title: Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum.
abstract: 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 (t1/2) showed a 0.326 power relationship with weight; thus, the population estimate of t1/2 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.
authors.affiliation: Glaxo Wellcome, Beckenham, and Pharmaceutical Systems Inc., Talent, Oregon, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Hussein
authors.forename: J
authors.initials: J
authors.lastname: Eaves
authors.forename: D B
authors.initials: DB
authors.lastname: Hutchinson
authors.forename: C J
authors.initials: CJ
authors.lastname: Canfield
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053626:Atovaquone; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D005260:Female; D005681:Gabon; D006801:Humans; D007630:Kenya; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009285:Naphthoquinones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010679:Philippines; D013785:Thailand; D015024:Zambia
chemical_list: D000962:Antimalarials; D009285:Naphthoquinones; D053626:Atovaquone