Global Pharmaceutical Research & Development , Bausch & Lomb, Incorporated, Rochester, NY 14609, USA.
J Ocul Pharmacol Ther. 2010 Oct;26(5):449-58. doi: 10.1089/jop.2010.0054.
The purpose of this investigation was to evaluate the ocular pharmacokinetic/pharmacodynamic (PK/PD) relationship for besifloxacin, moxifloxacin, and gatifloxacin using rabbit ocular PK data, along with in vitro minimum inhibitory concentration (MIC90) values against methicillin- and ciprofloxacin-resistant Staphylococcus aureus (MRSA-CR) and Staphylococcus epidermidis (MRSE-CR).
Rabbits received a topical instillation of Besivance™ (besifloxacin ophthalmic suspension, 0.6%), Vigamox (moxifloxacin hydrochloride ophthalmic solution, 0.5% as base), or Zymar (gatifloxacin ophthalmic solution, 0.3%), and ocular tissues and plasma were collected from 4 animals/treatment/collection time at 8 predetermined time intervals during the 24h after dosing. Ocular levels of each agent were measured by LC/MS/MS, and PK parameters (Cmax, Tmax, and AUC₀₋₂₄) were determined. AUC₀₋₂₄/MIC₉₀ ratios were calculated for tears, conjunctiva, cornea, and aqueous humor using previously reported MIC₉₀values for MRSA-CR and MRSE-CR.
All of the fluoroquinolones tested demonstrated rapid penetration into ocular tissues after a single instillation. Besifloxacin demonstrated the highest exposure in tear fluid, while exposure in conjunctiva was comparable for all 3 compounds. Peak concentrations of all fluoroquinolones in aqueous humor were at or below ~1g/mL. In comparison with their MIC₉₀values against MRSE-CR and MRSA-CR, besifloxacin achieved an AUC₀₋₂₄/MIC₉₀ ratio of ~800 in tears, compared with values of ≤10 for moxifloxacin and gatifloxacin. In cornea, conjunctiva, and aqueous humor, the AUC₀₋₂₄/MIC₉₀ ratios were <10 for all compounds. However, in these tissues AUC₀₋₂₄/MIC₉₀ ratios for besifloxacin were 1.5- to 38-fold higher than moxifloxacin and gatifloxacin.
In rabbits, besifloxacin demonstrates a nonclinical ocular PK profile characterized by high and sustained concentrations in tear fluid, resulting in AUC₀₋₂₄/MIC₉₀ ratios of ~800 for ciprofloxacin-resistant MRSE and MRSA after a single administration. Although besifloxacin had the highest AUC₀₋₂₄/MIC₉₀ratios for intraocular tissues, the ratios for all of the drugs were below the target values needed for effective bacterial killing of ciprofloxacin-resistant MRSE and MRSA. Taken together, these nonclinical data indicate that besifloxacin has a favorable ocular PK/PD profile, consistent with the reported clinical efficacy of besifloxacin in the treatment of bacterial conjunctivitis, and consistent with the profile needed for ocular surface sterilization.
本研究旨在评估贝西沙星、莫西沙星和加替沙星的眼部药代动力学/药效学（PK/PD）关系，使用兔眼部 PK 数据以及针对耐甲氧西林和环丙沙星的金黄色葡萄球菌（MRSA-CR）和表皮葡萄球菌（MRSE-CR）的体外最小抑菌浓度（MIC90）值。
兔子接受了 BesivanceTM（贝西沙星眼用混悬液，0.6%）、Vigamox（莫西沙星盐酸眼用溶液，0.5% 为基础）或 Zymar（加替沙星眼用溶液，0.3%）的局部滴眼，在给药后 24 小时内的 8 个预定时间间隔，从 4 只/治疗/采集时间的动物中收集眼组织和血浆。通过 LC/MS/MS 测量每种药物的眼内水平，并确定 PK 参数（Cmax、Tmax 和 AUC₀₋₂₄）。使用先前报道的 MRSA-CR 和 MRSE-CR 的 MIC₉₀值，计算泪液、结膜、角膜和房水中的 AUC₀₋₂₄/MIC₉₀比值。
所有测试的氟喹诺酮类药物在单次滴眼后均迅速渗透到眼部组织中。贝西沙星在泪液中表现出最高的暴露，而三种化合物在结膜中的暴露相当。所有氟喹诺酮类药物在房水中的峰浓度均在~1g/mL 或以下。与它们对 MRSE-CR 和 MRSA-CR 的 MIC₉₀值相比，贝西沙星在泪液中的 AUC₀₋₂₄/MIC₉₀比值约为 800，而莫西沙星和加替沙星的比值≤10。在角膜、结膜和房水中，所有化合物的 AUC₀₋₂₄/MIC₉₀比值均<10。然而，在这些组织中，贝西沙星的 AUC₀₋₂₄/MIC₉₀比值是莫西沙星和加替沙星的 1.5-38 倍。
在兔子中，贝西沙星表现出非临床眼部 PK 特征，其特点是在泪液中具有高且持续的浓度，导致单次给药后对耐环丙沙星的 MRSE 和 MRSA 的 AUC₀₋₂₄/MIC₉₀比值约为 800。尽管贝西沙星在眼内组织中的 AUC₀₋₂₄/MIC₉₀比值最高，但所有药物的比值均低于有效杀死耐环丙沙星的 MRSE 和 MRSA 所需的目标值。综上所述，这些非临床数据表明，贝西沙星具有良好的眼部 PK/PD 特征，与贝西沙星在治疗细菌性结膜炎方面的临床疗效一致，也与眼表杀菌所需的特征一致。
