Z Hussein, C J Eaves, D B Hutchinson & C J Canfield1
Glaxo Wellcome Research and Development, Beckenham, United Kingdom and 1Pharmaceutical Systems Inc, Talent, Oregon, United States
The pharmacokinetics of proguanil were evaluated in patients with acute P falciparum malaria receiving concomitantly proguanil and atovaquone from 6 Phase II/III clinical trials. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 272 males and 96 females. Of the 370 patients,, 114 and 256 patients were classified as ëpoorà and ëextensiveà metabolisers of proguanil, respectively. Proguanil plasma concentration-time profiles were fitted to a one compartment model with first-order absorption and elimination using non-linear mixed effect modelling (NONMEM).
Oral clearance showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in ëpoorà than ëextensiveà metabolisers. According to weight of each populations, the final population estimates of clearance in Blacks, Orientals and Malays who are ëextensiveà metabolisers were 61.9, 70.4 and 73.7L/hr, respectively. Age, gender an dose had no significant effects on clearance. Apparent volume of distribution showed a 0.88 power relationship with body weight and was 32% larger in patients aged >15 years than in children (² 15 years) with final population estimates of 645 and 1868L, respectively, according to their weight. The effect of other covariates on volume was not examined. The final magnitudes of interpatient variability in clearance and volume of distribution were relatively low at 22.5 and 17.0%, respectively.
In conclusion, population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and ëpoorà metabolisers on clearance are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.
Reference: PAGE 5 (1996) Abstr 581 [www.page-meeting.org/?abstract=581]
Poster: poster