Mechanism Of Action
Atovaquone is a quinone antimicrobial drug [see Microbiology].
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]; 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
|Steady-State Plasma Atovaquone
No. of Successes/No. in Group
|0 to <5
|5 to <10
|10 to <15
|15 to <20
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.
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) Cmax concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/mL.
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/mm3) 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.
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.
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
The metabolism of atovaquone is unknown.
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.
Patients With Hepatic Or Renal Impairment
The pharmacokinetics of atovaquone have not been
studied in patients with hepatic or renal impairment.
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) Cmax was 24.0 ± 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 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
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.
Concomitant treatment with tetracycline has been associated with a 40% reduction
in plasma concentrations of atovaquone.
Concomitant treatment with metoclopramide has been associated with a 50%
reduction in steady-state atovaquone plasma concentrations.
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%]).
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.
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.
Atovaquone is active against P. jirovecii [see Clinical Studies].
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.
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
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
(n = 527)
(n = 510)
(n = 188)
(n = 172)
(n = 169)
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.
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].
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
|Outcome of Therapya
||Number of Subjects (%)
(n = 160)
(n = 162)
|Therapy failure due to:
| -Lack of response
| -Adverse reaction
|Required alternate PCP therapy during 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
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
|Outcome of Therapy
(n = 56)
(n = 53)
(n = 14)
(n = 11)
|Therapy failure due to:
| -Lack of response
| -Adverse reaction
|Required alternate PCP therapy