Interaction Trial between Artemether-Lumefantrine (Riamet®) and Quinine in Healthy Subjects

Abstract

Forty-two healthy Caucasian subjects were randomized in a double-blind, parallel three-group study (14 subjects per group) to investigate potential electrocardiographic and pharmacokinetic interactions between the antimalarials artemether-lumefantrine (six-dose regimen of Riamet over 3 days) and quinine (2-h intravenous infusion of 10 mg/kg body weight, not exceeding 600 mg in total, 2 h after the last dose of Riamet). The study medications were all safe and well tolerated after all treatments. Neither the pharmacokinetics of lumefantrine nor the pharmacokinetics of quinine was influenced by the presence of the other drug. Plasma levels of artemether and dihydroartemisinin appeared to be lower following the combined treatment Riamet + quinine, but this was not considered to be clinically relevant. Riamet alone had no effect on QTc interval. Infusion of quinine alone caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine, with this effect being slightly but significantly greater when quinine was infused after Riamet. It would thus appear that the inherent risk of QTc prolongation of IV quinine was enhanced by prior administration of Riamet. However, these occasional QTc prolongations, which were small in magnitude and not correlated with plasma concentrations of any of the compounds, were not considered to be of clinical importance. In conclusion, overlapping therapy with artemether-lumefantrine and IV quinine in the treatment of patients with complicated or multidrug-resistant Plasmodium falciparum malaria may result in a modest increased risk of QTc prolongation, but this is far outweighed by the potential therapeutic benefit.

Population Pharmacokinetics of Artemether, Lumefantrine, and Their Respective Metabolites in Papua New Guinean Children with Uncomplicated Malaria

“…The AUCs for ARM and DHA in the present study were similar to those reported previously in adults with malaria (21, 24) but higher than those in healthy adults (14,19,20). Our terminal elimination half-life for ARM was longer than those reported in these studies (16.4 versus 1.5 to 3.9 h), while for DHA, it was shorter (0.80 versus 1.2 to 2.1 h).…”

“…Both ARM and DHA have short half-lives (14, 19-21, 24, 25, 31) but a rapid effect on parasitemia. LUM is a highly lipophilic drug with a longer half-life (11,13,14,19,20,24,30) which is combined with ARM primarily to prevent late recrudescence. Although the pharmacokinetic (PK) properties of ARM, DHA, and LUM in adults have been well documented (4, 5, 11, 13-15, 19-22, 24, 30), there are scant and inconsistent data relating to the disposition of desbutyl-lumefantrine (DBL), a potent LUM metabolite (26,28,29,32) that may influence AL's treatment outcome (32).…”

Population Pharmacokinetics and Pharmacodynamics of Artemether and Lumefantrine during Combination Treatment in Children with Uncomplicated Falciparum Malaria in Tanzania

“…The predicted median LUM concentration on day 3, calculated from 1,000 realizations of the pharmacokinetic model under the study conditions, came to 9.3 M and was similar to the median of 11.3 M reported by Checci and colleagues from pediatric patients in Uganda (4). The typical value of CL/F was estimated to 77 ml/h/kg, which is within the range of 40 to 200 ml/h/kg reported in adults (6,16).…”

“…Follow-up duration was 72 h. A clinical assessment was performed at 0, 2,4,8,16,24,36,48,60, and 72 h. This included a physical examination and questions related to malaria-associated symptoms/ potential side effects of the study drug as well symptoms and/or signs of severe malaria.…”

“…Venous blood samples for drug concentration analyses and for determination of parasitemia were obtained at 0, 2,4,8,16,24,36,48,60, and 72 h following treatment initiation. Whole blood (700 l) was collected in BD Microtainer plasma tubes with lithium heparin and gel.…”