Pyronaridine-artesunate retreatment for malaria
Authors: Sabine Bélard, Florian Kurth
Journal: The Lancet Infectious Diseases (2015)

In The Lancet Infectious Diseases, Issaka Sagara and colleagues1Sagara I Beavogui AH Zongo I et al.Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial.Lancet Infect Dis. 2015; (published online Oct 23.)http://dx.doi.org/10.1016/S1473-3099(15)00318-7PubMed Google Scholar report a large trial of the safety and efficacy of repeated administration of pyronaridine-artesunate, a novel artemisinin combination therapy (ACT) for uncomplicated malaria. ACTs are the therapeutic cornerstone of malaria control and have contributed to reducing the global malaria burden substantially. The aim to expand the range of partner drugs for combination with artemisinin derivatives and continued efforts to optimise efficacy, tolerability, costs, and treatment regimens led to the development of the pyronaridine-artesunate combination. About 15 years ago pyronaridine, an antimalarial drug first synthesised in the 1970s,2Kurth F Belard S Basra A Ramharter M Pyronaridine-artesunate combination therapy for the treatment of malaria.Curr Opin Infect Dis. 2011; 24: 564-569Crossref PubMed Scopus (19) Google Scholar entered clinical testing in combination with artesunate under the lead of a public–private product development partnership between Shin Poong Pharmaceutical Company and Medicines for Malaria Venture. This novel ACT showed excellent efficacy against Plasmodium falciparum malaria in a series of phase 2 and 3 studies3Bukirwa H Unnikrishnan B Kramer CV Sinclair D Nair S Tharyan P Artesunate plus pyronaridine for treating uncomplicated Plasmodium falciparum malaria.Cochrane Database Syst Rev. 2014; 3 (CD006404.)PubMed Google Scholar and, noteworthy, was systematically assessed for treatment of Plasmodium vivax malaria.4Poravuth Y Socheat D Rueangweerayut R et al.Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial.PLoS One. 2011; 6: e14501Crossref PubMed Scopus (71) Google Scholar In 2012, pyronaridine-artesunate was granted a positive scientific opinion by the European Medicines Agency under Article 58 and added to WHO's list of prequalified medicines. However, because of insufficient clinical trial data at that time and concerns about drug-induced hepatotoxicity, the recommended indication was restricted to a single treatment course. Drug-induced liver injury is one of the most common reasons for failure of new compounds during clinical development and for withdrawal from the market.5Maddur H Chalasani N Idiosyncratic drug-induced liver injury: a clinical update.Curr Gastroenterol Rep. 2011; 13: 65-71Crossref PubMed Scopus (16) Google Scholar Generally, either an intrinsic (dose-dependent injury—eg, through accumulation of the drug or reactive metabolites) or idiosyncratic mechanism (metabolic or immunoallergic injury through re-exposure after initial sensitisation) is postulated in drug-induced liver injury. The long half-life of artemisinin partner drugs with their inherent risk of accumulation and the need for repeated antimalarial treatment in endemic regions clearly emphasise the necessity of retreatment trials. The prospective multicentre randomised trial by Sagara and colleagues1Sagara I Beavogui AH Zongo I et al.Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trial.Lancet Infect Dis. 2015; (published online Oct 23.)http://dx.doi.org/10.1016/S1473-3099(15)00318-7PubMed Google Scholar compared safety and efficacy of pyronaridine-artesunate tablet or granule formulation after a first malaria treatment episode versus retreatment in children and adults. Artemether-lumefantrine was the comparator treatment. The primary safety outcome was the incidence of post-treatment hepatotoxicity. About a third of 1015 pyronaridine-artesunate-treated patients were retreated in this study. Neither an increase in the frequency nor severity of hepatotoxicity events, or in other adverse events was noted after retreatment compared with first treatment episodes. Overall, the incidence of hepatotoxicity events was about 1% in both groups and all events resolved without sequelae. The investigators concluded that safety and efficacy of pyronaridine-artesunate were similar with first treatment versus retreatment of malaria and that these findings lend support for the wider use of pyronaridine-artesunate. Close active follow-up for 6 weeks after treatment, monthly home visits thereafter, and provision of health care 24 h per day by the study team despite the long study period in a challenging geographical setting, and the large sample size of retreated patients are important strengths of the study. A more comprehensive diagnostic work up of differential diagnoses underlying hepatotoxicity could have further strengthened the main conclusion of this trial. The unintended retreatment of four patients with hepatotoxic events after the first treatment episode (who should have been excluded from retreatment in this study) provides further reassurance because none of the patients showed any symptoms of recurrence or exacerbation of hepatotoxicity. Although the overall results of this study are highly reassuring, some concerns remain at this stage of the clinical development of pyronaridine-artesunate: most importantly, the exclusion of patients with liver diseases, increases in liver enzymes, or HIV infection in the phase 2 and 3 trials. Moreover, few data are available for very small children. However, these patients constitute important target populations for the treatment of malaria in endemic regions. Co-medication such as antiretroviral treatment and use of traditional herbal medicine might interfere with any new antimalarial drug and should therefore be assessed further. These important concerns need to be addressed in further clinical phase 3 trials or in post-marketing surveillance. More evidence for the safety of pyronaridine-artesunate in susceptible populations will promote the exploitation of the many benefits of pyronaridine-artesunate. A fixed-dose once-daily regimen including the availability of a granule formulation for children,6Kurth F Belard S Adegnika AA Gaye O Kremsner PG Ramharter M Do paediatric drug formulations of artemisinin combination therapies improve the treatment of children with malaria? A systematic review and meta-analysis.Lancet Infect Dis. 2010; 10: 125-132Summary Full Text Full Text PDF PubMed Scopus (34) Google Scholar the absence of a major effect of food intake on bioavailability, a long shelf life, a long post-treatment prophylactic effect, and projected low price lend support to pyronaridine-artesunate becoming a powerful new arrow in the quiver for the fight against malaria. We declare no competing interests. SB and FK were study physicians in phase 2 and 3 clinical trials of pyronaridine-artesunate. SB and FK are participants in the Charité Clinical Scientist Program funded by the Charité–Universitätsmedizin Berlin and the Berlin Institute of Health. Safety and efficacy of re-treatments with pyronaridine-artesunate in African patients with malaria: a substudy of the WANECAM randomised trialThe findings that pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa. Full-Text PDF Open Access