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

Authors:
Monia Guidi
Monia Guidi
Unit of Pharmacogenetics and Clinical Psychopharmacology
Switzerland
Thomas Mercier
Thomas Mercier
Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois
Manel Aouri
Manel Aouri
Division of Clinical Pharmacology and Toxicology
Switzerland
Chantal Csajka
Chantal Csajka
University of Lausanne
Switzerland
Bernhards Ogutu
Bernhards Ogutu
Kenya Medical Research Institute
United States
Gwenaelle Carn
Gwenaelle Carn
Indiana University School of Medicine
India
Jean-Rene Kiechel
Jean-Rene Kiechel
United States

Malar J 2019 Apr 18;18(1):139. Epub 2019 Apr 18.

Drugs for Neglected Diseases initiative, Geneva, Switzerland.

Background: 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.

Methods: 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). 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.

Results: 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.

Conclusions: 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.

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http://dx.doi.org/10.1186/s12936-019-2754-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471806PMC
April 2019
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