A Model-Based Dose–Response Meta-Analysis of Ocular Hypotensive Agents as a Drug Development Tool to Evaluate New Therapies in Glaucoma

Abstract

Abstract

Purpose:

To characterize dose and response for intraocular pressure (IOP) reduction and incidence of hyperemia using a model-based meta-analysis of IOP-lowering monotherapy studies to evaluate new ocular antihypertensive therapies for glaucoma.

Methods:

Published randomized controlled trials, regulatory documents, and sponsor reports of IOP-lowering monotherapies were used to develop dose–response models to characterize efficacy (IOP change from baseline) and safety (incidence of hyperemia) profiles.

Results:

The meta-analysis for efficacy included 31 trials with 6,516 patients receiving bimatoprost, latanoprost, travoprost, timolol, or placebo. Estimated IOP reduction with placebo was −2.01 mmHg. Maximal IOP reduction was similar among the prostaglandin analogs (estimate, −6.27 mmHg; baseline, 25 mmHg). Estimated median effective IOP-lowering dose (ED₅₀) was 0.002%, 0.00098%, and 0.00063% daily with bimatoprost, latanoprost, and travoprost, respectively. The hyperemia (safety) analysis included 25 trials with 6,244 patients. Typical maximal estimated difference between drug and placebo was 43%, and estimated ED₅₀ of 0.011%, 0.014%, and 0.0015% daily for bimatoprost, latanoprost, and travoprost, respectively. Latanoprost treatment was predicted to incur the lowest rate of hyperemia of the prostaglandins, for equivalent IOP reduction.

Conclusions:

Model-based meta-analyses for IOP reduction and incidence of hyperemia among prostaglandin analogs are well described by maximal efficacy models and can provide a useful methodology for evaluating glaucoma therapies.