An Alternate Effective Dosing Regimen for IV Artesunate

Abstract and Commentary

By Lin H. Chen MD

Dr. Chen is Assistant Clinical Professor, Harvard Medical School and Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge, MA.

Dr. Chen has received research grants from the Centers for Disease Control and Prevention and Xcellerex

Synopsis: A 3-dose regimen (12mg/kg total dose) of intravenous artesunate is comparable to the standard 5-dose regimen in achieving rapid parasite clearance and is very effective in treating severe malaria in African children.

Source: Kremsner PG, et al. A simplified intravenous artesunate regimen for severe malaria. J Infect Dis 2012;205:312-9.

Currently, intravenous artesunate for the treatment of severe falciparum malaria is dosed at 0, 12, 24, 48, and 72 hours with a total dose of 12 mg/kg (5-dose regimen). Kremsner et al conducted a randomized, double-blind, placebo-controlled, dose-finding study in African children using a 3-dose regimen of IV artesunate at the same total dose. Patients were followed up clinically along with parasitological examinations weekly through day 28. This study utilized a product developed by the Walter Reed Army Institute of Research, and manufactured per current Good Manufacturing Practice (cGMP) guidelines by SRI International.

This study enrolled all African children from Gabon and Malawi, aged 6 months to 10 years, who had received a diagnosis of Plasmodium falciparum malaria with 5000 parasites/µL on initial blood smear, and whose severe illness required hospitalization. Among 197 children randomized, a total of 171 were in the "per protocol (PP)" population, with 86 in the 5-dose treatment group and 85 in the 3-dose treatment group; 156 continued through day 28 post treatment.

In the PP population, 78% of the 3-dose patients and 85% of the 5-dose patients achieved 99% parasite clearance in 24 hours, a -7.2% treatment difference. There were no significant differences in mean parasite reductions at either 24 or 48 hours.

Adverse events [AEs] were reported by 133 patients (69%), 68% of those in the 5-dose group and 69% of those in the 3-dose group. The two groups did not have significant differences in the number of patients with AEs or serious AEs.

Two patients died, resulting in a mortality rate of 1.1% in the PP population, both in the 3-dose treatment group. One case was a 4-year-old girl who became comatose and died 2 days after admission; this occurred despite decline of parasitemia to 0.3% within 24 hours of admission and clearance by the time of death. The other case was a 34-month old boy who died on day 1, when he developed seizures and respiratory distress at 10 hours after the first dose of artesunate.

Pharmacokinetic studies showed that children receiving the higher dose regimen of artesunate 4 mg/kg (3-dose regimen) had a slightly slower clearance (0.83 fold; 95% CI, .73–.95; P=.008) for dihydroartemisinin (DHA). The investigators found no associations between the outcome and estimates of pharmacokinetic parameters of artesunate and DHA.

Commentary

Artemisinin is a compound that originated from a Chinese herbal plant, Artemesia annua, and artesunate is an artemisinin derivative that is effective in treating severe malaria. A Cochrane systematic review that included 8 randomized controlled trials comparing intravenous, intramuscular, or rectal artesunate with intravenous or intramuscular quinine for severe malaria found that artesunate significantly reduced the risk of death both in adults (RR 0.61, 95% CI 0.50-0.75; 1664 participants, five trials) and children (RR 0.76, 95% CI 0.65-0.90; 5765 participants, four trials).1 An open-label, randomized trial comparing IV artesunate versus quinine in 5425 African children (age <15 years) with severe malaria demonstrated a relative reduction for risk of death 22.5% (95% CI 8.1-36.9; p=0.0022) in the artesunate group.2

The dosing of artesunate was derived empirically by the World Health Organization, and subsequently adjusted based on previous clinical trial results to 2.4 mg/kg at hours 0, 12, 24, and then daily for 7 days.3,4 Kremsner et al aimed at simplifying treatment courses by reducing the number of artesunate doses and achieving rapid parasite clearance without increased drug toxicity. Furthermore, they estimated that the 3-dose regimen could reduce cost by 40%.

A number of factors influence the cost-effectiveness of severe malaria treatment, including drug cost, laboratory tests, IV fluids, hospitalization charges, and estimates of the cost per disability-adjusted life year (DALY) averted and the cost per death averted. Taking into account these factors, IV artesunate and quinine treatments appear to have been similar in the African Quinine Artesunate Malaria Treatment trial that involved >5400 children.5 The artesunate treatment group had 22.5% lower mortality than the quinine treatment group and both had similar rates of neurological sequelae. Additionally, artesunate showed low incremental cost per DALY averted of US$ 3.8 and an incremental cost per death averted of US$ 123.

The absence of drug-induced hemolysis in this trial provides much reassurance. A retrospective analysis of 25 travelers with severe imported malaria treated with IV artesunate in Europe led to cure in all.6 Parasitemia responded rapidly to IV artesunate, but hemolysis occurred in 6 patients at 5 centers despite their decline in parasitemia, and necessitated blood transfusion in five patients.6 Some speculate that the product used to treat the patients in Europe had not met the cGMP guidelines. Hence it is important that the product utilized in this study had been manufactured under cGMP guidelines.

The pharmacodynamics of artesunate are becoming partially clarified although the main pharmacokinetic variables are not consistently related to efficacy.7,8 IV artesunate appears to be associated with high initial artesunate concentrations that decline rapidly, with estimated half-life of <15 minutes.8 DHA, the active metabolite of artesunate, reaches peak level within 25 minutes after administration, and is eliminated with a short half-life of 30-60 minutes. Some evidence suggests that pregnancy and acute malaria infection may affect the pharmacokinetics of artesunate and/or DHA following a dose of artesunate.8

Kremsner et al found only slightly slower drug clearance in the higher dose (3-dose) treatment, but no associations between pharmacokinetic estimates and clinical outcome. Additional assessments are needed regarding the influences on the pharmacokinetics of artesunate and DHA and their relationships to artesunate efficacy. Finally, the 3-dose artesunate is found to be comparable to the 5-dose regimen using parasitemia as the end point. The two fatalities that occurred in this trial likely would not have responded to any existing treatments. Nonetheless, extremely severe cases merit detailed analyses to assess the potential for any additional or synergistic treatments.

References

  1. Sinclair D, et al. Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev 2011;(3):CD005967. 92.
  2. Dondorp AM, et al. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 2010; 376:1647–57.
  3. World Health Organization. Guidelines for the treatment of malaria, second edition. Available at http://bit.ly/FRkfWt Accessed February 22, 2012.
  4. Dondorp A, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomized trial. Lancet 2005; 366:717–25.
  5. Lubell Y, et al. Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa. Bull World Health Organ. 2011;89(7):504-12.
  6. Zoller T, et al. Intravenous artesunate for severe malaria in travelers, Europe. Emerg Infect Dis 2011;17(5):771-7.
  7. Simpson JA, et al. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med 2006; 3:e444.
  8. Morris CA, et al. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J 2011 10:263.