Alteration of pharmacokinetics of proguanil in healthy volunteers following concurrent administration of efavirenz

Abstract

Efavirenz and proguanil are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of proguanil is mediated principally by CYP2C19 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on proguanil disposition. Fifteen healthy volunteers were each given 300 mg single oral doses of proguanil alone or with the 9th dose of efavirenz (400 mg daily for 11 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for proguanil and its major metabolite, cycloguanil, using a validated HPLC method. Co-administration of proguanil and efavirenz resulted in significant increases ( p < 0.05) in C max, T max, AUC T and elimination half-life ( T 1/2 β ) of proguanil compared with values for proguanil alone [ C max: 2.55 ± 0.24 mg/l vs 3.75 ± 0.48 mg/l; T max: 2.80 ± 0.99 h vs 4.80 ± 0.99 h; AUC T: 45.58 ± 12.75 mg h/l vs 97.00 ± 23.33 mg h/l; T 1/2 β : 16.50 ± 4.55 h vs 23.24 ± 4.08 h]. Also, efavirenz caused a pronounced decrease in the AUC(metabolite)/AUC(unchanged drug) ratio of proguanil along with a significant decrease ( p < 0.05) in C max and AUC of the metabolite. These results indicate that efavirenz significantly alters the pharmacokinetics of proguanil. These suggest that the protection against malaria by proguanil may be decreased when the drug is co-administered with efavirenz and the antimalarial efficacy is dependent on cycloguanil plasma levels.