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Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing

Ali Mohamed Ali 1, 2, 3 Melissa Penny 1, 2 Thomas Smith 1, 2 Lesley Workman 4 Philip Sasi 5 George O Adjei 6 Francesca Aweeka 7 Jean-René Kiechel 8 Vincent Jullien 9 Marcus Rijken 10 Rose Mcgready 10, 11 Julia Mwesigwa 12, 13 Kim Kristensen 14 Kasia Stepniewska 11 Joel Tarning 11, 10 Karen Barnes 4 Paolo Denti 4 Achille Massougbodji Adama Gansané Adicat Adeothy Agnès Aubouy Alphonse Ouedraogo Anna Annerberg Arnaud Bruneel Aung Pyae Phyo Aye Kyi Win A. Benakis Bamenla Goka Bernard Gourmel Bernhards Ogutu Birgit Schramm Bryan Mcgee Caroline Morgan Charles Obonyo Charles Mazinda D. Parzy Elizabeth Ashley Elisabeth Baudin Elizabeth Juma Eric Comte Esperance Ouedraogo François Nosten F. Sugnaux Gilles Cottrell Grant Dorsey Gwenaelle Carn Hortense Kossou Hyacinthe Amedome Joan Kalyango Jean-François Faucher Joel Jones Julie Simpson Justin Doritchamou J. Kurtzhals Loretxu Pinoges Lotte Hoegberg L. Bertaux L. Tshilolo Muepu Malaika Martin Bergstrand Michael Alifrangis Michel Branger Michel Cot Mireille Cammas Moses Kamya Nicholas Day Nicholas White N. Taudon Onike Rodrigues Palang Chotsiri Parastou Valeh Pascal Houzé Philippe Deloron Philippe Guérin Philip Rosenthal Poe Hsi Polina German Pratap Singhasivanon Richard Smith R. Lwango Sodiomon Sirima Sunil Parikh S. Sese Alegre Tamara Clark Timothy Sundaygar Troy Drysdale Walter Taylor V. Sinou Yah Zolia
Abstract : Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.
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Submitted on : Tuesday, February 9, 2021 - 4:20:02 PM
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Ali Mohamed Ali, Melissa Penny, Thomas Smith, Lesley Workman, Philip Sasi, et al.. Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2018, 62 (10), pp.e02193-17. ⟨10.1128/AAC.02193-17⟩. ⟨hal-03136362⟩



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