espiratory 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 eva luated 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 pl |
