title: Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®).
abstract: BACKGROUND
  Artemether-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.
  
  
  METHODS
  This 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).
  
  
  RESULTS
  A 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.
  
  
  CONCLUSIONS
  A 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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01619878.
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme, Ministère de la Santé, 01 BP 2208, Ouagadougou, Burkina Faso. talfred@fasonet.bf.
authors.forename: Alfred B
authors.initials: AB
authors.lastname: Tiono
authors.affiliation: Unité de Recherche Clinique de Nanoro (IRSS-CRUN), BP 218, Ouagadougou, CMS11, Burkina Faso. tintohalidou@yahoo.fr.
authors.forename: Halidou
authors.initials: H
authors.lastname: Tinto
authors.affiliation: Service de Pédiatrie, Hôpital de la Mère et de l'Enfant Lagune, Cotonou, 01 BP 107, Benin. amomj@yahoo.fr.
authors.forename: Maroufou J
authors.initials: MJ
authors.lastname: Alao
authors.affiliation: Institute of Tropical Disease Research and Prevention, University of Calabar Teaching Hospital, Calabar, PMB 1278, Nigeria. mmeremiku@yahoo.co.uk.
authors.forename: Martin
authors.initials: M
authors.lastname: Meremikwu
authors.affiliation: Kinshasa School of Public Health, University of Kinshasa, 11850, Kinshasa, Democratic Republic of Congo. antotshe@yahoo.com.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Tshefu
authors.affiliation: Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya. bernhards.ogutu@indepth-network.org.
authors.forename: Bernhards
authors.initials: B
authors.lastname: Ogutu
authors.affiliation: Centre National de Recherche et de Formation sur le Paludisme, Ministère de la Santé, 01 BP 2208, Ouagadougou, Burkina Faso. aouedraogo.cnrfp@fasonet.bf.
authors.forename: Alphonse
authors.initials: A
authors.lastname: Ouedraogo
authors.affiliation: Unité de Recherche Clinique de Nanoro (IRSS-CRUN), BP 218, Ouagadougou, CMS11, Burkina Faso. lingani10@yahoo.fr.
authors.forename: Moussa
authors.initials: M
authors.lastname: Lingani
authors.affiliation: Novartis Pharma AG, CH-4002, Basel, Switzerland. marc.cousin@novartis.com.
authors.forename: Marc
authors.initials: M
authors.lastname: Cousin
authors.affiliation: Novartis Pharma AG, CH-4002, Basel, Switzerland. gilbert.lefevre@novartis.com.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lefèvre
authors.affiliation: Novartis Healthcare Private Limited, Hyderabad, India. jay_prakash.jain@novartis.com.
authors.forename: Jay Prakash
authors.initials: JP
authors.lastname: Jain
authors.affiliation: Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, 1215, Meyrin, Switzerland. duparcs@mmv.org.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA. kamal.hamed@novartis.com.
authors.forename: Kamal
authors.initials: K
authors.lastname: Hamed
mesh_terms: D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; C039060:artenimol