Population pharmacokinetic and time-to-event modelling of the antimalarial drug lumefantrine in young children with severe acute malnutrition
Palang Chotsiri (1,2), Lise Denoeud-Ndam (3), Alassane Dicko (4), Elisabeth Baudin(3), Ousmane Guindo (5), Francesco Grandesso (3), Halimatou Diawara (4), Sibiri Sissoko (4), Koualy Sanogo (4), Seydou Traoré (4), Sekouba Keita (4), Amadou Barry (4), Martin de Smet (6), Estrella Lasry (7), Michiel Smit (8), Lubbe Wiesner (8), Karen I. Barnes (8,9), Abdoulaye A. Djimde (4), Philippe J. Guerin (9,10), Rebecca F. Grais (3), Ogobara K. Doumbo (4), Jean-François Etard (3,11), and Joel Tarning (1,10)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand, (2) Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (3) Epicentre, Paris, France, (4) 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. (5) Epicentre, Maradi, Niger. (6) Medecins Sans Frontieres, Brussels, Belgium. (7) Medecins Sans Frontieres, New York, NY, USA. (8) Division of Clinical Pharmacology, University of Cape Town, Cape Town, South Africa. (9) WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK. (10) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK. (11)TransVIHMI UMI 233, Institut de Recherche pour le Développement (IRD) – Inserm U 1175 – Montpellier 1 University, Montpellier, France.
Objectives: Malaria and severe acute malnutrition (SAM) are a common co-morbidity in Sub-Saharan African children. The pathophysiological properties of SAM might adversely affect the pharmacokinetic properties of administered drugs. This is the first study aimed to investigate the pharmacokinetic properties of the antimalarial drug lumefantrine in children with SAM at two sites in Niger and Mali.
Methods: 131 SAM children and 266 non-SAM children with uncomplicated falciparum malaria were recruited and administered a standard weight-based treatment of artemether-lumefantrine twice daily for 3 days. Pharmacokinetic and pharmacodynamic properties of lumefantrine were investigated using nonlinear mixed-effects modelling (NONMEM v.7). All malnutrition related covariates were evaluated using a stepwise covariate modelling approach as well as a full covariate modelling approach. Time to malaria re-reinfection was used as a pharmacodynamic endpoint.
Results: Lumefantrine capillary plasma concentrations were adequately described by two transit-absorption compartments followed by three-distribution compartments. Pharmacokinetic parameters were scaled using an allometric function of body weight. Elimination clearance of lumefantrine was also influenced by the level of enzyme maturation in these very young children (6-59 months). Mid-upper arm circumference (MUAC) is a well-established measure of SAM, and it was a significant covariate on the relative bioavailability of lumefantrine in the children studied here, resulting in a 23.8% decreased drug absorption per 1 cm reduction in MUAC. Parasite density at the time of malaria detection was used for interpolation of the likely time interval of malaria acquisition. An interval-censoring time-to-event model with a sigmoid EMAX inhibitory effect of lumefantrine described the recurrent malaria in this vulnerable population successfully.
Conclusions: The pharmacokinetic and pharmacodynamic properties of lumefantrine were successfully described by the developed pharmacometric model. Modelling conducted here suggests that children with SAM are at risk of under-dosing compared to well-nourished children.
