Artemether Bioavailability after Oral or IntramuscularAdministration in Uncomplicated FalciparumMalaria

Drug treatment of severe malaria must be rapidly effective. Suppositories may be valuable for childhood malaria when circumstances prevent oral or parenteral therapy. We compared artesunate suppositories (n ‫؍‬ 41; 8 to 16 mg/kg of body weight at 0 and 12 h and then daily) with intramuscular (i.m.) artemether (n ‫؍‬ 38; 3.2 mg/kg at 0 h and then 1.6 mg/kg daily) in an open-label, randomized trial with children with severe Plasmodium falciparum malaria in Papua New Guinea (PNG). Parasite density and temperature were measured every 6 h for >72 h. Primary endpoints included times to 50% and 90% parasite clearance (PCT 50 and PCT 90 ) and the time to per os status. In a subset of 29 patients, plasma levels of artemether, artesunate, and their common active metabolite dihydroartemisinin were measured during the first 12 h. One suppository-treated patient with multiple complications died within 2 h of admission, but the remaining 78 recovered uneventfully. Compared to the artemether-treated children, those receiving artesunate suppositories had a significantly earlier mean PCT 50 (9.1 versus 13.8 h; P ‫؍‬ 0.008) and PCT 90 (15.6 versus 20.4 h; P ‫؍‬ 0.011). Mean time to per os status was similar for each group. Plasma concentrations of primary drug plus active metabolite were significantly higher in the artesunate suppository group at 2 h postdose. The earlier initial fall in parasitemia with artesunate is clinically advantageous and mirrors higher initial plasma concentrations of active drug/ metabolite. In severely ill children with malaria in PNG, artesunate suppositories were at least as effective as i.m. artemether and may, therefore, be useful in settings where parenteral therapy cannot be given.

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, concerns regarding its unpredictable absorption after i.m. injection, particularly with the most severely ill children, exist (12,25,27,32).…”

mentioning

confidence: 99%

Artesunate Suppositories versus Intramuscular Artemether for Treatment of Severe Malaria in Children in Papua New Guinea

Karunajeewa

Reeder

Lorry

et al. 2006

“…doses at 0 and 12 h (25). In addition, a variety of studies have suggested a time-dependent reduction in the F values of artemisinin derivatives during treatment (3,14,32,35), including during the first few days of ARTS therapy (24).…”

Section: Discussionmentioning

confidence: 99%

Disposition of Artesunate and Dihydroartemisinin after Administration of Artesunate Suppositories in Children from Papua New Guinea with Uncomplicated Malaria

Karunajeewa

Ilett

Dufall³

et al. 2004

A detailed pharmacokinetic analysis was performed with 47 children from Papua New Guinea with uncomplicated falciparum or vivax malaria treated with artesunate (ARTS) suppositories (Rectocaps) given in two doses of approximately 13 mg/kg of body weight 12 h apart. Following an intensive sampling protocol, samples were assayed for ARTS and its primary active metabolite, dihydroartemisinin (DHA), by liquid chromatography-mass spectrometry. A population pharmacokinetic model was developed to describe the data. Following administration of the first dose, the mean maximal concentrations of ARTS and DHA were 1,085 nmol/liter at 0.9 h and 2,525 nmol/liter at 2.3 h, respectively. The absorption half-life for ARTS was 2.3 h, and the conversion half-life (ARTS to DHA) was 0.27 h, while the elimination half-life of DHA was 0.71 h. The mean common volumes of distribution for ARTS and DHA relative to bioavailability were 42.8 and 2.04 liters/kg, respectively, and the mean clearance values relative to bioavailability were 6 and 2.2 liters/h/kg for ARTS and DHA, respectively. Substantial interpatient variability was observed, and the bioavailability of the second dose relative to that of the first was estimated to be 0.72. The covariates age, sex, and ␣-thalassemia genotype were not influential in the pharmacokinetic model development; but the inclusion of weight as a covariate significantly improved the performance of the model. An ARTS suppositories dose of 10 of 20 mg/kg is appropriate for use in children with uncomplicated malaria.

“…Estimates of the relative bioavailabilities of oral versus intramuscular artemether have varied substantially (15,16), in part because there is marked interindividual pharmacokinetic variability with both routes of administration. It is likely, given its poor solubility, that the absolute bioavailability of artemether is much less than that of the chemically related but water-soluble derivative artesunate, which may be as high as 80% (17).…”

mentioning

confidence: 99%

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in Healthy Adults

Salman

Bendel²,

Lee

et al. 2015

Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (>1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (>1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing.