Efficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger

BMC Medicine

Research Article

Michiel Smit¹  Lubbe Wiesner¹  Karen I. Barnes²  Ousmane Guindo³  Lise Denoeud-Ndam⁴  Francesco Grandesso⁴  Rebecca F. Grais⁴  Elisabeth Baudin⁴  Jean-François Etard⁵  Sekouba Keita⁶  Seydou Traoré⁶  Amadou Barry⁶  Halimatou Diawara⁶  Abdoulaye A. Djimde⁶  Sibiri Sissoko⁶  Koualy Sanogo⁶  Ogobara K. Doumbo⁶  Alassane Dicko⁶  Martin de Smet⁷  Estrella Lasry⁸  Philippe J. Guerin⁹ 

[1] Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa;Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa;WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK;Epicentre, Maradi, Niger;Epicentre, Paris, France;Epicentre, Paris, France;TransVIHMI UMI 233, Institut de Recherche pour le Développement (IRD) – Inserm U 1175 – Montpellier 1 University, Montpellier, France;Malaria Research and Training Center, Faculté de Médecine et d’Odonto-stomatologie et Faculté de Pharmacie, Université des Sciences Techniques et Technologies de Bamako, Bamako, Mali;Medecins Sans Frontieres, Brussels, Belgium;Medecins Sans Frontieres, New York, NY, USA;WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK;

关键词: Plasmodium falciparum;    Severe acute malnutrition;    Artemether-lumefantrine;    Treatment outcome;    Pharmacokinetics;    Niger;    Mali;   

DOI  :  10.1186/s12916-016-0716-1

 received in 2016-06-22, accepted in 2016-10-07,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundSevere acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without.MethodsChildren under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF – Plumpy’Nut®) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7.ResultsA total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR-corrected ACPR was 100 % (95 % CI, 96.8–100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4–99.7 %) at day 28 and 98.3 % (95.6–99.4 %) at day 42 in non-SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04–4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049).ConclusionsThis study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7.Trial registrationClinicalTrials.gov: NCT01958905, registration date: October 7, 2013.

【 授权许可】

CC BY   
© The Author(s). 2016