Induction of Amodiaquine Metabolism by Rifampicin Following Concurrent Administration in Healthy Volunteers

Abstract

Background and objective: Malaria and tuberculosis remain endemic in tropical regions and most often coexist, increasing the burden of malaria mortality due to unintended interactions of the co-administered drugs employed in the management of the infections. Rifampicin (RIF) and amodiaquine (ADQ) are likely to be administered concurrently in the treatment of patients with tuberculosis and malaria. The metabolism of ADQ is mediated principally by CYP2C8, while RIF is a known inducer of this enzyme. This study, therefore, investigated the effect of RIF on the disposition of ADQ, a major partner drug in the first-line treatment against uncomplicated malaria in line with the World Health Organization recommendations. Methods:Sixteen healthy volunteers received oral 150 mg dose of RIF daily for 5 days with or without oral 600 mg single dose of ADQ on the fifth day (5 th dose) with a 4-week wash out period, in a crossover fashion. Blood samples were collected at predetermined time intervals of 0, 1, 2, 4, 6, 8, 12, 24, 36 and 48 h. Plasma samples were analyzed for ADQ and its major metabolite desethylamodiaquine using a validated RP-high-performance liquid chromatography. Pharmacokinetic parameters were obtained using appropriate software and subjected to appropriate statistical analysis. Results:Coadministration of ADQ and RIF resulted in significant decreases in the critical pharmacokinetic parameters of ADQ, such as area under the curve (AUC 0-∞ ) of about 66%, time to peak plasma concentration (Tmax) of about 10%, maximum plasma concentration of about 44%, and elimination half-life of about 55%, while the AUC 0-∞ and Tmax of the main metabolite desethylamodiaquine increased about 2-fold and 3-fold respectively during the coadministration of RIF with ADQ. The metabolic ratio increased significantly, from 1.55 to 2.68. The AUC 0-∞ and Tmax of the drug ADQ, as well as the maximum concentration of both the drug and its metabolite fell outside the point of estimates of the test/reference ratio of the geometric means of 80-125% of bioequivalence range. Conclusions:An interaction was established during coadministration of RIF and ADQ, confirming RIF as a strong inducer of CYP2C8 in vivo, which may lead to malaria therapeutic failure or adverse drug reactions with ADQ and contribute to the rate at which resistance to ADQ develops.

Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles

“…The induction of these CYP enzymes results in an increased elimination of administered drugs, and this often results in reduced pharmacological effects [ 2 , 172 ]. For instance coadministration of amodiaquine and rifampicin in healthy volunteers resulted in significant decreases in the critical pharmacokinetic parameters of the drug, as opposed to increases in those of the main metabolite desethylamodiaquine, leading to a significant increase in the metabolic ratio from 1.55 to 2.68 [ 173 ]. No other TB drugs have been documented to inhibit or induce the CYP enzyme system; however, there were some investigations carried out on pyrazinamide and ethionamide to identify any inhibition of CYP enzymes by these drugs [ 174 ].…”

Insights and Current Perspectives on Pharmacogenomics of Antimalarial Drugs

“…3) has been an antimalarial drug of choice in the treatment of Plasmodium vivax and Plasmodium ovale hypnozoites, and for malaria prophylaxis. It is metabolized principally by CYP2D6 isoenzyme to active metabolites, the mainly 5-hydroxy derivative of primaquine, that are responsible for the pharmacological effect of primaquine [12]. CYP2D6 gene is highly polymorphic with over 90 known allelic variants, demonstrating signi cant inter-individual and inter-ethnic differences in its activity (…”

“…Pharmacogenomics is a part of personalized medicine or precision medicine that individualizes therapy by using SNPs and tailormaking medicines to each patient for effective therapy [11]. We have carried out numerous studies in our laboratories on pharmacokinetics and pharmacogenomics of different antimalarial drugs and diverse antiinfective agents to generate data for optimization of the drug e cacies [12][13][14].…”