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

• Published in: Malaria Journal
• Main Authors: Monia Guidi, Thomas Mercier, Manel Aouri, Laurent A. Decosterd, Chantal Csajka, Bernhards Ogutu, Gwénaëlle Carn, Jean-René Kiechel
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMC 2019
• Subjects: Population pharmacokinetics; Mefloquine; Artesunate; Dihydroartemisinin; Arctic medicine. Tropical medicine; RC955-962; Infectious and parasitic diseases; RC109-216; Arctic
• Online Access: https://doi.org/10.1186/s12936-019-2754-6; https://doaj.org/article/a3d2c07258f14a25907fb259e6ac354b

Abstract 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 ...