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Open Access Research

Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials

Stephan Duparc1*, Isabelle Borghini-Fuhrer1, Carl J Craft12, Sarah Arbe-Barnes3, Robert M Miller3, Chang-Sik Shin4 and Lawrence Fleckenstein5

Author Affiliations

1 Medicines for Malaria Venture (MMV), International Center Cointrin, Route de Pré-Bois 20, PO Box 1826, CH-1215, Geneva 15, Switzerland

2 Current address: Libertyville, IL, USA

3 Aptiv Solutions, Stevenage BioScience Catalyst, SG1 2FX, Stevenage, UK

4 Shin Poong Pharmaceutical Co Ltd, Seoul, Republic of Korea

5 College of Pharmacy, University of Iowa (UoI), Iowa City, IA, USA

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Malaria Journal 2013, 12:70  doi:10.1186/1475-2875-12-70

Published: 21 February 2013

Abstract

Background

Pyronaridine-artesunate (PA) is indicated for the treatment of acute uncomplicated Plasmodium falciparum and Plasmodium vivax malaria.

Methods

Individual 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.

Results

The 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.

Conclusions

Pyronaridine-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 registration

Clinicaltrials.gov: NCT00331136; NCT00403260; NCT00422084; NCT00440999; NCT00541385; NCT01594931

Keywords:
Pyronaridine-artesunate; Artemether-lumefantrine; Mefloquine + artesunate; Malaria; Plasmodium falciparum; Plasmodium vivax; Randomized clinical trial