Population pharmacokinetics and pharmacodynamics of the artesunate-mefloquine fixed dose combination for the treatment of uncomplicated falciparum malaria in African children.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_BBD62F6B6F27
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Population pharmacokinetics and pharmacodynamics of the artesunate-mefloquine fixed dose combination for the treatment of uncomplicated falciparum malaria in African children.
Journal
Malaria journal
Author(s)
Guidi M., Mercier T., Aouri M., Decosterd L.A., Csajka C., Ogutu B., Carn G., Kiechel J.R.
ISSN
1475-2875 (Electronic)
ISSN-L
1475-2875
Publication state
Published
Issued date
18/04/2019
Peer-reviewed
Oui
Volume
18
Number
1
Pages
139
Language
english
Notes
Publication types: Journal Article ; Multicenter Study ; Randomized Controlled Trial
Publication Status: epublish
Abstract
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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
24/04/2019 10:24
Last modification date
20/08/2019 15:29
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