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Pyronaridine-artesunate granules versus artemether-lumefantrine crushed tablets in children with Plasmodium
Kassoum Kayentao1, Ogobara K Doumbo, Louis K Pénali
1Malaria Research and Training Center, Faculté de Médecine de Pharmacie et d'Odonto-Stomatologie, Bamako, Mali.
Insights
A new pediatric malaria treatment, pyronaridine-artesunate granules, proved effective and non-inferior to artemether-lumefantrine in children. This formulation offers a safe and comparable option for treating uncomplicated Plasmodium falciparum malaria.
Area of Science:
- Tropical Medicine
- Pediatric Infectious Diseases
- Pharmacology
Background:
- Children are disproportionately affected by malaria, necessitating effective pediatric treatments.
- Development of a pyronaridine-artesunate pediatric granule formulation addresses this need for uncomplicated Plasmodium falciparum malaria.
Purpose of the Study:
- To evaluate the efficacy and safety of a novel pyronaridine-artesunate pediatric granule formulation.
- To compare this new formulation against artemether-lumefantrine in children with uncomplicated Plasmodium falciparum malaria.
Main Methods:
- Phase III, multi-center, comparative, open-label clinical trial involving children aged ≤12 years with confirmed uncomplicated Plasmodium falciparum malaria.
- Randomized controlled trial (2:1) comparing pyronaridine-artesunate granules (once daily) to artemether-lumefantrine crushed tablets (twice daily) for three days, both orally dosed by bodyweight.
- Primary endpoint: Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using PCR genotyping.
Main Results:
- Day-28 PCR-corrected ACPR was 97.1% for pyronaridine-artesunate (n=339) and 98.8% for artemether-lumefantrine (n=167), demonstrating non-inferiority.
- Pyronaridine-artesunate met the primary endpoint, showing statistically significant efficacy (>90% ACPR).
- Adverse event incidence was comparable: 37.2% for pyronaridine-artesunate versus 44.4% for artemether-lumefantrine; similar mild elevations in liver enzymes were observed.
Conclusions:
- The pyronaridine-artesunate pediatric granule formulation is efficacious and non-inferior to artemether-lumefantrine for treating uncomplicated Plasmodium falciparum malaria in children.
- The safety profiles of both treatments were similar, with no significant differences in drug-related adverse events or liver enzyme elevations.
- Pyronaridine-artesunate granules represent a viable option for inclusion in pediatric malaria treatment programs.
Background:
Children are most vulnerable to malaria. A pyronaridine-artesunate pediatric granule formulation is being developed for the treatment of uncomplicated Plasmodium falciparum malaria.
Methods:
This phase III, multi-center, comparative, open-label, parallel-group, controlled clinical trial included patients aged ≤12 years, bodyweight ≥5 to <25 kg, with a reported history of fever at inclusion or in the previous 24 h and microscopically-confirmed uncomplicated P. falciparum malaria. Patients were randomized (2:1) to pyronaridine-artesunate granules (60/20 mg) once daily or artemether-lumefantrine crushed tablets (20/120 mg) twice daily, both dosed by bodyweight, orally (liquid suspension) for three days.
Results:
Of 535 patients randomized, 355 received pyronaridine-artesunate and 180 received artemether-lumefantrine. Day-28 adequate clinical and parasitological response (ACPR), corrected for re-infection using polymerase chain reaction (PCR) genotyping (per-protocol population) was 97.1% (329/339; 95% CI 94.6, 98.6) for pyronaridine-artesunate; 98.8% (165/167; 95% CI 95.7, 99.9) for artemether-lumefantrine. The primary endpoint was achieved: pyronaridine-artesunate PCR-corrected day-28 ACPR was statistically significantly >90% (P < .0001). Pyronaridine-artesunate was non-inferior to artemether-lumefantrine: treatment difference -1.8% (95% CI -4.3 to 1.6). The incidence of drug-related adverse events was 37.2% (132/355) with pyronaridine-artesunate, 44.4% (80/180) with artemether-lumefantrine. Clinical biochemistry results showed similar mean changes versus baseline in the two treatment groups. From day 3 until study completion, one patient in each treatment group had peak alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and peak total bilirubin >2xULN (i.e. within the Hy's law definition).
Conclusions:
The pyronaridine-artesunate pediatric granule formulation was efficacious and was non-inferior to artemether-lumefantrine. The adverse event profile was similar for the two comparators. Pyronaridine-artesunate should be considered for inclusion in paediatric malaria treatment programmes.
Trial Registration:
ClinicalTrials.gov: identifier NCT00541385.
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