Abstract
BackgroundPyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.MethodsIndividual patient data on safety outcomes were integrated from six randomized clinical trials conducted in Africa and Asia in patients with microscopically confirmed P. falciparum (five studies) or P. vivax (one study) malaria. Efficacy against P. falciparum was evaluated across three Phase III clinical trials.ResultsThe safety population included 2,815 patients randomized to PA, 1,254 to comparators: mefloquine + artesunate (MQ + AS), artemether-lumefantrine (AL), or chloroquine. All treatments were generally well tolerated. Adverse events occurred in 57.2% (1,611/2,815) of patients with PA versus 51.5% (646/1,254) for comparators, most commonly (PA; comparators): headache (10.6%; 9.9%), cough (5.9%; 5.6%) and anaemia (4.5%; 2.9%). Serious averse events were uncommon for all treatments (0–0.7%). Transient increases in alanine aminotransferase and aspartate aminotransferase were observed with PA but did not lead to any clinical sequelae. For P. falciparum malaria, day-28 PCR-corrected adequate clinical and parasitological response with PA was 93.6% ([1,921/2,052] 95% CI 92.6, 94.7) in the intent-to-treat population and 98.5% ([1,852/1,880] 95% CI 98.0, 99.1) in the per-protocol population. Median parasite clearance time was 24.1 h with PA, 31.9 h with MQ + AS, and 24.0 h with AL. Median fever clearance time was 15.5 h with PA, 15.8 h with MQ + AS, and 14.0 h with AL. By day 42, P. falciparum gametocytes had declined to near zero for all treatments.ConclusionsPyronaridine-artesunate was well tolerated with no safety concerns with the exception of mostly mild transient rises in transaminases. Efficacy was high and met the requirements for use as first-line therapy. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes.Trial registrationClinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931
Highlights
Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria
Artemisinin tolerance – observed as extended parasite clearance times with artemisinin-based combination therapy (ACT) treatment – has emerged among P. falciparum from the Cambodia–Thailand border areas [8,9,10,11,12,13,14,15], with some evidence of resistance spreading at the Thailand–Myanmar border [16]
Source data Individual patient data were integrated from six PA randomized clinical trials, two Phase II studies and four Phase III studies, conducted in sub-Saharan Africa, Southeast Asia and India between 2005 and 2008 (Table 1) [15,22,23,24,25]
Summary
Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. The important contribution of Plasmodium vivax infection to global malaria morbidity is being recognized [3,4,5,6]. Artemisinin tolerance – observed as extended parasite clearance times with ACT treatment – has emerged among P. falciparum from the Cambodia–Thailand border areas [8,9,10,11,12,13,14,15], with some evidence of resistance spreading at the Thailand–Myanmar border [16]. For P. vivax, the WHO recommends ACT in areas where chloroquine resistance has emerged [7]; most notably Indonesia, though there are reports from further east in the Malay archipelago to Papua New Guinea and Vietnam as well as from South America and Oceania [17,18]. Using ACT in areas co-endemic for P. falciparum and P. vivax has been suggested as a strategy to overcome difficulties in differential diagnosis and in cases of mixed infection [17,19,20]
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