Palang Chotsiri (1), Lise Denoeud-Ndam (2), Elisabeth Baudin (2), Ousmane Guindo (3), Halimatou Diawara (4), Oumar Attaher (4), Michiel Smit (5), Philippe J. Guerin (6,7), Lubbe Wiesner (5), Karen I. Barnes (5,6), Richard M. Hoglund (1,7), Alassane Dicko (8), Jean-Francois Etard (2,9), Joel Tarning (1,6,7)
1. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; 2 Epicentre, Paris, France; 3 Epicentre, Maradi, Niger; 4 Malaria Research and Training Centre, Faculty of Medicine Pharmacy and Dentistry, University of Bamako, Bamako, Mali; 5 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; 6 WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK; 7 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK; 8 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; 9 TransVIHMI UMI 233, Institut de recherche pour le développement (IRD) – Inserm U 1175 – Montpellier 1 University, Montpellier, France
Objectives: Young children (
Methods: This clinical trial was an open-labelled comparative intervention study of artemether-lumefantrine in 131 SAM and 266 non-SAM children, aged 6 to 59 months, with uncomplicated falciparum malaria. For each child, five capillary blood samples were collected in pre-specified time-windows. Lumefantrine capillary blood concentration-time data and time-to-malaria reinfection during the 42-days of follow-up were analysed using nonlinear mixed-effects modelling (NONMEM v7.3). Time-to-malaria reinfection was modelled using an interval-censoring time-to-event model. The lag-time between an emerging blood stage infection from the liver and the microscopy detection of malaria was accounted for by back-extrapolating the observed number of parasites at the time of microscopic detection with a fixed exponential parasite growth rate [2]. The In vivo minimum inhibitory concentration (MIC) of lumefantrine was estimated based on the individually predicted lumefantrine concentration at the start of the blood stage infection [3]. The final PK/PD model was used to simulate lumefantrine exposures and treatment outcomes in SAM and non-SAM children using alternative dosing strategies; (1) increased dosing, (2) intensified dosing, and (3) extended dosing regimens.
Results: Lumefantrine was described adequately by two transit-absorption compartments followed by two disposition compartments. The fraction of observed concentrations below the LLOQ were low (6.26%), but omitting the data (M1) resulted in misspecifications while imputations (M6) resulted in a good predictive performance. Allometrically scaled body weight and an enzymatic maturation effect were included in the PK model. All investigated indicators of malnutrition were highly correlated and had a significant impact on relative bioavailability of lumefantrine. MUAC resulted in the largest drop in objective function value (ΔOFV = -64.4) and was retained in the final model. The median bioavailability was reduced by 25.4% (95% CI: 21.3%, 27.1%) per 1 cm reduction of MUAC. Impact of malnutrition-associated indicators were investigated further using a full-covariate approach, supporting the impact of malnutrition. Risk of recurrent malaria was characterised successfully by an interval-censored time-to-event model with a sigmoid EMAX-model describing the effect of lumefantrine. No covariates were found to have a significant impact in the model. The in vivo MIC of lumefantrine was estimated between 164 ng/mL and 182 ng/mL. Both the intensified and extended dosing regimens were able to increase the exposure to lumefantrine in SAM children to similar levels as that seen in non-SAM children receiving standard dosing, but resulted in a moderate improvement in protective efficacy. However, time above MIC should be highly correlated to therapeutic efficacy since residual lumefantrine concentrations above the MIC value eliminate residual parasites in order to avoid recrudescent infections. Time above MIC in SAM children was increased to 9.81 (95% CI: 6.67, 50.8) days and 12.3 (95% CI: 8.10, 52.0) days after the intensified and extended dosing regimens, respectively, equivalent to that seen in non-SAM children after standard dosing (9.33 (95% CI: 6.60, 39.3) days).
Conclusions: Malnutrition had a significant impact on the absorption of lumefantrine, resulting in substantially lower drug exposure with increasing malnutrition. Research on altered dosing regimens should be considered for optimal treatment of malaria in malnourished children.
References:
[1] World Health Organization (WHO). World Malaria Report 2018 (Geneva, Switzerland., 2018).
[2] Martin Bergstrand, François Nosten, Khin Maung Lwin, Mats O. Karlsson, Nicholas J. White, Joel Tarning. Characterisation of an in vivo concentration-effect relationship for piperaquine in malaria chemoprevention. Science Translational Medicine. 2014 Oct 29;6(260):260ra147.
[3] Palang Chotsiri, Issaka Zongo, Paul Milligan, Yves Daniel Compaore, Anyirékun Fabrice Somé, Daniel Chandramohan, Warunee Hanpithakpong, Francois Nosten, Brian Greenwood, Philip J. Rosenthal, Nicholas J. White, Jean-Bosco Ouédraogo, Joel Tarning. Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children. Nature Communications. 2019 Jan 29;10(1):480.
Reference: PAGE 28 (2019) Abstr 9031 [www.page-meeting.org/?abstract=9031]
Poster: Drug/Disease Modelling - Infection