Felices Mathieu, Borghini-Fuhrer Isabelle, Abla Nada, Chalon Stephan
PhinC Development, Massy, France.
MMV Medicines for Malaria Venture, Geneva, Switzerland.
Clin Transl Sci. 2025 Jul;18(7):e70305. doi: 10.1111/cts.70305.
A novel oral combination of the long-acting antimalarials pyronaridine (PYR) and piperaquine (PQP) has potential for malaria chemoprevention. This single-center randomized, double-blind, placebo-controlled study assessed the effects of PYR and PQP alone and when co-administered on Fridericia-corrected QT interval (QTcF). Between February 14, 2022, and May 31, 2022, thirty-seven healthy black adults of African sub-Saharan origin were enrolled and randomized to PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8) or double placebo (n = 6) administered once daily (fasted) for 3 days at doses approved for malaria treatment. Triplicate digitalized electrocardiogram (ECG) recordings and pharmacokinetic samples were taken at matched timepoints. Concentration-response analysis was performed for QTcF changes from baseline (ΔQTcF), and the impact of PYR, PQP, and PYR + PQP administration on placebo-corrected ΔQTcF (ΔΔQTcF) was assessed. The final qualified and validated concentration-QTc model included a linear component for PYR and an E component for PQP. The maximum predicted effect on ΔΔQTcF on day 3 was +4.94 msec (90% CI 0.338, 9.54) with PYR + placebo, +19.2 msec (14.6, 23.8) with PQP + placebo, and + 23.1 msec (18.5, 27.6) with PYR + PQP. As expected, PQP increased ΔΔQTcF above the regulatory threshold of concern (+10 msec), whereas PYR did not. The small additional increase in ΔΔQTcF with PYR + PQP coadministration was explained mainly by an increase in PQP C (1.4-fold) versus monotherapy. In healthy adults, PYR + PQP coadministration does not appear to increase significantly the effect of PQP on ΔΔQTcF versus PQP administered alone. However, further studies are needed in malaria patients to confirm these findings in the target population. Trial Registration: ClinicalTrials.gov identifier: NCT05160363; EudraCT number: 2021-005698-21.
长效抗疟药咯萘啶（PYR）和哌喹（PQP）的新型口服组合具有疟疾化学预防的潜力。这项单中心随机、双盲、安慰剂对照研究评估了单独使用以及联合使用PYR和PQP对弗里德里西亚校正QT间期（QTcF）的影响。在2022年2月14日至2022年5月31日期间，招募了37名撒哈拉以南非洲裔健康黑人成年人，并将其随机分为接受PYR + PQP（n = 15）、PYR + 安慰剂（n = 8）、PQP + 安慰剂（n = 8）或双安慰剂（n = 6）治疗，每天一次（空腹），按批准的疟疾治疗剂量给药3天。在匹配的时间点采集三次数字化心电图（ECG）记录和药代动力学样本。对QTcF相对于基线的变化（ΔQTcF）进行浓度-反应分析，并评估PYR、PQP和PYR + PQP给药对安慰剂校正的ΔQTcF（ΔΔQTcF）的影响。最终合格且经过验证的浓度-QTc模型包括PYR的线性成分和PQP的E成分。第3天对ΔΔQTcF的最大预测效应在PYR + 安慰剂组为+4.94毫秒（90%CI 0.338，9.54），在PQP + 安慰剂组为+19.2毫秒（14.6，23.8），在PYR + PQP组为+23.1毫秒（18.5，27.6）。正如预期的那样，PQP使ΔΔQTcF升高超过了监管关注阈值（+10毫秒），而PYR则没有。PYR + PQP联合给药时ΔΔQTcF的小幅额外升高主要是由于与单药治疗相比，PQP的血药浓度增加了1.4倍。在健康成年人中，与单独使用PQP相比，PYR + PQP联合给药似乎并未显著增加PQP对ΔΔQTcF的影响。然而，需要在疟疾患者中进行进一步研究以在目标人群中证实这些发现。试验注册：ClinicalTrials.gov标识符：NCT05160363；欧洲临床试验数据库编号：2021 - 005698 - 21。
