University of Illinois Chicago, Chicago, Illinois, USA.
Pulmonary Associates, PA, Phoenix, Arizona, USA.
Antimicrob Agents Chemother. 2024 Nov 6;68(11):e0110324. doi: 10.1128/aac.01103-24. Epub 2024 Oct 1.
SPR720 is a phosphate ester prodrug that is converted rapidly to SPR719, the active moiety, which exhibits potent activity against clinically relevant mycobacterial species including complex (MAC) and . SPR720 is in clinical development for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) due to MAC. This study evaluated the safety and the intrapulmonary pharmacokinetics of SPR719 in healthy volunteers. A total of 30 subjects received oral SPR720 1,000 mg once daily for 7 days followed by bronchoscopy and bronchoalveolar lavage, with blood samples collected for plasma pharmacokinetic assessments. Mean SPR719 area under the concentration-time curve from time 0 to 24 hours (AUC) and maximum concentration () for plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) were 52,418 ng·h/mL and 4,315 ng/mL, 59,880 ng·h/mL and 5,429 ng/mL, and 128,105 ng·h/mL and 13,033 ng/mL, respectively. The ratios of ELF to total plasma concentrations of SPR719 based on AUC and were 1.14 and 1.26, and the ratios of AM to total plasma concentrations of SPR719 based on AUC and were 2.44 and 3.02, respectively. When corrected for protein binding, the ratios of ELF to unbound plasma concentrations of SPR719 for AUC and were 19.87 and 21.88, and the ratios of AM to unbound plasma concentrations of SPR719 for AUC and were 42.50 and 52.53, respectively. No unexpected safety findings were observed. Results from this study of the intrapulmonary disposition of SPR719 support further investigation of SPR720 as a potential oral agent for the treatment of patients with NTM-PD.This study is registered with Clinicaltrials.gov as NCT05955586.
SPR720 是一种磷酸酯前药，可迅速转化为 SPR719，即活性部分，对包括复杂（MAC）和 在内的临床相关分枝杆菌具有强大的活性。SPR720 正在开发用于治疗由于 MAC 引起的非结核分枝杆菌肺病 (NTM-PD)。本研究评估了健康志愿者中 SPR719 的安全性和肺内药代动力学。总共 30 名受试者接受了 7 天的每日口服 SPR720 1000mg，随后进行支气管镜检查和支气管肺泡灌洗，并采集血样进行血浆药代动力学评估。血浆、上皮衬里液 (ELF) 和肺泡巨噬细胞 (AM) 中 SPR719 从 0 到 24 小时的时间曲线下面积 (AUC) 和最大浓度 () 的平均值分别为 52418ng·h/mL 和 4315ng/mL、59880ng·h/mL 和 5429ng/mL，以及 128105ng·h/mL 和 13033ng/mL。基于 AUC 和 的 SPR719 的 ELF 与总血浆浓度比分别为 1.14 和 1.26，基于 AUC 和 的 SPR719 的 AM 与总血浆浓度比分别为 2.44 和 3.02。当校正蛋白结合时，基于 AUC 和 的 SPR719 的 ELF 与未结合血浆浓度比分别为 19.87 和 21.88，基于 AUC 和 的 SPR719 的 AM 与未结合血浆浓度比分别为 42.50 和 52.53。未观察到意外的安全性发现。SPR719 肺内分布的研究结果支持进一步研究 SPR720 作为治疗 NTM-PD 患者的潜在口服药物。该研究在 ClinicalTrials.gov 上注册为 NCT05955586。
