r 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 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.
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 (14.2)], 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
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, r |
