Stein Daniel S, Jain Jay Prakash, Kangas Michael, Lefèvre Gilbert, Machineni Surendra, Griffin Paul, Lickliter Jason
Novartis Institute for BioMedical Research, East Hanover, New Jersey, USA
Novartis Institute for BioMedical Research, Hyberabad, India.
Antimicrob Agents Chemother. 2015;59(6):3493-500. doi: 10.1128/AAC.00340-15. Epub 2015 Apr 6.
KAE609 represents a new class of potent, fast-acting, schizonticidal antimalarials. This study investigated the safety and pharmacokinetics of KAE609 in combination with the long-acting antimalarial piperaquine (PPQ) in healthy volunteers. A two-way pharmacokinetic interaction was hypothesized for KAE609 and PPQ, as both drugs are CYP3A4 substrates and inhibitors. The potential for both agents to affect the QT interval was also assessed. This was an open-label, parallel-group, single-dose study with healthy volunteers. Subjects were randomized to four parallel dosing arms with five cohorts (2:2:2:2:1), receiving 75 mg KAE609 plus 320 mg PPQ, 25 mg KAE609 plus 1,280 mg PPQ, 25 mg KAE609 alone, 320 mg PPQ alone, or 1,280 mg PPQ alone. Triplicate electrocardiograms were performed over the first 24 h after dosing, with single electrocardiograms at other time points. Routine safety (up to 89 days) and pharmacokinetic (up to 61 days) assessments were performed. Of the 110 subjects recruited, 99 completed the study. Coadministration of PPQ had no overall effect on exposure to KAE609, although 1,280 mg PPQ decreased the KAE609 maximum concentration (Cmax) by 17%. The group that received 25 mg KAE609 plus 1,280 mg PPQ showed a 32% increase in the PPQ area under the concentration-time curve from 0 to infinity (AUCinf), while the group that received 75 mg KAE609 plus 320 mg PPQ showed a 14% reduction. Mean changes from baseline in the QT interval corrected by Fridericia's method (QTcF) and the QT interval corrected by Bazett's method (QTcB) with PPQ were consistent with its known effects. PPQ but not KAE609 exposure correlated with corrected QT interval (QTc) increases, and KAE609 did not affect the PPQ exposure-QTc relationship. The QTcF effect for PPQ (least-squares estimate of the difference in mean maximal changes from baseline of 7.47 ms [90% confidence interval, 3.55 to 11.4 ms]) was consistent with the criteria for a positive thorough QT study. No subject had QTcF or QTcB values of >500 ms. Both drugs given alone or in combination were well tolerated, with no deaths, serious adverse events (AEs), or severe AEs reported. Most AEs were mild; upper respiratory tract infections, headache, diarrhea, and oropharyngeal pain were most common. PPQ and KAE609 coadministration had no relevant effect on exposure to either agent, and KAE609 did not affect or potentiate the known effects of PPQ on cardiac conduction.
KAE609代表了一类新型的强效、速效、裂殖体杀灭性抗疟药。本研究在健康志愿者中调查了KAE609与长效抗疟药哌喹（PPQ）联合使用时的安全性和药代动力学。由于两种药物都是CYP3A4底物和抑制剂，因此假设KAE609和PPQ存在双向药代动力学相互作用。还评估了两种药物影响QT间期的可能性。这是一项针对健康志愿者的开放标签、平行组、单剂量研究。受试者被随机分为四个平行给药组，共五个队列（2:2:2:2:1），分别接受75毫克KAE609加320毫克PPQ、25毫克KAE609加1280毫克PPQ、单独25毫克KAE609、单独320毫克PPQ或单独1280毫克PPQ。给药后的前24小时内进行三次心电图检查，其他时间点进行单次心电图检查。进行了常规安全性（长达89天）和药代动力学（长达61天）评估。在招募的110名受试者中，99名完成了研究。PPQ的共同给药对KAE609的暴露总体上没有影响，尽管1280毫克PPQ使KAE609的最大浓度（Cmax）降低了17%。接受25毫克KAE609加1280毫克PPQ的组，从0到无穷大的浓度-时间曲线下面积（AUCinf）中的PPQ增加了32%，而接受75毫克KAE609加320毫克PPQ的组则降低了14%。采用弗里德里西亚法（QTcF）和巴泽特法（QTcB）校正后的QT间期相对于基线的平均变化与PPQ已知的作用一致。PPQ的暴露与校正后的QT间期（QTc）增加相关，而KAE609的暴露则无关，并且KAE609不影响PPQ暴露-QTc关系。PPQ的QTcF效应（平均最大变化相对于基线的差异的最小二乘估计为7.47毫秒[90%置信区间，3.55至11.4毫秒]）与阳性全面QT研究的标准一致。没有受试者的QTcF或QTcB值>500毫秒。单独或联合使用的两种药物耐受性良好，未报告死亡、严重不良事件（AE）或严重AE。大多数AE为轻度；上呼吸道感染、头痛、腹泻和口咽痛最为常见。PPQ和KAE609的共同给药对任何一种药物的暴露均无相关影响，并且KAE609不影响或增强PPQ对心脏传导的已知作用。
