The most common adverse reaction associated with netarsudil dosed once daily in controlled clinical studies was conjunctival hyperemia which was reported by 53% of patients. Other common adverse affects reported (about 20%) include corneal verticillata, instillation site pain, and even conjunctival hemorrhage. Still other reactions include instillation site erythema, corneal staining, blurred vision, increased lacrimiation, erythema of eyelid, and reduced visual acuity being reported by 5-10% of patients in clinical studies. When using multiple dose containers of topical ophthalmic products there is a possibilty of contaminating the containers with agents that may cause bacterial keratitis by patients who in many cases have a concurrent corneal disease or a disruption of the ocular epithelial surface. Although systemic exposure to netarsudil from ocular administration is low, there is no formal available data on the safe use of netarsudil in pregnant women. There is no formal data available on whether significant netarsudil levels could be present in human milk following ocular administration, on the effects on the breastfed enfant, or on the effects on milk production. The safety and effectiveness of using netarsudil in pediatric patients below the age of 18 years have not been established. No overall differences in safety or effectiveness have been observed between elderly and other aduly patients. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of netarsudil. Netarsudil was not mutagenic in the Ames test, in the mouse lymphoma test, or in the in vivo rat micronucleus test. Studies to evaluate the effects of netarsudil on male or female fertility in animals have not been performed.
The active metabolite of netarsudil, AR-13503 is highly protein bound in plasma, at approximately 60% bound. As AR-13503 is considered to bind less extensively to plasma proteins as its parent netarsudil, the % protein binding of netarsudil may be at least 60% or higher.
The systemic exposure of netarsudil and its active metabolite, AR-13503, after topical ocular administration of netarsudil opthalmic solution 0.02% once daily (one drop bilaterally in the morning) for eight days in 18 healthy subjects demonstrated no quantifiable plasma concentrations of netarsudil (lower limit of quantitation [LLOQ] 0.100 ng/mL) post dose on Day 1 and Day 8. Only one plasma concentration at 0.11 ng/mL for the active metabolite was observed for one subject on Day 8 at 8 hours post dose.
Clinical studies assessing the *in vitro* metabolism of netarsudil using corneal tissue from humans, human plasma, and human liver microsomes and microsomal S9 fractions demonstrated that netarsudil metabolism occurs through esterase activity. Subsequent metabolism of netarsudil's esterase metabolite, AR-13503, was not detectable. In fact, esterase metabolism in human plasma was not detected during a 3 hour incubation.
来源:DrugBank
吸收、分配和排泄
分布容积
由于netarsudil及其活性代谢产物表现出高度的蛋白结合，因此预计其分布体积较低。
As netarsudil and its active metabolite demonstrate a high degree of protein binding, it is expected to exhibit a low volume of distribution.
来源:DrugBank
吸收、分配和排泄
清除
网拉苏迪尔的清除率受到其局部给药和吸收后低血浆浓度以及高血浆蛋白结合的影响。
The clearance of netarsudil is strongly influenced by its low plasma concetrations following topical administration and absorption and high protein binding in human plasma inn.
Described herein are compounds and compositions for treating glaucoma and/or reducing intraocular pressure. Compositions may comprise an isoquinoline compound and a prostaglandin or a prostaglandin analog. Compounds described herein include those in which an isoquinoline compound is covalently linked to a prostaglandin or a prostaglandin analog, and those in which an isoquinoline compound and a prostaglandin free acid together form a salt.
[EN] PROCESS FOR THE PREPARATION OF (S)-NETARSUDIL, ITS SALTS & POLYMORPHS<br/>[FR] PROCÉDÉ DE PRÉPARATION DE (S)-NÉTARSUDIL, SES SELS ET POLYMORPHES
申请人：MICRO LABS LTD
公开号：WO2021001713A1
公开（公告）日：2021-01-07
The present invention relates to a process for the preparation of (S)-Netarsudil or its pharmaceutically acceptable salts using novel intermediates. The present invention further provides novel salts, novel intermediates and novel polymorphic forms of the (S)-Netarsudil salts and process for the preparation of the same.
Disclosed are solid state forms of Netarsudil mesylate, processes for preparation thereof, uses thereof, and pharmaceutical compositions thereof.
揭示了奈他索胺甲酸盐的固态形式，其制备方法，用途和药物组合物。
PROCESS FOR THE PREPARATION OF KINASE INHIBITORS AND INTERMEDIATES THEREOF
申请人：Aerie Pharmaceuticals, Inc.
公开号：US20170204065A1
公开（公告）日：2017-07-20
Described are processes for the synthesis of certain compounds, useful for treating diseases, e.g. eye disease, such as glaucoma and ocular hypertension, in a subject.
Described herein are compounds and compositions for treating glaucoma and/or reducing intraocular pressure. Compositions may comprise an isoquinoline compound and a prostaglandin or a prostaglandin analog. Compounds described herein include those in which an isoquinoline compound is covalently linked to a prostaglandin or a prostaglandin analog, and those in which an isoquinoline compound and a prostaglandin free acid together form a salt.
