Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum

The population pharmacokinetics of atovaquone were examined in 458 black, Oriental, and Malay patients with acute Plasmodium falciparum malaria receiving atovaquone alone or concomitantly with other drugs. Oral clearance (CL/F) showed a 0.674 power relationship with weight and is similar in Oriental and Malay subjects but 58.5% lower in black subjects. On the basis of mean body weight, the population estimate of CL/F is 3.28, 8.49, and 9.13 L/hr in black, Oriental, and Malay subjects, respectively. The relationship between apparent volume of distribution (V-area/F) and weight was linear and similar in all three races at 7.98 L/kg. The population estimate of V-area/F is 345, 383, and 428 L in black, Oriental, and Malay subjects, respectively. The bioavailability of the high and low doses of atovaquone was similar. Neither CL/F nor V-area/F were significantly affected by age, gender, and the coadministration with chloroguanide (proguanil), pyrimethamine and tetracycline. Half-life (t(1/2)) showed a 0.326 power relationship with weight; thus, the population estimate of t(1/2) in black, Oriental, and Malay subjects is 72.9, 31.3, and 32.5 hours, respectively. The final magnitudes of interpatient variability in CL/F and V-area/F were 68% and 49%, respectively.