspension. In this crossover trial, MEPRON suspension 500 mg once daily (not the approved dosage), or TMP-SMX tablets (trimethoprim 160 mg and sulfamethoxazole 800 mg) 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.

Zidovudine: Data from 14 HIV-1-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.

Microbiology

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 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. jiroveci to be 0.1 to 3.0 mcg/mL.

Drug Resistance

Phenotypic resistance to atovaquone in vitro has not been demonstrated for P. jiroveci. However, in 2 subjects who developed 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.

Clinical Studies

Prevention Of PCP

The indication for prevention of PCP is based on the results of 2 clinical trials comparing MEPRON 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 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 suspension 1,500 mg once daily (n = 175), MEPRON 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
MEPRON Suspension 1,500 mg/day
(n = 527)
Dapsone 100 mg/day
(n = 510)
MEPRON Suspension 750 mg/day
(n = 188)
MEPRON 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)  
aThose events occurring during or within 30 days of stopping assigned treatment.
bRelative risk < 1 favors MEPRON and values > 1 favor comparator. Trial results did not show superiority of MEPRON to the comparator.
cThe 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.

Treatment Of PCP

The indication for treatment of mild-to-moderate PCP is based on the results of two 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 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 suspension and tablet formulations established the currently recommended suspension dose of 750 mg twice daily [see Pharmacokinetics].

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

Outcome of Therapya Number of Subjects (%)
MEPRON Tablets
(n = 160)
TMP-SMX
(n = 162)
Therapy success 99 62% 103 64%
Therapy failure due to:
-Lack of response 28 17% 10 6%
-Adverse reaction 11 7% 33 20%
-Unevaluable 22 14% 16 10%
Required alternate PCP therapy during trial 55 34% 55 34%
aAs 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

Outcome of Therapy Primary Treatment Salvage Treatment
MEPRON
(n = 56)
Pentamidine
(n = 53)
MEPRON
(n = 14)
Pentamidine
(n = 11)
Therapy success 32 57% 21 40% 13 93% 7 64%
Therapy failure due to:
  -Lack of response 16 29% 9 17% 0   0  
  -Adverse reaction 2 3.6% 19 36% 0   3 27%
  -Unevaluable 6 11% 4 8% 1 7% 1 9%
Required alternate PCP therapy during trial 19 34% 29 55% 0   4 36%

Last reviewed on RxList: 6/26/2015
This monograph has been modified to include the generic and brand name in many instances.

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