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Editors Selection IGR 22-2

Medical Treatment: ROCK Inhibitor Mechanism of Action

Makoto Araie

Comment by Makoto Araie on:

94676 Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study, Sit AJ; Gupta D; Kazemi A et al., American Journal of Ophthalmology, 2021; 226: 262-269


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Netarsudil is a Rho kinase (ROCK) and norepinephrine transporter inhibitor and its 0.02% ophthalmic solution (Netarsudil 0.02%) has been approved in USA since 2017 as an ocular hypotensive agent of which hypotensive effect was equivalent to timolol 0.5%. Sit ,i>et al. reported the results of a double-blinded, vehicle-controlled, paired eye comparison study where effects of Netarsudil 0.02% was studied in a total of 20 primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients. After seven-day q.d. instillation of Netarsudil 0.02%, mean diurnal intraocular pressure (IOP) and episcleral venous pressure (EVP) were significantly decreased from 22.94 ± 1.64 to 18.42 ± 1.57 mmHg and from 7.68 ± 1.31 to 6.90 ± 1.01 mmHg, respectively, while mean diurnal tonographic outflow facility was significantly increased from 0.126±0.038 to 0.164±0.053µl/min/mmHg, and the differences between Netarsudil- and vehicle treated fellow eyes were also statistically significant, averaging -3.54 and -0.89 mmHg and 0.03µl/min/mmHg, respectively. Although several agents have been reported to decrease EVP in experimental animals1-3 or normal volunteers,4 Netarsudil 0.02% is the first commercially available ocular hypotensive eye drop of which EVP decreasing effect was confirmed in POAG or OHT patients. Further, this study first confirmed the outflow facility increasing effect of Netarsudil 0.02%5 in POAG or OHT patients.

Netarsudil 0.02% is the first commercially available ocular hypotensive eye drop of which EVP decreasing effect was confirmed in POAG or OHT patients

As indicated by Goldmann's equation, IOP = EVP+1/C(F-U) where C indicates conventional outflow facility, F aqueous flow rate and U uveoscleral outflow rate, decrease in EVP is directly reflected in the decrease of IOP. In other words, given the same baseline IOP, F, C and U, Netarsudil 0.02% has potential to further lower the IOP by about 0.9 mmHg. This characteristic effect of Netarsudil 0.02% may be especially of clinical relevance in regions where prevalence of POAG with normal IOP (normal-tension glaucoma, NTG) is relatively high6,7 (mean IOP of POAG at screening was approximately 15 mmHg in Japan6). Since the expected IOP reduction rate by ocular hypotensive eye drops in NTG eyes is about 15% (2.25 mmHg in an eye with IOP of 15 mmHg),8 the use of Netarsudil 0.02% may be able to reduce the IOP by 3.15 mmHg (2.25 + 0.8 = 3.15), that is, a 40 % increase in the topical-drug induced ocular hypotensive effect. The lower the baseline IOP, the greater this relative increase in ocular hypotensive effect becomes. As discussed by the authors, every 1 mmHg reduction of IOP is expected to reduce further of visual field deterioration by 10 %.9

The advent of Netarsudil 0.02% may stimulate investigation of physiology/pharmacology of not only pre-, but also post-Schlemm's canal aqueous pathway

In Japan, another ROCK inhibitor ophthalmic solution, Ripasdil 0.4%, has been available as a second-line therapeutic drug since 2014. A phase-2 study conducted in Japanese POAG or OHT patients with IOP between 23.0 and 23.4 mmHg showed that Repasudil 0.4% reduced IOP by 1.6 mmHg when compared to the placebo-treated eyes.10 Although no direct comparison of Ripasudil 0.4% to Netarsudil 0.02% has been published yet, it may be interesting to know whether the difference (if there is one) in ocular hypotensive effect between these two eye drops, if it exists, is attributable to the difference in the effect on EVP between them. As compared to physiology/pharmacology of conventional (pre-Schlemm's canal) and uveoscleral pathways or that of aqueous humor production, there is a relative paucity of information on the post-Schlemm's canal aqueous pathway. The advent of Netarsudil 0.02% may stimulate investigation of physiology/pharmacology of not only pre-, but also post-Schlemm's canal aqueous pathway.

References

  1. Zamora DO, Kiel JW. Episcleral venous pressure responses to topical nitroprusside and N-nitro-L arginine methyl ester. Invest Ophthalmol Vis Sci. 2010;51:1614-1620.
  2. Chowdhury UR, Rinkoski TA, Bahler CK et al. Effect of cromakalim prodrug 1 (CKLP1) on aqueous humor dynamics and feasibility of combination therapy with existing ocular hypotensive agents. Invest Ophthalmol Vis Sci. 2017;58:5371-5342.
  3. Lee SS, Burke J, Shen JH et al. Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs. Vet Ophthalmol. 2018;21:376-381.
  4. Abreu MM, Kim YY, Shin DH, Netland PA. Topical verapamil and episcleral venous pressure. Ophthalmology 1998;105:2251-2255.
  5. Kazemi A, McLaren CC, Kopczynski CC, Heah TG, Novack GD, Sit AJ. The effects of netarsudil ophthalmic solution on aqueous humor dynamics in a randomized study in humans. J Ocul Pharmacol Ther. 2018;34:380-386.
  6. Iwase A, Suzuki Y, Araie M, et al. The prevalence of primary open-angle glaucoma in Japanese. The Tajimi Study. Ophthalmology 2004;111:1641-1648.
  7. Kim C-s, Seong GJ, Lee N-h, Song K-c, Namil Study group, Korean Glaucoma Society. Prevalence of primary open-angle glaucoma in central south Korea the Namil Study. Ophthalmology 2011;118:1024-1030.


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