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Title: Antimalarial activity of KAF156 in falciparum and vivax malaria
Authors: Nicholas J. White
Tran T. Duong
Chirapong Uthaisin
Fran'ois Nosten
Aung P. Phyo
Borimas Hanboonkunupakarn
Sasithon Pukrittayakamee
Podjanee Jittamala
Kittiphum Chuthasmit
Ming S. Cheung
Yiyan Feng
Ruobing Li
Baldur Magnusson
Marc Sultan
Daniela Wieser
Xiaolei Xun
Rong Zhao
Thierry T. Diagana
Peter Pertel
F. Joel Leong
Mahidol-Oxford Tropical Medicine Research Unit
Department of Clinical Tropical Medicine
Mahidol University
Phusing Hospital
Mae Ramat District Hospital
Nuffield Department of Clinical Medicine
National Institute of Malaria, Parasitology and Entomology
Novartis International AG
Novartis Institutes for BioMedical Research
Novartis Institutes for Biomedical Research
Novartis Institute for Tropical Diseases Pte. Ltd.
Novartis Institutes for BioMedical Research, Inc.
Keywords: Medicine
Issue Date: 22-Sep-2016
Citation: New England Journal of Medicine. Vol.375, No.12 (2016), 1152-1160
Abstract: © 2016 Massachusetts Medical Society. All rights reserved. Background KAF156 belongs to a new class of antimalarial agents (imidazolopiperazines), with activity against asexual and sexual blood stages and the preerythrocytic liver stages of malarial parasites. METHODS We conducted a phase 2, open-label, two-part study at five centers in Thailand and Vietnam to assess the antimalarial efficacy, safety, and pharmacokinetic profile of KAF156 in adults with acute Plasmodium vivax or P. falciparum malaria. Assessment of parasite clearance rates in cohorts of patients with vivax or falciparum malaria who were treated with multiple doses (400 mg once daily for 3 days) was followed by assessment of the cure rate at 28 days in a separate cohort of patients with falciparum malaria who received a single dose (800 mg). RESULTS Median parasite clearance times were 45 hours (interquartile range, 42 to 48) in 10 patients with falciparum malaria and 24 hours (interquartile range, 20 to 30) in 10 patients with vivax malaria after treatment with the multiple-dose regimen and 49 hours (interquartile range, 42 to 54) in 21 patients with falciparum malaria after treatment with the single dose. Among the 21 patients who received the single dose and were followed for 28 days, 1 had reinfection and 7 had recrudescent infections (cure rate, 67%; 95% credible interval, 46 to 84). The mean ('SD) KAF156 terminal elimination half-life was 44.1'8.9 hours. There were no serious adverse events in this small study. The most common adverse events included sinus bradycardia, thrombocytopenia, hypokalemia, anemia, and hyperbilirubinemia. Vomiting of grade 2 or higher occurred in 2 patients, 1 of whom discontinued treatment because of repeated vomiting after receiving the single 800-mg dose. More adverse events were reported in the single-dose cohort, which had longer follow-up, than in the multiple-dose cohorts. CONCLUSIONS KAF156 showed antimalarial activity without evident safety concerns in a small number of adults with uncomplicated P. vivax or P. falciparum malaria.
ISSN: 15334406
Appears in Collections:Scopus 2016-2017

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