Abstract
Purpose :
Nonadherence to topical medications is a serious concern in the treatment of glaucoma. The purpose of this study was to conduct a pharmacokinetic/pharmacodynamic (PK/PD) model-based meta-analysis (MBMA) to quantify and predict the impact of nonadherence on intraocular (IOP) response to topical glaucoma medications.
Methods :
105 prospective, randomized, masked trials (240 arms) investigating the efficacy of 22 topical medications as monotherapy to lower IOP in 20,114 open angle glaucoma/ocular hypertension patients were eligible and included in the MBMA. Treatment duration ranged from 1 day to 5 years. Drug classes include: alpha agonists, beta blockers, carbonic anhydrase inhibitors, mitoics, and prostaglandin analogs. To account for the circadian behavior of IOP, the baseline PD model was characterized as the sum of 24- and 12-hour period harmonics in a Fourier series. An indirect-response PD model was utilized to account for the drug effect. The PK model was based on generalized kinetics of these drugs in the aqueous humor. The impact of nonadherence was evaluated via simulations for 4 patterns of nonadherence: clustered, random, regular and partial. For each pattern, 25%, 50%, 75% and 100% of trial adherence rates were simulated.
Results :
The estimated change from baseline (CFB) in IOP decreased with decreasing adherence. At 100% adherence, mean CFB was anywhere from -7.55 and to as high as -9.29 mmHg depending on the dose schedule and method of IOP measurement. Whereas at 25% adherence rate, the CFB was between -1.61 and -5.71 mmHg, across mean, peak and trough measurements. Clustered had the largest effect on IOP lowering across all IOP measures versus partial with the least effect. Nonadherence affected daily dosed more significantly than twice daily dosed treatments. The effect of nonadherence was more pronounced for peak and trough IOP measures compared to mean IOP measures.
Conclusions :
A MBMA of topical glaucoma medications was conducted to explore the impact of nonadherence on IOP lowering across 5 drug classes. Simulations from the model established that nonadherence, of any pattern, has a negative and significant impact on IOP response suggesting a need for novel glaucoma therapies that provide sustained treatment effect and minimize the need for daily patient compliance.
This is a 2020 ARVO Annual Meeting abstract.