EFFECTS OF CO-TRIMOXAZOLE CO-ADMINISTRATION ON THE PHARMACOKINETICS OF AMODIAQUINE IN HEALTHY VOLUNTEERS

摘要

Objectives: Amodiaquine (AQ) is a 4-aminoquinoline antimalarial drug that is rapidly and extensively metabolized mainly by CYP2C8 enzyme to N-desethylamodiaquine (DEAQ). Co-trimoxazole (CTZ) is a combination (sulfamethoxazole and trimethoprim) antimicrobial agent with the trimethoprim component being a potent inhibitor of CYP2C8. AQ and CTZ are likely to be co-administered in the treatment of patients with malaria and susceptible bacterial infections. This study evaluates the effect of CTZ co-administration on the pharmacokinetics of AQ. Methods: In an open, two-way crossover study, 16 healthy volunteers were randomized to receive 600 mg single oral dose of AQ with or without the eleventh dose of CTZ (960 mg every 12 h for 7 days.) Blood samples were collected at pre-determined time intervals and analyzed for AQ and its major metabolite, DEAQ using a validated HPLC method. Results: Co-administration of AQ and CTZ resulted in significant increases in the total area under the concentration–time curve (AUC T ), maximum plasma concentration (C max ) and terminal elimination half-life (T ? ) of AQ compared with values with AQ dosing alone (AUC T :234.36±57.21 vs 366.42±62.48 h ng/ml; C max :24.86±7.28 vs 40.28±11.15 ng/ml; T ? : 6.49±3.56 vs 9.24±2.97 h), while the oral plasma clearance markedly decreased (3862.66±756.38 vs 2654.28±650.12 L/h). Co-administration also led to a pronounced decrease in the ratio of AUC (metabolite) /AUC (unchanged drug) and highly significant decreases in C max and AUC of the metabolite. Conclusion: Study evaluated for the first time the effect of CTZ co-administration on the pharmacokinetics of AQ in healthy adult volunteers. CTZ significantly increased AQ exposure and decreased plasma levels of the active metabolite DEAQ. Keywords: Amodiaquine, Desethylamodiaquine, Co-trimoxazole, Pharmacokinetics, CYP2C8.