serval:BIB_BBD62F6B6F27
Population pharmacokinetics and pharmacodynamics of the artesunate-mefloquine fixed dose combination for the treatment of uncomplicated falciparum malaria in African children.
10.1186/s12936-019-2754-6
000465081000001
30999915
Guidi
M.
author
Mercier
T.
author
Aouri
M.
author
Decosterd
L.A.
author
Csajka
C.
author
Ogutu
B.
author
Carn
G.
author
Kiechel
J.R.
author
article
2019-04-18
Malaria journal
1475-2875
1475-2875
journal
18
1
139
The World Health Organization (WHO) recommends combinations of an artemisinin derivative plus an anti-malarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infections. In Africa, artesunate-mefloquine (ASMQ) is an infrequently used artemisinin-based combination therapy (ACT) because of perceived poor tolerance to mefloquine. However, the WHO has recommended reconsideration of the use of ASMQ in Africa. In this large clinical study, the pharmacokinetics (PK) of a fixed dose combination of ASMQ was investigated in an African paediatric population to support dosing recommendations used in Southeast Asia and South America.
Among the 472 paediatric patients aged 6-59 months from six African centres included in the large clinical trial, a subset of 50 Kenyan children underwent intensive sampling to develop AS, its metabolite dihydroartemisinin (DHA) and MQ PK models. The final MQ PK model was validated using sparse data collected in the remaining participants (NONMEM <sup>®</sup> ). The doses were one or two tablets containing 25/55 mg AS/MQ administered once a day for 3 days according to patients' age. A sensitive LC-MS/MS method was used to quantify AS, DHA and MQ concentrations in plasma. An attempt was made to investigate the relationship between the absence/presence of malaria recrudescence and MQ area under the curve (AUC) using logistic regression.
AS/DHA concentration-time profiles were best described using a one-compartment model for both compounds with irreversible AS conversion into DHA. AS/DHA PK were characterized by a significant degree of variability. Body weight affected DHA PK parameters. MQ PK was characterized by a two-compartment model and a large degree of variability. Allometric scaling of MQ clearances and volumes of distribution was used to depict the relationship between MQ PK and body weight. No association was found between the model predicted AUC and appearance of recrudescence.
The population pharmacokinetic models developed for both AS/DHA and MQ showed a large variability in drug exposure in the investigated African paediatric population. The largest contributor to this variability was body weight, which is accommodated for by the ASMQ fixed dose combination (FDC) dosing recommendation. Besides body weight considerations, there is no indication that the dosage should be modified in children with malaria compared to adults. Trial registration Pan African Clinical Trials Registry PACTR201202000278282 registration date 2011/02/16.
Antimalarials/pharmacokinetics
Antimalarials/pharmacology
Artesunate/pharmacokinetics
Artesunate/pharmacology
Child, Preschool
Dose-Response Relationship, Drug
Drug Combinations
Female
Humans
Infant
Kenya
Malaria, Falciparum/drug therapy
Male
Mefloquine/pharmacokinetics
Mefloquine/pharmacology
Prospective Studies
Recurrence
Artesunate
Dihydroartemisinin
Mefloquine
Population pharmacokinetics
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Multicenter Study ; Randomized Controlled Trial
Publication Status: epublish
University of Lausanne
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