Original articleMultiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria
Introduction
Artemether, a semi-synthetic derivative of artemisinin (Qinghaosu) extracted from the plant Artemisia annua, has proved to be a safe and effective treatment for uncomplicated, severe and multidrug-resistant malaria [1], [2]. Artemether shows rapid anti-malarial activity, but like the related anti-parasitic compounds artemisinin, artesunate and arteether, a high rate of recrudescence of infection is often associated with short course monotherapy [3]. In order to ensure a clinical cure rate above 90% for non-severe malaria, therapeutic drug concentrations need to be maintained for at least three life cycles of Plasmodium falciparum [4]. This means that a 5- to 7-day course of artemether may be necessary [5], which can be difficult to achieve in patients from areas where the disease is endemic and compliance is low. However, similar cure rates can be achieved with shorter treatment duration by combining artemether with a long-acting anti-malarial drug [6], [7]. One such drug is lumefantrine or benflumetol, a novel synthetic anti-malarial developed by the Academy of Military Medical Sciences in Beijing and registered in China in 1992. Lumefantrine is a fluorene derivative belonging to the aminoalcohol class like mefloquine and halofantrine. It acts slowly with a median absorption half-life of 5.3 h, a tmax of 10 h and a terminal elimination half-life of 4.5 days in patients [8]. With a mean 50% inhibitory concentration of 11.9 nmol/l lumefantrine exhibits high in vitro activity against chloroquine-sensitive and -resistant P. falciparum isolates, comparable with that of mefloquine [9]. In clinical studies lumefantrine is associated with a high cure rate even when given as monotherapy (R. Mull, data in preparation). A fast parasite clearance and 28 day cure rates of 82–98% (depending on the dosing regimen) have been reported in clinical trials with a fixed-combination tablet of artemether and lumefantrine (co-artemether, CGP 56697 or Riamet™) [7], [10], [11].
The optimal dosing regimen for many artemisinin derivatives is still not well-defined. Pharmacokinetic studies can be a useful tool in obtaining more insight into the optimalisation of a treatment regimen. The objectives of this study were to investigate multiple dose pharmacokinetics of artemether in chinese patients with uncomplicated malaria due to P. falciparum infection. We further evaluated the influence of lumefantrine on the pharmacokinetics of artemether by comparing artemether with co-artemether tablets.
Section snippets
Setting
In a randomised, double-blind, single-centre trial in a hospital on the island of Hainan, China, the anti-malarial efficacy and tolerability of co-artemether was compared with its individual components, artemether and lumefantrine, in patients with naturally acquired P. falciparum infection. This study focuses on the pharmacokinetic properties of artemether and its demethylated metabolite dihydroartemisinin.
Patients
Patients with symptomatic, previously untreated, uncomplicated P. falciparum infection
Results
Male (84%) and female (16%) patients, all of chinese origin, aged between 13 and 57 years (median 22 years) and weighing between 45 and 75 kg (median 50 kg) with uncomplicated P. falciparum infection with a parasitaemia ranging from 1038 to 162 771 per μl (median 22 959 per μl) were recruited and at random, 48 patients received artemether and 40 patients co-artemether.
The data sets obtained from the extensive sampling in the first 12 patients in each group (part I) were used for pharmacokinetic
Discussion
In this study we observed decreasing Cmax values for artemether from dose 1 to dose 4 over 48 h. The active metabolite dihydroartemisinin, in vitro twice as active as artemether against Plasmodium species, showed a tendency to rise from dose 1 to dose 4. This means that these decreasing artemether concentrations over time will probably not influence the efficacy of the drug. These changes were not accompanied by concomitant changes in absorption or elimination rates. However, for artemether, V
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