Shen Jie, Goodkin Margot L, Tong Warren, Attar Mayssa
Clinical Pharmacology.
Clinical Development.
Clin Ophthalmol. 2017 Sep 28;11:1761-1767. doi: 10.2147/OPTH.S143428. eCollection 2017.
Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed.
New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve.
Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6-8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation.
Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties), formulations of bimatoprost 0.01% can be administered once or twice daily. These findings support development of bimatoprost 0.01%-based fixed-dose combination therapies administered twice daily for patients who require multiple adjunctive medications to control their IOP.
固定复方药物对需要多种药物来降低眼压（IOP）的患者有益，但如果作用机制互补的药物给药频率不同，则将它们联合使用具有挑战性。本研究比较了每天给药一次或两次的0.01%比马前列素眼用溶液的体内药代动力学和眼耐受性。还回顾了青光眼患者每日两次给药的报告。
将0.01%比马前列素单药治疗或0.01%比马前列素/0.1%溴莫尼定固定复方制剂，每日一次或两次给予新西兰白兔双眼，持续4天。采集眼组织并用液相色谱-串联质谱法进行分析。计算的药代动力学参数包括最大观察浓度、达峰时间和浓度-时间曲线下面积。
由于广泛代谢，所有样本中比马前列素浓度在给药后1小时低于定量限。然而，比马前列素酸暴露在给药后6-8小时仍可测量，并且在每日给药一次或两次的0.01%比马前列素或0.01%比马前列素/0.1%溴莫尼定固定复方制剂治疗的动物的房水和虹膜睫状体（药理作用部位）中相似。增加兔的给药频率并未提高与药物相关的结膜充血发生率（人类使用比马前列素最常见的不良事件），表明每种制剂每日一次和每日两次给药方案的眼耐受性相当。
在兔中，0.01%比马前列素作为单药治疗以及与0.1%溴莫尼定固定复方制剂每日给药一次或两次，显示出比马前列素酸相似的药代动力学特征，尤其是在虹膜睫状体中。先前临床研究的主要发现表明，通过改变苯扎氯铵（一种具有角膜渗透增强特性的防腐剂）的浓度，0.01%比马前列素制剂可以每日给药一次或两次。这些发现支持开发基于0.01%比马前列素的固定剂量复方疗法，用于需要多种辅助药物来控制眼压的患者每日两次给药。
