Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®)

Malaria Journal

Research

Alphonse Ouedraogo¹  Alfred B Tiono¹  Bernhards Ogutu²  Martin Meremikwu³  Antoinette Tshefu⁴  Stephan Duparc⁵  Jay Prakash Jain⁶  Gilbert Lefèvre⁷  Marc Cousin⁷  Kamal Hamed⁸  Maroufou J Alao⁹  Moussa Lingani^1,10  Halidou Tinto^1,10 

[1] Centre National de Recherche et de Formation sur le Paludisme, Ministère de la Santé, 01 BP 2208, Ouagadougou, Burkina Faso;Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya;Institute of Tropical Disease Research and Prevention, University of Calabar Teaching Hospital, PMB 1278, Calabar, Nigeria;Kinshasa School of Public Health, University of Kinshasa, 11850, Kinshasa, Democratic Republic of Congo;Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, 1215, Meyrin, Switzerland;Novartis Healthcare Private Limited, Hyderabad, India;Novartis Pharma AG, CH-4002, Basel, Switzerland;Novartis Pharmaceuticals Corporation, One Health Plaza, 07936-1080, East Hanover, NJ, USA;Service de Pédiatrie, Hôpital de la Mère et de l’Enfant Lagune, 01 BP 107, Cotonou, Benin;Unité de Recherche Clinique de Nanoro (IRSS-CRUN), BP 218, CMS11, Ouagadougou, Burkina Faso;

关键词: Artemether-lumefantrine;    Dispersible;    Efficacy;    Infants;    Pharmacokinetics;    Safety;    <5 kg body weight;   

DOI  :  10.1186/s12936-015-0682-7

 received in 2014-12-29, accepted in 2015-03-25,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundArtemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.MethodsThis multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).ResultsA total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.ConclusionsA three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.Trial RegistrationClinicaltrials.gov NCT01619878.

【 授权许可】

Unknown   
© Tiono et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.