Pharmacokinetics

Absorption: Atovaquone is a highly lipophilic compound with low aqueous solubility. The bioavailability of atovaquone is highly dependent on formulation and diet. The suspension formulation provides an approximately twofold increase in atovaquone bioavailability in the fasting or fed state compared to the previously marketed tablet formulation. The absolute bioavailability of a 750- mg dose of MEPRON Suspension administered under fed conditions in nine HIV- infected (CD4 100 cells/ mm³) volunteers was 47% ± 15%. In the same study, the bioavailability of a 750- mg dose of the previously marketed tablet formulation was 23% ± 11%.

Administering atovaquone with food enhances its absorption by approximately two- fold. In one study, 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 were 324 ± 115 and 801 ± 320 hr· mcg/ mL under fasting and fed conditions, 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 study in 19 HIV- infected volunteers (CD4 <200 cells/ mm³ ) receiving daily doses of 500 mg MEPRON Suspension. AUC was 280 ± 114 hr· mcg/ mL when atovaquone was administered with food as compared to 169 ± 77 hr· mcg/ mL under fasting conditions. Maximum plasma atovaquone concentration (C_max) was 15.1 ± 6.1 and 8.8 ± 3.7 mcg/ mL when atovaquone was administered with food and under fasting conditions, 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 1000 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 C_max concentrations were 15.1 ± 6.1, 15.3 ± 7.6, and 16.8 ± 6.4 mcg/ mL. When MEPRON Suspension was administered to five HIV- 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 C_max was 24.0 ± 5.7 mcg/ mL. The minimum plasma atovaquone concentration (C_min) associated with the 750- mg twice- daily regimen was 16.7 ± 4.6 mcg/ mL.

Distribution: Following the intravenous administration of atovaquone, the 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 three HIV- infected children who received 750 mg atovaquone as the tablet formulation four 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 intravenous (IV) administration in nine HIV- infected volunteers was 10.4 ± 5.5 mL/ min (0.15 ± 0.09 mL/ min per 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 studies following administration of MEPRON Suspension. The half- life of atovaquone is long due to presumed enterohepatic cycling and eventual fecal elimination. In a study 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.

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