POPULATION PHARMACOKINETICS OF PROGUANIL IN PATIENTS WITH ACUTE PLASMODIUM-FALCIPARUM MALARIA AFTER COMBINED THERAPY WITH ATOVAQUONE

1 The pharmacokinetics of proguanil were evaluated in patients with ac ute P. falciparum malaria receiving concomitantly proguanil hydrochlor ide and atovaquone. The population consisted of 203 Blacks, 112 Orient als and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizer s of proguanil, respectively. Body weight and age ranged between 11-11 0 kg and 3-65 years, respectively. 2 A one compartment model with firs t-order absorption and elimination was fitted to proguanil plasma conc entration-time profiles, using non-linear mixed effect modelling (NONM EM). 3 Oral clearance (CL(o)) showed a 0.785 power relationship with b ody weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the me an weight of each population, the final population estimates of CL(o) in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.31 h(-1), respectively. Age, gender and dose had no significant effects on CL(o). 4 Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final populatio n estimates were 562 and 1629 l in children (less than or equal to 15 years) and patients aged > 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covaria tes on V/F was not examined. 5 The final magnitudes of interpatient va riability in CL(o) and V/F were relatively low at 22.5 and 17.0%, resp ectively. 6 Population pharmacokinetic parameter estimates in Black, O riental and Malay patients with acute P. falcipraum malaria are in goo d agreement with results of pharmacokinetic studies in healthy Caucasi an volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' met abolizers on CL(o) are unlikely to be clinically significant. Hence, d ose recommendation will be solely based on body weight.