Our preliminary data (16
) suggested that rectal artesunate at 10 to 20 mg/kg was rapidly absorbed in children with uncomplicated malaria in PNG, with plasma concentrations of drug and the active metabolite dihydroartemisinin reaching those achieved after parenteral administration of conventional 2- to 4-mg/kg artesunate doses. At the same time, we were concerned that the current standard therapy for severe malaria in PNG, i.m. artemether, could be suboptimal because of poor absorption (12
). Evidence that artesunate suppositories are effective for severe malaria in adults (3
) provided further justification for a trial of rectal artesunate with PNG children with complicated P. falciparum
infections. The present study demonstrates the benefits of rectally administered artesunate for the initial treatment of severe malaria in children, with a more rapid fall in parasite density than that observed after i.m. artemether. The lower rates of initial parasite clearance in our artemether-treated patients probably reflect the poor absorption of this drug from its i.m. depot, leading to concentrations of artemether plus dihydroartemisinin in a subset of our patients that were six- to eightfold lower 1 to 2 h postdose than the equivalent drug/metabolite levels after rectal artesunate.
The median concentrations of artesunate, artemether, and dihydroartemisinin in the present subjects were in accord with those of previous studies of rectal artesunate (16
) or i.m. artemether (12
) when administered in equivalent mg/kg doses. The median maximum concentration of drug in serum (Cmax
) for 10 Vietnamese adults with severe malaria treated with an initial i.m. dose of 3.2 mg/kg artemether was 574 (range, 67 to 1,641) nmol/liter, and most had peak plasma dihydroartemisinin concentrations of <25 nmol/liter (12
). A study of Thai adults with uncomplicated malaria treated with 2 mg/kg i.m. artemether demonstrated a mean Cmax
of 121 nmol/liter dihydroartemisinin equivalents by bioassay (32
). This was some 16 times less than that seen with equivalent oral dosing, and peak levels occurred at a median of 8 (range, 4 to 24) h after administration (32
). Studies of African children with severe malaria have shown a mean Cmax
of between 116 to 257 nmol/liter as dihydroartemisinin equivalents (25
Two studies with Thai adults demonstrated higher plasma levels of artemether and a much greater rate of conversion of artemether to dihydroartemisinin (14
). The reasons for these apparently discrepant results are unclear but may relate to infection severity (one Thai study was performed with healthy volunteers), ethnic factors, and/or the different age ranges of the subjects. These factors may have impacted hepatic perfusion or hepatic and/or extrahepatic enzymatic metabolism of the parent drug. Alternatively, the dihydroartemisinin assay used for the Thai studies, one of the first such assays developed, may have had a different specificity to other methods.
Based on in vitro parasite culture data, artemether may be intrinsically less potent than either artesunate or dihydroartemisinin (29
). This suggests that the total artemisinin concentration derived by adding plasma artemether and dihydroartemisinin concentrations overestimates bioactivity compared to artesunate plus dihydroartemisinin. Dose-response relationships for the artemisinin derivatives remain relatively poorly understood. However, when artesunate is given orally, a positive in vivo relationship between mg/kg dosage and parasite clearance rate appears to exist up to doses of 2 mg/kg, above which a maximal effect is achieved (1
). This threshold dose equates with peak plasma concentrations of 1,400 to 2,800 nmol/liter dihydroartemisinin equivalents at 1 to 2 h postdose (28
). As an extension of this finding, the total plasma artemisinin concentrations achieved with our artemether-treated patients at 1 and 2 h (medians of 438 and 441 nmol/liter, respectively), while exceeding published 50% inhibitory concentrations for artemether and dihydroartemisinin (8
), explain the inferior pharmacodynamic response of this group, particularly with individuals at the lower end of the range of absorption. Indeed, another study has identified a subset of patients with relatively poor outcomes in whom plasma artemether concentrations are undetectable by either bioassay or high-performance liquid chromatography (limits of detection, approximately 35 nmol/liter) (27
It could be argued that the different pharmacokinetic and pharmacodynamic outcomes in the present study were a function of the total doses administered. The mg/kg dose of artesunate was approximately three times that of artemether. However, it seems unlikely that increasing the dose of artemether would be either practical or effective. An increased dose means an increased injection volume that would be painful and difficult to administer to small children. Furthermore, larger injection volumes may lead to compression of capillary beds surrounding the injection site that could further limit drug absorption (18
Our study was inadequately powered to detect between-treatment differences in either death or permanent neurological sequelae. However, the mortality and rate of neurological complications in our patients were reassuringly low, with only one such event, a death 2 h after study entry, among 79 severely ill children. Indeed, the range of complications present at study entry for this child and the rapid clinical deterioration suggest strongly that any form of intervention would have had limited benefit. One of our surrogate endpoints (PC%12
) was also used in the only other study to evaluate the efficacy of artesunate suppositories for treatment of severe malaria (4
). In the latter study, initial parasite clearance was more rapid with rectal artesunate than with i.m. quinine (4
). Because of differences in pharmacokinetics and parasite stage specificity, artemisinin drugs clear parasites more rapidly than quinine, regardless of route of administration (23
). Our study was concerned with efficacy comparison within the artemisinin group rather than between classes of antimalarial agents.
Since the present study was performed, a large, multicenter, Southeast Asian study has demonstrated that i.v. artesunate is associated with a lower mortality (15%) than i.v. quinine (22%) for severe malaria (9
). The benefit of i.v. artesunate was not significant in subjects <15 years of age (9
), but this may have been a function of low numbers of patients and a lack of statistical power. These data and the fact that i.v. or i.m. injection of artesunate provides early and reliable therapeutic levels of drug and metabolite (12
) without the close observation needed after rectal administration (16
) confirm parenteral artesunate as first-line hospital-based treatment for severe malaria, including with children. Where facilities do not exist to safely administer antimalarial drugs by injection, the present and other data (4
) indicate that artesunate suppositories are an appropriate alternative.
Both of the drugs used in the present study were well tolerated, although a small number of children in each group (1 in 16 overall) developed generally mild gastrointestinal symptoms after 2 to 4 days of treatment. The time course of these symptoms relative to parasite and fever clearance, their occurrence in both groups of patients, and the fact that they have not been reported in previously published studies could imply that they arose because of a reaction to artemisinin drugs in susceptible Melanesian subjects. However, their spontaneous resolution during oral artesunate therapy suggests that they were a delayed effect of severe malaria on intestinal function.
Rectocaps artesunate suppositories are manufactured to international good manufacturing practice standards and cost approximately $0.38 and $0.68 for 50-mg and 200-mg suppositories, respectively. Based on the number of days of treatment required prior to oral therapy and the dosages administered to the children in the present study, the average cost of rectal treatment was $2.44. The equivalent average cost of i.m. artemether at $1.50/ampoule was $2.49 per child. Because this comparison does not take into account consumables needed to administer injections, rectal artesunate is at least as cost-effective as i.m. artemether for the initial treatment of severe pediatric malaria in PNG. Nevertheless, the close observation necessary to ensure that suppositories are retained may be problematic, even in a hospital setting. Thus, we recommend parenteral artemisinin therapy where drug availability and facilities allow, with suppositories as an excellent alternative where injections cannot be given.