Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial

Abstract

Background Pyronaridine-artesunate (PA) is a registered artemisinin-based combination therapy, potentially useful for mass drug administration campaigns. However, further data are needed to evaluate its efficacy, safety and tolerability as full or incomplete treatment in asymptomatic Plasmodium falciparum-infected individuals. Methods This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was PCR-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population. Results A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens, but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3xULN) in alanine transaminase/aspartate transaminase were observed for 6/301 (2.0%) participants. Conclusion PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns.

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

“…Parallel groups of participants were administered with PYR‐PQP, PYR + placebo, PQP + placebo, and placebo + placebo (double‐dummy). All treatments were well‐tolerated, with no trends suggesting an increase in the frequency or severity of adverse events compared with the known safety profiles for PYR‐AS or DHA‐PQP in asymptomatic and symptomatic malaria patients 12,20–23,25,27,33,34 …”

“…All treatments were well-tolerated, with no trends suggesting an increase in the frequency or severity of adverse events compared with the known safety profiles for PYR-AS or DHA-PQP in asymptomatic and symptomatic malaria patients. 12,[20][21][22][23]25,27,33,34 Increased exposures for PYR or PQP following coadministration over 3 days were not anticipated. The DDI risk assessment performed prior to conducting the study was based on in vitro and clinical DDI data, indicating that PYR and PQP are both CYP3A4 substrates (~60% and 80% metabolized via this pathway, respectively), whereas only PQP is a moderate CYP3A4 inhibitor.…”

“…All treatments were well‐tolerated, with no trends suggesting an increase in the frequency or severity of adverse events compared with the known safety profiles for PYR‐AS or DHA‐PQP in asymptomatic and symptomatic malaria patients. 12 , 20 , 21 , 22 , 23 , 25 , 27 , 33 , 34 …”

Sporozoite immunization: innovative translational science to support the fight against malaria

“… As envisioned by the authors, a malaria elimination campaign would be designed for a target geographical region including appropriate community engagement. Mass drug administration (MDA) such as artesunate + pyronaridine [ 290 ] would be conducted prior to immunization to reduce the suppression of vaccine responses by existing parasitemia and to eliminate the human parasite reservoir. Intensified vector control would help to eliminate the mosquito reservoir.…”