Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria

Abstract

Background The World Health Organization (WHO) recommends artemisinin‐based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine‐artesunate is a novel ACT. Objectives To evaluate the efficacy of pyronaridine‐artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine‐artesunate and other pyronaridine treatments compared to alternative treatments. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the ISRCTN registry for ongoing or recently completed trials. The date of the last search was 27 October 2021. Selection criteria For the efficacy analysis, we included randomized controlled trials (RCTs) of pyronaridine‐artesunate for treating uncomplicated P falciparum malaria. For the safety analysis, we included RCTs that used pyronaridine alone or in combination with any other antimalarials. In addition to these analyses, we conducted a separate systematic review summarizing data on safety from non‐randomized studies (NRS) of any patient receiving pyronaridine (NRS safety review). Data collection and analysis Two review authors independently extracted all data and assessed the certainty of the evidence. We meta‐analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Main results We included 10 relevant RCTs. Seven RCTs were co‐funded by Shin Poong Pharmaceuticals, and three were funded by government agencies. Efficacy analysis (RCTs) For the efficacy analysis, we identified five RCTs comprising 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. The analysis included 541 children aged less than five years. Overall, pyronaridine‐artesunate had a polymerase chain reaction (PCR)‐adjusted treatment failure rate of less than 5%. We evaluated pyronaridine‐artesunate versus the following. • Artemether‐lumefantrine. Pyronaridine artesunate may perform better for PCR‐adjusted failures at day 28 (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low‐certainty evidence); for unadjusted failures at day 28 (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low‐certainty evidence); and for unadjus...

Randomized, placebo‐controlled, double‐blind phase I trial of co‐administered pyronaridine and piperaquine in healthy adults of sub‐Saharan origin

“…10,11,37 In a meta-analysis of eight randomized clinical trials, ALT elevations greater than five times the ULN occurred in 1.1% (41/3785) of patients with uncomplicated malaria, with one reported case in which raised ALT occurred with raised bilirubin. 24 However, to our knowledge, no study reported severe drug-induced liver injury in patients with malaria with PYR-AS. 24 Examination of the hypertransaminasemia cases by two independent liver safety experts concluded that there was no clear difference between the observed increases in ALT/AST in this study versus previous reports with PYR-AS in healthy White patients or patients with malaria.…”

“…24 However, to our knowledge, no study reported severe drug-induced liver injury in patients with malaria with PYR-AS. 24 Examination of the hypertransaminasemia cases by two independent liver safety experts concluded that there was no clear difference between the observed increases in ALT/AST in this study versus previous reports with PYR-AS in healthy White patients or patients with malaria. 10,11,20,[24][25][26][37][38][39][40][41] For this limited number of cases, there was no evidence that PQP co-administration increased the incidence or severity of PYR-induced ALT/ AST elevations or that sub-Saharan Africans were more at risk compared with previous reports of PYR-induced ALT/AST elevations in healthy White subjects.…”

“… 10 , 11 , 37 In a meta‐analysis of eight randomized clinical trials, ALT elevations greater than five times the ULN occurred in 1.1% (41/3785) of patients with uncomplicated malaria, with one reported case in which raised ALT occurred with raised bilirubin. 24 However, to our knowledge, no study reported severe drug‐induced liver injury in patients with malaria with PYR‐AS. 24 …”

“…Gastrointestinal adverse events are reported for PYR and PQP but are usually mild/moderate in severity 20–23 . For PYR, the main safety signal is transient asymptomatic elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), reported in patients with malaria and healthy volunteers 20,24–26 . Whereas increased ALT/AST is rare with PQP, the drug is known to prolong Fridericia‐corrected QT interval (QTcF).…”

“… 20 , 21 , 22 , 23 For PYR, the main safety signal is transient asymptomatic elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), reported in patients with malaria and healthy volunteers. 20 , 24 , 25 , 26 Whereas increased ALT/AST is rare with PQP, the drug is known to prolong Fridericia‐corrected QT interval (QTcF). Because of a clinically relevant food effect that increases systemic exposure, PQP should be administered in a fasted state to mitigate QTcF prolongation.…”