EXAMINATION OF SOME FACTORS RESPONSIBLE FOR A FOOD-INDUCED INCREASE IN ABSORPTION OF ATOVAQUONE

1 Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2 In 18 healthy male volunteers, a high-fat breakfast administered 45 min before 500 mg atovaquone as tablets increased AUC by 3.3-fold (95% CI 2.8-4.0) and C(max) 5.3-fold (4.3-6.6) compared with fasting. 3 The absorption of atovaquone from tablets was examined in 12 healthy male volunteers after an overnight fast, following toast alone, toast with 28 g butter (LOFAT), or toast with 56 g butter (HIFAT). Compared with absorption when fasted, toast had no significant effect but LOFAT increased AUC 3.0-fold (2.1-4.2) and C(max) 3.9-fold (2.6-5.8). HIFAT increased AUC 3.9-fold (2.7-5.5) and C(max) 5.6-fold (3.8-8.4). 4 The absorption of atovaquone was examined in nine healthy fasting male volunteers from tablets, an aqueous suspension, and an oily solution/suspension in miglyol (fractionated coconut oil). Compared with tablets, AUC following the aqueous suspension was increased 1.7-fold (1.0-2.7) and C(max) 2.4-fold (1.7-3.5). Following miglyol, AUC was increased to the same extent but C(max) was only increased 1.8-fold (1.2-2.6). 5 Atovaquone absorption was examined in eight healthy fasting male volunteers following an i.v. infusion of cholecystokinin octapeptide (CCK-OP) which decreased gallbladder volume by 82% (73%-90%) on occasion 1 or saline on occasion 2. AUC(0,12) was increased following CCK-OP by 1.6-fold (1.1-2.4) and C(max) by 1.5-fold (0.98-2.4). However, total AUC was not significantly increased (mean ratio 1.2, 95% CI 0.85-1.8). 6 In four healthy male volunteers who received 750 mg atovaquone containing 100 muCi [C-14]-atovaquone as a suspension following a high-fat meal, no drug was detected in chylomicrons separated from plasma. 7 The substantial increase in absorption of atovaquone from tablets after a fatty meal can be accounted for quantitatively by the fat content of the meal. Absorption from suspensions in water and miglyol was superior to that from tablets but both were inferior to the tablets following a high fat meal. Bile release may make some contribution to the food effect. Food probably increases atovaquone absorption by increasing its solubility in the gut lumen.