Crossover Randomized Study of Pharmacologic Effects of Ripasudil–Brimonidine Fixed-Dose Combination Versus Ripasudil or Brimonidine
Hidenobu Tanihara, Tetsuya Yamamoto, Makoto Aihara, Noriko Koizumi, H. Minami, Satoshi Kojima, Tomoyuki Isobe, Mizuho Kanazawa, Hideki Suganami, Yasuko Owada, Hiroshi Mikami, Michio Yagi, Hidetoshi Furuie, Tomoko Hayashibara, Eriko Kawai, Kiyoshi Kano, Hisashi Mashimo, Makoto Ando, Masashi Takat
Abstract
INTRODUCTION: -adrenoceptor agonist, and has demonstrated ability to lower intraocular pressure (IOP) and have various effects on conjunctival hyperemia and corneal endothelial cell morphology. This study evaluates the pharmacologic effects of RBFC treatment versus its separate components-ripasudil or brimonidine. METHODS: This single-center, prospective, randomized, open-label, blinded endpoint study with 3 × 3 crossover design randomly assigned healthy adult men to three groups (1:1:1) to undergo consecutive 8-day administration phases (with drug-free intervals of at least 5 days). Subjects received twice-daily instillation of RBFC → ripasudil → brimonidine (group A), ripasudil → brimonidine → RBFC (group B), or brimonidine → RBFC → ripasudil (group C). Endpoints included change in IOP, severity of conjunctival hyperemia, corneal endothelial cell morphology, pupil diameter, and pharmacokinetics. RESULTS: Eighteen subjects were assigned in total (six to each group). RBFC significantly reduced IOP from baseline at 1 h post-instillation on days 1 and 8 (12.7 vs. 9.1 and 9.0 mmHg, respectively; both P < 0.001), and provided significantly greater IOP reductions than ripasudil or brimonidine at several time points. The most common adverse drug reaction with all three treatments was mild conjunctival hyperemia, which transiently increased in severity with RBFC or ripasudil, peaking at 15 min post-instillation. In post hoc analyses, conjunctival hyperemia scores were lower with RBFC than with ripasudil at several time points. Transient morphologic changes in corneal endothelial cells occurred for up to several hours with RBFC or ripasudil, but not with brimonidine. Pupil diameter did not change with RBFC. CONCLUSION: RBFC significantly reduced IOP compared with each agent alone. A combination of each agent's pharmacologic profile was observed in that of RBFC. TRIAL REGISTRATION: Japan Registry of Clinical Trials; Registration No. jRCT2080225220.