Vision impairment remains a major health problem worldwide. Elevated intraocular pressure is a prime risk factor for blindness in the elderly. Netarsudil is a Rho-associated protein kinase (ROCK) inhibitor, which also inhibits norepinephrine transport. This narrative review summarizes the properties and clinical significance of netarsudil, a promising drug in topical glaucoma therapy.
Methods:
We searched PubMed, Medline and Scopus databases using relevant keywords to retrieve information on the physicochemical properties, formulation, mechanism of action, clinical pharmacokinetics, dose and toxicity of netarsudil.
Results:
Netarsudil showed promising effects in lowering the elevated intraocular pressure by two mechanisms. The US FDA approved netarsudil for clinical use in 2017 under the trademark of Rhopressa® while European Medicines Agency approved Rhokiinsa® in 2019. This drug is available as a 0.02% ophthalmic solution for once-daily topical application.
Conclusion:
The discovery of netarsudil is a breakthrough in the therapy of glaucoma with proven efficacy in a wide range of eye pressures and is well tolerated in cases with ocular hypertension and chronic glaucoma.
TaylorHR.Global blindness: the progress we are making and still need to make. Asia Pac J Ophthalmol (Phila)2019; 8(6): 424–428.
2.
CookCFosterP.Epidemiology of glaucoma: what’s new?Can J Ophthalmol2012; 47(3): 223–226.
3.
ThamYCLiXWongTY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology2014; 121(11): 2081–2090.
4.
SathyanarayanaSDRompicherlaNCVadakkepushpakathAN, et al. Development of thermosensitive ophthalmic in situ gels of bimatoprost for glaucoma therapy. Indian J Pharm Educ Res2020; 54(2): S154–S162.
5.
KhatriAShresthaJKThapaM, et al. Severity of primary open-angle glaucoma in patients with hypertension and diabetes. Diabetes Metab Syndr Obes2018; 11: 209–215.
6.
AcharjeeSGhoshBAl-DhubiabBE, et al. Understanding type 1 diabetes: etiology and models. Can J Diabetes2013; 37(4): 269–276.
7.
GrecoARizzoMIDe VirgilioA, et al. Emerging concepts in glaucoma and review of the literature. Am J Med2016; 129(9): 1000.e1007–1000.e1013.
8.
SharifNA.Ocular hypertension and glaucoma: a review and current perspectives. Int J Ophthalmol Vis Sci2017; 2: 22–36.
9.
GoelMPiccianiRGLeeRK, et al. Aqueous humor dynamics: a review. Open Ophthalmol J2010; 4: 52–59.
10.
ImpagnatielloFBastiaEAlmiranteN, et al. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br J Pharmacol2019; 176(8): 1079–1089.
11.
SchmidlDSchmettererLGarhöferG, et al. Pharmacotherapy of glaucoma. J Ocular Pharmacol Ther2015; 31(2): 63–77.
12.
HendersonAJHaddenMGuoC, et al. 2,3-Diaminopyrazines as Rho kinase inhibitors. Bioorg Med Chem Lett2010; 20(3): 1137–1140.
13.
ChenHHNamilASevernsB, et al. In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma. Bioorg Med Chem Lett2014; 24(8): 1875–1879.
14.
SerleJBKatzLJMcLaurinE, et al. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: Rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol2018; 186: 116–127.
15.
DassoLAl-KhaledTSontyS, et al. Profile of netarsudil ophthalmic solution and its potential in the treatment of open-angle glaucoma: evidence to date. Clin Ophthalmol2018; 12: 1939–1944.
16.
KopczynskiCCHeahT.Netarsudil ophthalmic solution 0.02% for the treatment of patients with open-angle glaucoma or ocular hypertension. Drugs Today (Barc)2018; 54(8): 467–478.
MoiseevRVMorrisonPWJSteeleF, et al. Penetration enhancers in ocular drug delivery. Pharmaceutics2019; 11(7): 321.
19.
SharifNA.Glaucomatous optic neuropathy treatment options: the promise of novel therapeutics, techniques and tools to help preserve vision. Neural Regen Res2018; 13(7): 1145–1150.
20.
RaoPVPattabiramanPPKopczynskiC.Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: bench to bedside research. Exp Eye Res2017; 158: 23–32.
21.
RenRLiGLeTD, et al. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Investig Ophthalmol Vis Sci2016; 57(14): 6197–6209.
22.
PattabiramanPPRinkoskiTPoeschlaE, et al. RhoA GTPase-induced ocular hypertension in a rodent model is associated with increased fibrogenic activity in the trabecular meshwork. Am J Pathol2015; 185(2): 496–512.
23.
LinCWShermanBMooreLA, et al. Discovery and preclinical development of netarsudil, a novel ocular hypotensive agent for the treatment of glaucoma. J Ocular Pharmacol Ther2018; 34(1–2): 40–51.
24.
SturdivantJMRoyaltySMLinCW, et al. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg Med Chem Lett2016; 26(10): 2475–2480.
25.
BaigMSAhadAAslamM, et al. Application of Box-Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: optimization, in vitro release, ocular tolerance, and antibacterial activity. Int J Biol Macromol2016; 85: 258–270.
26.
TanHBZhongYSChengY, et al. Rho/ROCK pathway and neural regeneration: a potential therapeutic target for central nervous system and optic nerve damage. Int J Ophthalmol2011; 4(6): 652–657.
27.
XuFHuangHWuY, et al. Upregulation of Gem relates to retinal ganglion cells apoptosis after optic nerve crush in adult rats. J Mol Histol2014; 45(5): 565–571.
28.
LiuJGaoHYWangXF.The role of the Rho/ROCK signaling pathway in inhibiting axonal regeneration in the central nervous system. Neural Regen Res2015; 10(11): 1892–1896.
29.
YamamotoKMaruyamaKHimoriN, et al. The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Investig Ophthalmol Vis Sci2014; 55(11): 7126–7136.
30.
TannaAPJohnsonM.Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology2018; 125(11): 1741–1756.
31.
TaniharaHInoueTYamamotoT, et al. Additive intraocular pressure-lowering effects of the Rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost: a report of 2 randomized clinical trials. JAMA Ophthalmol2015; 133(7): 755–761.
32.
KazemiAMcLarenJWKopczynskiCC, et al. The effects of netarsudil ophthalmic solution on aqueous humor dynamics in a randomized study in humans. J Ocular Pharmacol Ther2018; 34(5): 380–386.
33.
BacharachJDubinerHBLevyB, et al. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology2015; 122(2): 302–307.
34.
KhouriASSerleJBBacharachJ, et al. Once-daily netarsudil versus twice-daily timolol in patients with elevated intraocular pressure: the randomized pharse 3 ROCKET-4 study. Am J Ophthalmol2019; 204: 97–104.
35.
KahookMYSerleJBMahFS, et al. Long-term safety and ocular hypotensive efficacy evaluation of netarsudil ophthalmic solution: Rho kinase elevated IOP treatment trial (ROCKET-2). Am J Ophthalmol2019; 200: 130–137.
36.
BerrymanJDNovackGD.Efficacy and safety of netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma and ocular hypertension. Expert Rev Ophthalmol2019; 14(4–5): 191–197.
37.
AsraniSBacharachJHollandE, et al. Fixed-dose combination of netarsudil and latanoprost in ocular hypertension and open-angle glaucoma: pooled efficacy/safety analysis of phase 3 MERCURY-1 and -2. Adv Ther2020; 37(4): 1620–1631.
38.
AsraniSRobinALSerleJB, et al. Netarsudil/latanoprost fixed-dose combination for elevated intraocular pressure: three-month data from a randomized phase 3 trial. Am J Ophthalmol2019; 207: 248–257.
39.
WaltersTRAhmedIIKLewisRA, et al. Once-daily netarsudil/latanoprost fixed-dose combination for elevated intraocular pressure in the randomized phase 3 MERCURY-2 study. Ophthalmol Glaucoma2019; 2(5): 280–289.
40.
KusuharaSNakamuraM.Ripasudil hydrochloride hydrate in the treatment of glaucoma: safety, efficacy, and patient selection. Clin Ophthalmol2020; 14: 1229–1236.
41.
LuLJTsaiJCLiuJ.Novel pharmacologic candidates for treatment of primary open-angle glaucoma. Yale J Biol Med2017; 90(1): 111–118.
42.
TaniharaHKakudaTSanoT, et al. Safety and efficacy of ripasudil in Japanese patients with glaucoma or ocular hypertension: 3-month interim analysis of ROCK-J, a post-marketing surveillance study. Adv Ther2019; 36(2): 333–343.
43.
HoySM.Netarsudil ophthalmic solution 0.02%: first global approval. Drugs2018; 78(3): 389–396.
