Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial
The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of...
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creator | Bethell, Delia Se, Youry Lon, Chanthap Tyner, Stuart Saunders, David Sriwichai, Sabaithip Darapiseth, Sea Teja-Isavadharm, Paktiya Khemawoot, Phisit Schaecher, Kurt Ruttvisutinunt, Wiriya Lin, Jessica Kuntawungin, Worachet Gosi, Panita Timmermans, Ans Smith, Bryan Socheat, Duong Fukuda, Mark M |
description | The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia.
Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.
143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia |
doi_str_mv | 10.1371/journal.pone.0019283 |
format | Article |
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Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.
143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.
There is no pharmacodynamic benefit of increasing the daily dose of AS (4 mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.
ClinicalTrials.gov NCT00722150.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0019283</identifier><identifier>PMID: 21603629</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adolescent ; Adult ; Amebicides ; Antimalarials ; Armed forces ; Artemisinin ; Artemisinins - administration & dosage ; Artemisinins - adverse effects ; Artemisinins - pharmacokinetics ; Artemisinins - pharmacology ; Artesunate ; Cambodia ; Cancer therapies ; Clinical trials ; Dosage ; Dose-Response Relationship, Drug ; Drug dosages ; Drug Resistance ; Drug therapy ; Female ; Genotype & phenotype ; Humans ; Immunology ; Malaria ; Malaria - drug therapy ; Male ; Maximum Tolerated Dose ; Medical research ; Medicine ; Neutropenia ; Neutropenia - chemically induced ; Parasitemia ; Parasitemia - drug therapy ; Parasites ; Parasitology ; Patients ; Pharmacodynamics ; Pharmacology ; Plasmodium falciparum ; Randomization ; Substance abuse treatment ; Vector-borne diseases ; Young Adult</subject><ispartof>PloS one, 2011-05, Vol.6 (5), p.e19283</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Bethell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Bethell et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-97302f67325c2e9ec39e6a283f20c049a16d3abb5a0a51fe8bd2111d669e21a53</citedby><cites>FETCH-LOGICAL-c691t-97302f67325c2e9ec39e6a283f20c049a16d3abb5a0a51fe8bd2111d669e21a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094355/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094355/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21603629$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Borrmann, Steffen</contributor><creatorcontrib>Bethell, Delia</creatorcontrib><creatorcontrib>Se, Youry</creatorcontrib><creatorcontrib>Lon, Chanthap</creatorcontrib><creatorcontrib>Tyner, Stuart</creatorcontrib><creatorcontrib>Saunders, David</creatorcontrib><creatorcontrib>Sriwichai, Sabaithip</creatorcontrib><creatorcontrib>Darapiseth, Sea</creatorcontrib><creatorcontrib>Teja-Isavadharm, Paktiya</creatorcontrib><creatorcontrib>Khemawoot, Phisit</creatorcontrib><creatorcontrib>Schaecher, Kurt</creatorcontrib><creatorcontrib>Ruttvisutinunt, Wiriya</creatorcontrib><creatorcontrib>Lin, Jessica</creatorcontrib><creatorcontrib>Kuntawungin, Worachet</creatorcontrib><creatorcontrib>Gosi, Panita</creatorcontrib><creatorcontrib>Timmermans, Ans</creatorcontrib><creatorcontrib>Smith, Bryan</creatorcontrib><creatorcontrib>Socheat, Duong</creatorcontrib><creatorcontrib>Fukuda, Mark M</creatorcontrib><title>Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia.
Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.
143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.
There is no pharmacodynamic benefit of increasing the daily dose of AS (4 mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.
ClinicalTrials.gov NCT00722150.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Amebicides</subject><subject>Antimalarials</subject><subject>Armed forces</subject><subject>Artemisinin</subject><subject>Artemisinins - administration & dosage</subject><subject>Artemisinins - adverse effects</subject><subject>Artemisinins - pharmacokinetics</subject><subject>Artemisinins - pharmacology</subject><subject>Artesunate</subject><subject>Cambodia</subject><subject>Cancer therapies</subject><subject>Clinical trials</subject><subject>Dosage</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug dosages</subject><subject>Drug Resistance</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Immunology</subject><subject>Malaria</subject><subject>Malaria - drug therapy</subject><subject>Male</subject><subject>Maximum Tolerated Dose</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Neutropenia</subject><subject>Neutropenia - chemically induced</subject><subject>Parasitemia</subject><subject>Parasitemia - drug therapy</subject><subject>Parasites</subject><subject>Parasitology</subject><subject>Patients</subject><subject>Pharmacodynamics</subject><subject>Pharmacology</subject><subject>Plasmodium falciparum</subject><subject>Randomization</subject><subject>Substance abuse treatment</subject><subject>Vector-borne diseases</subject><subject>Young 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Wiriya</au><au>Lin, Jessica</au><au>Kuntawungin, Worachet</au><au>Gosi, Panita</au><au>Timmermans, Ans</au><au>Smith, Bryan</au><au>Socheat, Duong</au><au>Fukuda, Mark M</au><au>Borrmann, Steffen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-05-13</date><risdate>2011</risdate><volume>6</volume><issue>5</issue><spage>e19283</spage><pages>e19283-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia.
Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.
143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.
There is no pharmacodynamic benefit of increasing the daily dose of AS (4 mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.
ClinicalTrials.gov NCT00722150.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21603629</pmid><doi>10.1371/journal.pone.0019283</doi><tpages>e19283</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2011-05, Vol.6 (5), p.e19283 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1294869754 |
source | Electronic Journals Library; PubMed (Medline); MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science website; Free Full-Text Journals in Chemistry |
subjects | Adolescent Adult Amebicides Antimalarials Armed forces Artemisinin Artemisinins - administration & dosage Artemisinins - adverse effects Artemisinins - pharmacokinetics Artemisinins - pharmacology Artesunate Cambodia Cancer therapies Clinical trials Dosage Dose-Response Relationship, Drug Drug dosages Drug Resistance Drug therapy Female Genotype & phenotype Humans Immunology Malaria Malaria - drug therapy Male Maximum Tolerated Dose Medical research Medicine Neutropenia Neutropenia - chemically induced Parasitemia Parasitemia - drug therapy Parasites Parasitology Patients Pharmacodynamics Pharmacology Plasmodium falciparum Randomization Substance abuse treatment Vector-borne diseases Young Adult |
title | Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial |
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