Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, United States.
Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, United States.
EBioMedicine. 2022 Jun;80:104065. doi: 10.1016/j.ebiom.2022.104065. Epub 2022 May 19.
SJ733, a newly developed inhibitor of P. falciparum ATP4, has a favorable safety profile and rapid antiparasitic effect but insufficient duration to deliver a single-dose cure of malaria. We investigated the safety, tolerability, and pharmacokinetics of a multidose SJ733 regimen and a single-dose pharmacoboost approach using cobicistat to inhibit CYP3A4, thereby increasing exposure.
Two multidose unboosted cohorts (n = 9) (SJ733, 300 mg and 600 mg daily for 3 days) followed by three single-dose boosted cohorts combining SJ733 (n = 18) (75-, 300-, or 600-mg single dose) with cobicistat (150-mg single dose) as a pharmacokinetic booster were evaluated in healthy volunteers (ClinicalTrials.gov: NCT02661373).
All participants tolerated SJ733 well, with no serious adverse events (AEs), dose-limiting toxicity, or clinically significant electrocardiogram or laboratory test findings. All reported AEs were Grade 1, clinically insignificant, and considered unlikely or unrelated to SJ733. Compared to unboosted cohorts, the SJ733/cobicistat-boosted cohorts showed a median increase in area under the curve and maximum concentration of 3·9 × and 2·6 ×, respectively, and a median decrease in the ratio of the major CYP3A-produced metabolite SJ506 to parent drug of 4·6 × . Incorporating these data in a model of parasite dynamics indicated that a 3-day regimen of SJ733/cobicistat (600 mg/150 mg daily) relative to a single 600-mg dose ± cobicistat would increase parasite clearance from 10 to 10 parasites/µL.
The multidose and pharmacoboosted approaches to delivering SJ733 were well-tolerated and significantly increased drug exposure and prediction of cure. This study supports the further development of SJ733 and demonstrates an innovative pharmacoboost approach for an antimalarial.
Global Health Innovative Technology Fund, Medicines for Malaria Venture, National Institutes of Health, and American Lebanese Syrian Associated Charities.
新型疟原虫 ATP4 抑制剂 SJ733 具有良好的安全性和快速抗寄生虫作用，但作用持续时间不足以实现疟疾的单剂治愈。我们研究了多剂量 SJ733 方案和使用考比司他抑制 CYP3A4 的单剂量药物增强的安全性、耐受性和药代动力学，从而增加了药物暴露。
两项未增强的多剂量队列（n=9）（SJ733，每日 300mg 和 600mg，连续 3 天），随后进行了三个单剂量增强队列，将 SJ733（n=18）与考比司他（150mg 单剂量）联合使用，考比司他作为药代动力学增强剂，以评估其在健康志愿者中的安全性、耐受性和药代动力学（ClinicalTrials.gov：NCT02661373）。
所有参与者均耐受 SJ733 良好，无严重不良事件（AE）、剂量限制性毒性或临床显著心电图或实验室检查结果。所有报告的 AE 均为 1 级，临床意义不大，且认为不太可能或与 SJ733 无关。与未增强的队列相比，SJ733/考比司他增强队列的 AUC 和 Cmax 中位数分别增加了 3.9×和 2.6×，主要由 CYP3A 产生的代谢物 SJ506 与母体药物的比值中位数降低了 4.6×。将这些数据纳入寄生虫动力学模型表明，与单剂量 600mg±考比司他相比，SJ733/考比司他（600mg/150mg 每日）的 3 天方案将使寄生虫清除率从 10 个寄生虫/μL 增加到 10 个寄生虫/μL。
SJ733 的多剂量和药物增强方法具有良好的耐受性，并显著增加了药物暴露和治愈预测。这项研究支持 SJ733 的进一步开发，并展示了一种创新的抗疟药物增强方法。
全球健康创新技术基金、疟疾药物倡议、美国国立卫生研究院和美国黎巴嫩叙利亚裔协会慈善基金会。
