Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®)

Abstract

BackgroundArtemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.MethodsThis multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).ResultsA total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.ConclusionsA three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.Trial RegistrationClinicaltrials.gov NCT01619878.

Comparative Brain Microanatomical and Neurochemical Alterations Following the Administration of Seven Oral Artemisinin-Based Combination Therapies in Swiss Mice

“…Furthermore, the reduction of size of Purkinje cells may be due to complication resulting from increase in lipid peroxidation and oxidative stress as seen with an increase in MDA concentrations in AA, AM, ASP, and AL-administered groups and more significant increase in DP, APy and AP-administered groups when compared to NC group. Damage to the Purkinje cells as seen in the histopathological assessment of the administered groups especially the DP, APy and AP groups may result from de-myelination and disruption of the cortico-cerebellar circuit due to brain concluded on the dosage as generally well tolerated compared to artemether and dihydroartemisinin with respect to preclinical safety margins for neurotoxicity reported by Tiono et al, [67] and likewise AL has been reported to elicit ototoxicity while used in the treatment of falciparum malaria in a randomized trial reported by Gurkor et al, [68].…”

Nauclea latifolia Ethanolic Leaves Extract Moderately Hepatoprotects, but Decreases Periodic Acid-Schiff and Up-regulates Cytokeratin-7 Expression in Prophylaxis Malaria

“…A three-day regimen of AL was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria (Tiono et al, 2015).…”

Is there evidence of anti-malarial multidrug resistance in Burkina Faso?

“…Sep–Dec 2012 [ 7 ] Single arm (28 days) 6–59 months (105) AL 86.7 PCR correction with msp2 only Decrease Re-infection classified as ACPR Increase Ouagadougou and Nanoro. 2012–2014 [ 8 ] Multicentre, multicounty, single arm (28 and 42 days) > 28 days and <5 kg (20) AL 100 day 28-100 day 42 a Re-infection classified as ACPR Increase Colsama and Sakary health centres, Bobo-Dioulasso Jun–Dec 2016 [ 9 ] RCT (28 days) > 6 months (281) AL vs ASAQ 85.2 vs 97.0 No PCR correction Decrease Nanoro health district Sep 2008-Jan 2010 [ 10 ] RCT (28 and 42 days) 6–59 months (340) AL vs ASAQ 89.8 vs 89.7 - day 28 66.7 vs 63.0 day 42 PCR correction with msp1 and msp2 Decrease Re-infection classified as ACPR Increase Unsupervised treatment Decease Nanoro health district Sep 2010-Oct 2012 [ 11 – 13 ] RCT (28 days) > 6 months (680) AL vs ASAQ 77.8 vs 84.1 PCR correction with msp1 and msp2 Decrease Re-infection classified as ACPR Increase Unsupervised treatment …”