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Recommended malarial treatment leaves young children, pregnant women underdosed
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Treatment regimens currently recommended for uncomplicated Plasmodium falciparum malaria may be inadequate for pregnant women during the second and third trimesters and for young children. Findings from a study published in PLoS Medicine demonstrate that increasing the duration and frequency of treatment may be more beneficial for this population.
“The fixed-dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria,” Frank Kloprogge, a senior research fellow at the Institute for Global Health, University College London, and colleagues wrote. “Relatively lower cure rates and lumefantrine levels have been reported in young children and pregnant women during their second and third trimester.”
Because of these low cure rates in young children and pregnant women, the researchers aimed to help guide optimal AL treatments by better understanding the pharmacokinetic and pharmacodynamic make-up of the drug and its metabolite, desbutyl-lumefantrine. Kloprogge and colleagues analyzed data collected from 31 pertinent clinical studies with results published between Jan. 1, 1990, and Dec. 31, 2012.
These studies included 4,546 patients with recorded lumefantrine concentrations. Individual concentration-time data, clinical covariates and outcome data were pulled from 4,122 patients for meta-analysis. The researchers then conducted silico simulations using a developed lumefantrine population pharmacokinetic model to determine optimal dosing.
When Kloprogge and colleagues examined patients’ venous plasma lumefantrine concentrations 7 days after receiving standard AL treatment, they observed concentrations of 24.2% in children weighing less than 15 kg and 13.4% in children weighing between 15 and 25 kg. Concentrations observed in pregnant women were 20.2% less than concentrations observed in adults who were not pregnant.
Patients who had parasitemia before beginning treatment demonstrated a lessened lumefantrine exposure, and these patients had significant limitations as to how the medication dosages were absorbed. The researchers recommended an extended-dose regimen for these children and pregnant women, which includes twice-daily doses for 5 days. Additionally, children and pregnant women may also be placed on a regimen that increases the frequency of doses (three daily doses for 3 days).
“From a pharmacological perspective, a dose extension — twice-daily dosing at the current dosage for 5 days — for children 25 kg or less and pregnant women during the second and third trimester probably has the greatest advantages for therapeutic efficacy,” Kloprogge and colleagues wrote. “A dose extension would result not only in adequate lumefantrine exposures but also, even more importantly, in an additional malaria asexual replication cycle being exposed to artemether/dihydroartemisinin. This would contribute to a lower parasite biomass.” – by Katherine Bortz
Disclosures: Kloprogge reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures.
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