EFFECTS OF CO-TRIMOXAZOLE CO-ADMINISTRATION ON THE PHARMACOKINETICS OF AMODIAQUINE IN HEALTHY VOLUNTEERS
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 concentrationâ€“time curve (AUCT), maximum plasma concentration (Cmax) and terminal elimination half-life (TÂ½) of AQ compared with values with AQ dosing alone (AUCT:234.36Â±57.21 vs 366.42Â±62.48 h ng/ml; Cmax:24.86Â±7.28 vs 40.28Â±11.15 ng/ml; TÂ½: 6.49Â±3.56 vs 9.24Â±2.97 h), while the oral plasma clearance markedly decreased (3862.66Â±756.38 vs 2654.28Â±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 Cmax 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.
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