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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients
PLoS Medicine, Volume 3, No. 11, Year 2006
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Description
Background: Intra-rectal artesunate has been developed as a potentially life-saving treatment of severe malaria in rural village settings where administration of parenteral antimalarial drugs is not possible. We studied the population pharmacokinetics of intra-rectal artesunate and the relationship with parasitological responses in patients with moderately severe falciparum malaria. Methods and Findings: Adults and children in Africa and Southeast Asia with moderately severe malaria were recruited in two Phase II studies (12 adults from Southeast Asia and 11 children from Africa) with intensive sampling protocols, and three Phase III studies (44 children from Southeast Asia, and 86 children and 26 adults from Africa) with sparse sampling. All patients received 10 mg/kg artesunate as a single intra-rectal dose of suppositories. Venous blood samples were taken during a period of 24 h following dosing. Plasma artesunate and dihydroartemisinin (DHA, the main biologically active metabolite) concentrations were measured by high-performance liquid chromatography with electrochemical detection. The pharmacokinetic properties of DHA were determined using nonlinear mixed-effects modelling. Artesunate is rapidly hydrolysed in vivo to DHA, and this contributes the majority of antimalarial activity. For DHA, a one-compartment model assuming complete conversion from artesunate and first-order appearance and elimination kinetics gave the best fit to the data. The mean population estimate of apparent clearance (CL/F) was 2.64 (l/kg/ h) with 66% inter-individual variability. The apparent volume of distribution (V/F) was 2.75 individual variability. The estimated DHA population mean elimination half-life was 43 min. Gender was associated with increased mean CL/F by 1.14 (95% CI: 0.36-1.92) (l/kg/h) for a male compared with a female, and weight was positively associated with V/F. Larger V/Fs were observed for the patients requiring early rescue treatment compared with the remainder, independent of any confounders. No associations between the parasitological responses and the posterior individual estimates of V/F, CL/F, and AUC0-6h were observed. Conclusions: The pharmacokinetic properties of DHA were affected only by gender and body weight. Patients with the lowest area under the DHA concentration curve did not have slower parasite clearance, suggesting that rectal artesunate is well absorbed in most patients with moderately severe malaria. However, a number of modelling assumptions were required due to the large intra- and inter-individual variability of the DHA concentrations. © 2006 Simpson et al.
Authors & Co-Authors
Simpson, Julie Anne
Unknown Affiliation
Agbenyega, Tsiri E.
Unknown Affiliation
Barnes, Karen Irma
Unknown Affiliation
Perri, Giovanni Di
Unknown Affiliation
Folb, Peter I.
Unknown Affiliation
Gomes, Melba F.
Unknown Affiliation
Krishna, Prof Sanjeev
Unknown Affiliation
Krudsood, Srivicha
Unknown Affiliation
Looareesuwan, Sornchai
Unknown Affiliation
Mansor, Sharif Mahsufi
Unknown Affiliation
McIlleron, Helen Margaret
Unknown Affiliation
Miller, Raymond
Unknown Affiliation
Molyneux, Malcolm Edward
Unknown Affiliation
Mwenechanya, James
Unknown Affiliation
Navaratnam, Visweswaran
Unknown Affiliation
Nosten, François Henry
Unknown Affiliation
Olliaro, Piero L.
Unknown Affiliation
Pang, Lorrin Wayie
Unknown Affiliation
Ribeiro, Isabela
Unknown Affiliation
Tembo, Madalitso
Unknown Affiliation
van Vugt, Michèle V.
Unknown Affiliation
Ward, Stephen Andrew
Unknown Affiliation
Weerasuriya, Kris
Unknown Affiliation
Win, Kyaw
Unknown Affiliation
White, Nicholas J.
Unknown Affiliation
Statistics
Citations: 67
Authors: 25
Affiliations: 18
Identifiers
Doi:
10.1371/journal.pmed.0030444
ISSN:
15491277
e-ISSN:
15491676
Research Areas
Infectious Diseases
Maternal And Child Health
Study Design
Cross Sectional Study
Participants Gender
Male
Female