Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria

Salman, Sam, Bendel, Daryl, Lee, Toong C., Templeton, David and Davis, Timothy M. E. (2015) Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria. Antimicrobial Agents and Chemotherapy, 59 6: 3208-3215. doi:10.1128/AAC.05014-14

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Author Salman, Sam
Bendel, Daryl
Lee, Toong C.
Templeton, David
Davis, Timothy M. E.
Title Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in African children with malaria
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 1098-6596
Publication date 2015-06-01
Year available 2015
Sub-type Article (original research)
DOI 10.1128/AAC.05014-14
Open Access Status File (Publisher version)
Volume 59
Issue 6
Start page 3208
End page 3215
Total pages 8
Place of publication Washigton, DC, United States
Publisher American Society for Microbiology
Collection year 2016
Language eng
Abstract The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197-3207, 2015,, the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg·h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg·h/liter, respectively; P≥0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick children before transfer for definitive management of severe or moderately severe malaria.
Keyword Malaria -- Treatment
Pharmacokinetic modeling
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Centre for Integrated Preclinical Drug Development Publications
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