Lack of a pharmacokinetic interaction between atovaquone and proguanil

Objective: To assess the magnitude of the putative effect of atovaquone on the pharmacokinetics of proguanil and to determine whether the pharmacokine tics of atovaquone are affected by concomitant administration of proguanil, with both drugs administered for 3 days to healthy adult volunteers. Methods: This was an open-label, randomized, three-way cross-over study, in which 18 healthy volunteers received 400 mg proguanil, 1000 mg atovaquone and 1000 mg atovaquone + 400 mg proguanil. Each treatment was given once da ily for 3 days with a 3-week wash-out period between each occasion. For the assay of proguanil, cycloguanil and atovaquone, blood was sampled before d osing and at regular intervals over 8 days when proguanil was given, and ov er 17 days when atovaquone was given. Results: The geometric mean of the area under the atovaquone plasma concent ration-time curve calculated from 0 to 24 h after the last dose (AUC(0-->24 h)) was 180 mu g . ml(-1) . h following administration of atovaquone alone and 193 mu g . ml(-1) . h following atovaquone with proguanil. The geometri c mean AUC(0-->24h) for proguanil was 6296 ng . ml(-1) . h after proguanil alone and 5819 ng . ml(-1) . h following proguanil with atovaquone. The cor responding values for the metabolite cycloguanil were 1297 ng . ml(-1) . h and 1187 ng . ml(-1) . h, respectively. The geometric mean elimination half -life (t(1/2)) Of atovaquone was 57.1 h when given alone and 59.0 h when ad ministered together with proguanil. The corresponding geometric mean values of t(1/2) for proguanil were 13.7 h and 14.5 h. Exploratory statistical an alysis showed no important gender effects on the pharmacokinetics of atovaq uone, proguanil, or cycloguanil. Conclusion: The pharmacokinetics of atovaquone and proguanil and its metabo lite, cycloguanil, were not different when atovaquone and proguanil were gi ven alone or in combination.