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Research Article

Population Pharmacokinetics of Artesunate and Dihydroartemisinin following Intra-Rectal Dosing of Artesunate in Malaria Patients

  • Julie A Simpson mail,

    To whom correspondence should be addressed. E-mail: julieas@unimelb.edu.au

    Affiliation: Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia

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  • Tsiri Agbenyega,

    Affiliation: School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

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  • Karen I Barnes,

    Affiliation: Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa

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  • Gianni Di Perri,

    Affiliation: Clinica di Malattie Infecttive, Ospedale Amedeo di Savoia, Torino, Italy

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  • Peter Folb,

    Affiliation: South African Medical Research Council, Tygerberg, South Africa

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  • Melba Gomes,

    Affiliation: UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland

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  • Sanjeev Krishna,

    Affiliation: Division of Cellular and Molecular Medicine, Centre for Infection, University of London, London, United Kingdom

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  • Srivicha Krudsood,

    Affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

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  • Sornchai Looareesuwan,

    Affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

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  • Sharif Mansor,

    Affiliation: Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia

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  • Helen McIlleron,

    Affiliation: Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa

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  • Raymond Miller,

    Affiliation: Pfizer Global Research and Development, Ann Arbor, Michigan, United States of America

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  • Malcolm Molyneux,

    Affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme and Malaria Project, College of Medicine, Blantyre, Malawi

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  • James Mwenechanya,

    Affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme and Malaria Project, College of Medicine, Blantyre, Malawi

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  • Visweswaran Navaratnam,

    Affiliation: Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia

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  • Francois Nosten,

    Affiliations: Shoklo Malaria Research Unit, Mae-Sot, Tak, Thailand, Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme, Mahidol University, Bangkok, Thailand

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  • Piero Olliaro,

    Affiliations: UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland, Centre for Tropical Medicine and Vaccinology, Churchill Hospital, University of Oxford, United Kingdom

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  • Lorrin Pang,

    Affiliation: Department of Health, Maui County, Hawaii, United States of America

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  • Isabela Ribeiro,

    Affiliation: UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland

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  • Madalitso Tembo,

    Affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme and Malaria Project, College of Medicine, Blantyre, Malawi

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  • Michele van Vugt,

    Affiliations: Shoklo Malaria Research Unit, Mae-Sot, Tak, Thailand, Department of AIDS and Tropical Medicine, Amsterdam Medical Center, Amsterdam, Netherlands

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  • Steve Ward,

    Affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom

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  • Kris Weerasuriya,

    Affiliation: Regional Office for South-East Asia, World Health Organization, New Delhi, India

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  • Kyaw Win,

    Affiliation: State Peace and Development Council, Myanmar

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  • Nicholas J White

    Affiliations: Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme, Mahidol University, Bangkok, Thailand, Centre for Tropical Medicine and Vaccinology, Churchill Hospital, University of Oxford, United Kingdom

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  • Published: November 28, 2006
  • DOI: 10.1371/journal.pmed.0030444

About the Authors

Julie A Simpson
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia
Tsiri Agbenyega
School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
Karen I Barnes, Helen McIlleron
Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa
Gianni Di Perri
Clinica di Malattie Infecttive, Ospedale Amedeo di Savoia, Torino, Italy
Peter Folb
South African Medical Research Council, Tygerberg, South Africa
Melba Gomes, Piero Olliaro, Isabela Ribeiro
UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland
Sanjeev Krishna
Division of Cellular and Molecular Medicine, Centre for Infection, University of London, London, United Kingdom
Srivicha Krudsood, Sornchai Looareesuwan
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Sharif Mansor, Visweswaran Navaratnam
Centre for Drug Research, Universiti Sains Malaysia, Penang, Malaysia
Raymond Miller
Pfizer Global Research and Development, Ann Arbor, Michigan, United States of America
Malcolm Molyneux, James Mwenechanya, Madalitso Tembo
Malawi-Liverpool-Wellcome Trust Clinical Research Programme and Malaria Project, College of Medicine, Blantyre, Malawi
Francois Nosten, Michele van Vugt
Shoklo Malaria Research Unit, Mae-Sot, Tak, Thailand
Francois Nosten, Nicholas J White
Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme, Mahidol University, Bangkok, Thailand
Piero Olliaro, Nicholas J White
Centre for Tropical Medicine and Vaccinology, Churchill Hospital, University of Oxford, United Kingdom
Lorrin Pang
Department of Health, Maui County, Hawaii, United States of America
Michele van Vugt
Department of AIDS and Tropical Medicine, Amsterdam Medical Center, Amsterdam, Netherlands
Steve Ward
Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Kris Weerasuriya
Regional Office for South-East Asia, World Health Organization, New Delhi, India
Kyaw Win
State Peace and Development Council, Myanmar

Corresponding Author

Email: julieas@unimelb.edu.au

Competing Interests

M. Gomes works for the World Health Organization, sponsor of the studies, and was involved in the decision to submit the manuscript for publication. During the study, K. Weerasuriya worked part-time for the World Health Organization, and is now employed full-time.

Author Contributions

J. Simpson analysed the data and wrote the paper. G. Di Perri, M. Gomes, R. Miller, M. Molyneux, V. Navaratnam, F. Nosten, P. Olliaro, L. Pang, I. Ribeiro, K. Weerasuriya, K. Win, S. Ward, and N. White designed the study. G. Di Perri, P. Folb, S. Mansor, M. Molyneux, I. Ribeiro, K. Win, and N. White analysed the data. T. Agbenyega, K. Barnes, S. Krishna, S. Krudsood, S. Looareesuwan, H. McIlleron, M. Molyneux, J. Mwenechanya, F. Nosten, M. Tembo, and M. van Vugt enrolled patients. H. McIlleron and F. Nosten collected data and did experiments. K. Barnes, G. Di Perri, P. Folb, M. Gomes, S. Krishna, S. Mansor, H. McIlleron, M. Molyneux, V. Navaratnam, F. Nosten, P. Olliaro, I. Ribeiro, M. van Vugt, and N. White contributed to writing the paper. K. Barnes adapted the study designed by the rectal artesunate task force to suit the South African context and was the principal investigator of the study in South Africa. M. Gomes managed the WHO Task Force, which designed the studies. This involved the review of protocols and case record forms, coordination and overall management of the studies, management of the samples for kinetic analyses, provision of individual study reports to regulatory authorities, provision of data and study protocols to the corresponding author for analysis, response to data queries, and contribution to the writing of the paper. S. Krudsood cared for all of the participants (Bangkok site) and managed the case record forms. S. Looareesuwan was the principle investigator for the Bangkok site. M. Molyneux analysed the clinical components of the data, reviewed the pharmacokinetic data, and also administered drugs, collected, stored, and dispatched pharmacokinetic samples, and observed, recorded, and analysed bedside and laboratory outcome measures for the Malawi group of patients. S. Mansor conducted the chromatographic assay and also the drug and pharmacokinetic analysis. R. Miller helped with the pharmacokinetic analysis of the data. J. Mwenechanya was responsible for sample collection, data entry, and patient follow-up post study. V. Navaratnam undertook the analysis of patient samples for drug levels and carried out basic pharmacokinetic analysis. L. Pang helped establish one of the field sites and convinced local investigators and sponsoring agencies of the feasibility, value, and ethical appropriateness of such a study. M. van Vugt was the treating physician in Mae-Sot. K. Weerasuriya contributed to the study design by developing the clinical trial protocol, and contributed to data collection by monitoring the clinical trial and some logistics in the specialized transport of specimens. K. Win was involved in the formulation of the first artesunate rectal capsules, was the first applicant for a TDR grant for clinical and kinetic studies, and participated in the TDR meetings for designing the early studies in 1995.