Publication: Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients
Issued Date
2006-11-01
Resource Type
ISSN
15491676
15491277
15491277
Other identifier(s)
2-s2.0-33845294744
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Mahidol University
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SCOPUS
Bibliographic Citation
PLoS Medicine. Vol.3, No.11 (2006), 2113-2123
Suggested Citation
Julie A. Simpson, Tsiri Agbenyega, Karen I. Barnes, Gianni Di Perri, Peter Folb, Melba Gomes, Sanjeev Krishna, Srivicha Krudsood, Sornchai Looareesuwan, Sharif Mansor, Helen McIlleron, Raymond Miller, Malcolm Molyneux, James Mwenechanya, Visweswaran Navaratnam, Francois Nosten, Piero Olliaro, Lorrin Pang, Isabela Ribeiro, Madalitso Tembo, Michele Van Vugt, Steve Ward, Kris Weerasuriya, Kyaw Win, Nicholas J. White Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Medicine. Vol.3, No.11 (2006), 2113-2123. doi:10.1371/journal.pmed.0030444 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/23529
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Title
Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients
Author(s)
Julie A. Simpson
Tsiri Agbenyega
Karen I. Barnes
Gianni Di Perri
Peter Folb
Melba Gomes
Sanjeev Krishna
Srivicha Krudsood
Sornchai Looareesuwan
Sharif Mansor
Helen McIlleron
Raymond Miller
Malcolm Molyneux
James Mwenechanya
Visweswaran Navaratnam
Francois Nosten
Piero Olliaro
Lorrin Pang
Isabela Ribeiro
Madalitso Tembo
Michele Van Vugt
Steve Ward
Kris Weerasuriya
Kyaw Win
Nicholas J. White
Tsiri Agbenyega
Karen I. Barnes
Gianni Di Perri
Peter Folb
Melba Gomes
Sanjeev Krishna
Srivicha Krudsood
Sornchai Looareesuwan
Sharif Mansor
Helen McIlleron
Raymond Miller
Malcolm Molyneux
James Mwenechanya
Visweswaran Navaratnam
Francois Nosten
Piero Olliaro
Lorrin Pang
Isabela Ribeiro
Madalitso Tembo
Michele Van Vugt
Steve Ward
Kris Weerasuriya
Kyaw Win
Nicholas J. White
Other Contributor(s)
University of Melbourne
Kwame Nkrumah University of Science and Technology
University of Cape Town
Ospedale Amedeo di Savoia
South African Medical Research Council
Organisation Mondiale de la Sante
University of London
Mahidol University
Universiti Sains Malaysia
Pfizer Inc.
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Shoklo Malaria Research Unit
University of Oxford
Department of Health
Academic Medical Centre, University of Amsterdam
Liverpool School of Tropical Medicine
State Peace and Development Council
Kwame Nkrumah University of Science and Technology
University of Cape Town
Ospedale Amedeo di Savoia
South African Medical Research Council
Organisation Mondiale de la Sante
University of London
Mahidol University
Universiti Sains Malaysia
Pfizer Inc.
Malawi-Liverpool-Wellcome Trust Clinical Research Programme
Shoklo Malaria Research Unit
University of Oxford
Department of Health
Academic Medical Centre, University of Amsterdam
Liverpool School of Tropical Medicine
State Peace and Development Council
Abstract
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 AUC0-6hwere 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.