Population pharmacokinetics of intravenous artesunate: a pooled analysis of individual data from patients with severe malaria.
There are ~660,000 deaths from severe malaria each year. Intravenous artesunate (i.v. ARS) is the first-line treatment in adults and children. To optimize the dosing regimen of i.v. ARS, the largest pooled population pharmacokinetic study to date of the active metabolite dihydroartemisinin (DHA) was performed. The pooled dataset consisted of 71 adults and 195 children with severe malaria, with a mixture of sparse and rich sampling within the first 12 h after drug administration. A one-compartment model described the population pharmacokinetics of DHA adequately. Body weight had the greatest impact on DHA pharmacokinetics, resulting in lower DHA exposure for smaller children (6-10 kg) than adults. Post hoc estimates of DHA exposure were not significantly associated with parasitological outcomes. Comparable DHA exposure in smaller children and adults after i.v. ARS was achieved under a dose modification for intramuscular ARS proposed in a separate analysis of children.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
S G
SG
Zaloumis
Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
J
J
Tarning
Institute for Infection and Immunity, St. George's, University of London, London, UK.
S
S
Krishna
Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
R N
RN
Price
1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
N J
NJ
White
School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Fremantle, Australia.
T M E
TM
Davis
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
J M
JM
McCaw
1] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK [2] World Health Organization, Genève, Switzerland.
P
P
Olliaro
1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
R J
RJ
Maude
1] Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon [2] Institute for Tropical Medicine, Department of Parasitology, University of Tübingen, Tübingen, Germany.
P
P
Kremsner
1] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK [2] Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
A
A
Dondorp
World Health Organization, Genève, Switzerland.
M
M
Gomes
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
K
K
Barnes
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
J A
JA
Simpson