Effects of concurrent administration of efavirenz on the disposition kinetics of amodiaquine in healthy volunteers

Abstract

Background/ObjectivesEfavirenz and amodiaquine are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of amodiaquine is mediated principally by CYP2C8 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on amodiaquine disposition. MethodsFourteen healthy volunteers were each given 600 mg single oral doses of amodiaquine alone or with the 9th dose of efavirenz (400 mg daily for 12 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for amodiaquine and its major metabolite, desethylamodiaquine, using a validated HPLC method. ResultsCo-administration of amodiaquine and efavirenz resulted in significant increases (p < 0.05) in Cmax, Tmax, AUCT and elimination half-life (T1/2) of amodiaquine compared with values for amodiaquine alone. Also, efavirenz caused a pronounced decrease in the AUC (metabolite)/AUC (unchanged drug) ratio of amodiaquine along with a significant decrease (p < 0.05) in Cmax and AUC of the metabolite. ConclusionEfavirenz significantly alters the pharmacokinetics of amodiaquine, exposure to amodiaquine is increased leading to toxic effect, and reduction in the antimalarial activity since amodiaquine is a prodrug that relies on its active metabolite against malaria parasites.