Osaka Pharmacology Clinical Research Hospital, 41-1-29 Miyahara, Yodogawa-ku, Osaka-shi, Osaka 532-0003, Japan.
Antimicrob Agents Chemother. 2010 Feb;54(2):866-70. doi: 10.1128/AAC.00567-09. Epub 2009 Nov 23.
S-013420 (EDP-420) is a novel bicyclolide (bridged bicyclic macrolide) antibacterial currently under development for the treatment of respiratory tract infections. The objective of the present study was to determine the plasma and intrapulmonary pharmacokinetic parameters of orally administered S-013420 in healthy volunteers. Twenty-eight healthy Japanese male subjects who never smoked were randomly allocated to seven groups of four subjects each who underwent bronchoalveolar lavage (BAL) at different times after dosing (2, 4, 6, 8, 10, 12, or 24 h). Blood samples were also taken at 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h after dosing. The S-013420 concentrations in plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs) were measured by using a combined high-performance liquid chromatography-mass spectrometric technique. A pharmacokinetic analysis of the plasma, ELF, and AM S-013420 concentration profiles was performed. S-013420 was rapidly absorbed in plasma, and the mean time to the maximum concentration in plasma was 2.27 h. S-013420 was rapidly distributed to the ELF and was slowly distributed to AMs. The areas under the concentration-time curves from time zero to 24 h (AUC0-24) for S-013420 were 20.3 times higher in ELF than in plasma and 244.6 times higher in AMs than in plasma. The mean maximum concentration in plasma was higher in ELF than in plasma and was much higher in AM than in plasma. Furthermore, pharmacodynamic calculations were done by using the AUC0-24/MIC90 ratio for common pneumonia pathogens (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis). The AUC0-24 for plasma/MIC90s for these four organisms were 41.8, 83.6, 1.3, and 20.9, respectively. The AUC0-24 for ELF/MIC90s were 849.6, 1,699.2, 26.6, and 424.8, respectively. Considering the good efficacy shown in a subsequent phase 2 study (S. Kohno, K. Yamaguchi, Y. Tanigawara, A. Watanabe, A. Aoki, Y. Niki, and J. Fujita, Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L-485), the good distribution of S-013420 in AMs and ELF observed in the present study is predictive of the good efficacy of S-013420 against respiratory pathogens.
S-013420（EDP-420）是一种新型的双环内酯（桥接双环大环内酯）类抗菌药物，目前正在开发用于治疗呼吸道感染。本研究的目的是确定口服给予 S-013420 后健康志愿者的血浆和肺内药代动力学参数。28 名从未吸烟的日本健康男性受试者被随机分为 7 组，每组 4 名受试者，在给药后不同时间（2、4、6、8、10、12 或 24 h）进行支气管肺泡灌洗（BAL）。给药后 0、0.5、1、2、4、6、8、10、12、24、48 和 72 h 也采集了血样。使用高效液相色谱-质谱联用技术测定血浆、上皮衬里液（ELF）和肺泡巨噬细胞（AMs）中的 S-013420 浓度。对血浆、ELF 和 AM S-013420 浓度曲线的药代动力学进行了分析。S-013420 在血浆中迅速吸收，血浆中最大浓度的平均达峰时间为 2.27 h。S-013420 迅速分布到 ELF 中，并缓慢分布到 AMs 中。S-013420 从 0 到 24 h 的浓度-时间曲线下面积（AUC0-24）在 ELF 中是血浆的 20.3 倍，在 AMs 中是血浆的 244.6 倍。血浆中 S-013420 的最大浓度高于血浆，而 AM 中的浓度高于血浆。此外，通过 AUC0-24/MIC90 比值对常见肺炎病原体（金黄色葡萄球菌、肺炎链球菌、流感嗜血杆菌和卡他莫拉菌）进行了药效学计算。这些四种生物的 AUC0-24/ MIC90 分别为 41.8、83.6、1.3 和 20.9。ELF 中的 AUC0-24/ MIC90 分别为 849.6、1699.2、26.6 和 424.8。考虑到随后的 2 期研究（S. Kohno、K. Yamaguchi、Y. Tanigawara、A. Watanabe、A. Aoki、Y. Niki 和 J. Fujita，Abstr. 47th Intersci. Conf. Antimicrob. Agents Chemother.，abstr. L-485）中显示出的良好疗效，本研究中观察到 S-013420 在 AMs 和 ELF 中的良好分布预示着 S-013420 对呼吸道病原体具有良好的疗效。
