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Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial.

Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K, Ruttvisutinunt W, Lin J, Kuntawungin W, Gosi P, Timmermans A, Smith B, Socheat D, Fukuda MM - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. delia.bethell@afrims.org

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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00722150.

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Related in: MedlinePlus

IC50 values at baseline using HRP2 methodology in fresh cultured parasite isolates from 131 patients.
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pone-0019283-g005: IC50 values at baseline using HRP2 methodology in fresh cultured parasite isolates from 131 patients.

Mentions: IC50 data are shown in Figure 5. Sigmoidal dose response curves were obtained from DHA and AS coated HRP2 ELISA plates in 131 of 143 (92%) subjects; 67/75 in AS2; 39/40 in AS4, and 25/28 in AS6. Median (IQR) IC50 values for DHA were 8.19 (IQR 5.13–14.0) nM and for AS were 5.66 (3.57–7.81) nM, more than double the values measured at the same site using the same methodology 3 years previously 1. Individual IC50 values for DHA and AS did not correlate well with most parasitological parameters, and did not differentiate between cured and recrudescent patients (Table 7). In contrast, the median (IQR) DHA IC50 for patients remaining parasitemic at 72 hours was 9.60 (6.82–14.7) nM, significantly higher than the median IC50 of 6.26 (4.22–13.4) nM for subjects clearing parasites within 72 hours (p = 0.013). There was no significant difference observed between AS IC50 for patients who were and were not parasitemic at 72 hours (5.98 vs. 5.38 nM, p = 0.067).


Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial.

Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K, Ruttvisutinunt W, Lin J, Kuntawungin W, Gosi P, Timmermans A, Smith B, Socheat D, Fukuda MM - PLoS ONE (2011)

IC50 values at baseline using HRP2 methodology in fresh cultured parasite isolates from 131 patients.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3094355&req=5

pone-0019283-g005: IC50 values at baseline using HRP2 methodology in fresh cultured parasite isolates from 131 patients.
Mentions: IC50 data are shown in Figure 5. Sigmoidal dose response curves were obtained from DHA and AS coated HRP2 ELISA plates in 131 of 143 (92%) subjects; 67/75 in AS2; 39/40 in AS4, and 25/28 in AS6. Median (IQR) IC50 values for DHA were 8.19 (IQR 5.13–14.0) nM and for AS were 5.66 (3.57–7.81) nM, more than double the values measured at the same site using the same methodology 3 years previously 1. Individual IC50 values for DHA and AS did not correlate well with most parasitological parameters, and did not differentiate between cured and recrudescent patients (Table 7). In contrast, the median (IQR) DHA IC50 for patients remaining parasitemic at 72 hours was 9.60 (6.82–14.7) nM, significantly higher than the median IC50 of 6.26 (4.22–13.4) nM for subjects clearing parasites within 72 hours (p = 0.013). There was no significant difference observed between AS IC50 for patients who were and were not parasitemic at 72 hours (5.98 vs. 5.38 nM, p = 0.067).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. delia.bethell@afrims.org

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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00722150.

Show MeSH
Related in: MedlinePlus