title: Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00722150.
authors: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. delia.bethell@afrims.org
authors: Delia
authors: D
authors: Bethell
authors: Youry
authors: Y
authors: Se
authors: Chanthap
authors: C
authors: Lon
authors: Stuart
authors: S
authors: Tyner
authors: David
authors: D
authors: Saunders
authors: Sabaithip
authors: S
authors: Sriwichai
authors: Sea
authors: S
authors: Darapiseth
authors: Paktiya
authors: P
authors: Teja-Isavadharm
authors: Phisit
authors: P
authors: Khemawoot
authors: Kurt
authors: K
authors: Schaecher
authors: Wiriya
authors: W
authors: Ruttvisutinunt
authors: Jessica
authors: J
authors: Lin
authors: Worachet
authors: W
authors: Kuntawungin
authors: Panita
authors: P
authors: Gosi
authors: Ans
authors: A
authors: Timmermans
authors: Bryan
authors: B
authors: Smith
authors: Duong
authors: D
authors: Socheat
authors: Mark M
authors: MM
authors: Fukuda
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