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 (400mg 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(1/2beta)) 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 mgh/l vs 97.00+/-23.33 mgh/l; T(1/2beta): 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.