Clinical implications of pharmacogenetics for glaucoma therapeutics

Glaucoma is a leading cause of irreversible blindness worldwide and is estimated to affect nearly 70 million people and to cause blindness in about 7 million people. The pathology shared by the heterogeneous group of glaucoma disorders is progressive optic nerve damage that is characterized by ‘cupping’ of the optic disk. This progressive glaucomatous optic atrophy gradually leads to visual field loss. The precise mechanisms leading to optic nerve axon damage have not been fully elucidated. Intuitively, direct treatment of the optic nerve is an obvious therapeutic strategy; however, there are no completed clinical trials that have tested the proof-of-concept that ‘neuroprotection’ is a viable treatment for glaucoma. At present, ophthalmologists treat the only known modifiable risk factor for glaucoma, clinically significant elevated intraocular pressure (IOP). Given our current understanding of the human genome and glaucoma therapeutics, the question is, are there genetic determinants for the pharmacodynamic variation in drug response to glaucoma medications? In order to begin to answer this question we need to assess the following two issues: (1) What is the evidence that lowering IOP is important for ‘protecting’ the susceptible optic nerve in patients with glaucoma? (2) What are the variables in assessing the IOP response to glaucoma medications? The first issue has been addressed in five randomized clinical trials, and the results provide strong evidence that reducing IOP slows the progression of glaucomatous optic neuropathy. In the Advanced Glaucoma Intervention Study (AGIS), there was a clear IOP ‘dose–response’ relationship with visual field progression which showed a striking lack of visual field progression in patients who had a mean IOP of 12.3 mmHg. In the other four trials, the treatment interventions, which included medications, laser or filtration surgeries, were based on either setting a minimum target pressure [Ocular Hypertension Treatment Study (OHTS) and Early Manifest Glaucoma Trial Group (EMGT)], calculated target pressure (Collaborative Initial Glaucoma Treatment Study) or percent IOP lowering (OHTS, EMGT and Collaborative Normal Tension Glaucoma Study). Based on these trials, there has been a shift in reporting the effectiveness of glaucoma drugs. Prior to 1996 most glaucoma pharmacology trials reported efficacy as a ‘mean IOP’ and the standard deviations or standard errors of the mean. Now, more studies report on ‘percent IOP reduction’ as an index of response to glaucoma medications. The second issue may be addressed by investigating the basic pharmacology of glaucoma therapeutics. There are five major classes of glaucoma medications: muscarinic cholinergic agonists, carbonic anhydrase inhibitors, b-adrenergic receptor (AR) antagonists, a2-AR agonists, and prostaglandin F receptor agonists. Though nonselective AR agonists had been used, their use is now extremely limited because they are not as effective compared to the newer drugs. The mechanism of action of these drugs is directed either to decrease the production of the clear intraocular fluid (aqueous humor) by the ciliary body or to enhance the outflow of aqueous humor through the trabecular meshwork and/or uveoscleral pathway (Figure 1). Elevated IOP is usually caused by outflow obstruction, and not from increased aqueous humor secretion. There are some susceptible optic nerves that sustain damage at normal IOPs. Despite our understanding of the pharmacology of these medications, we cannot explain the variable IOP response to glaucoma drugs between patients. The IOP response to a drug has been reported in numerous formats: mean IOP pretreatment, mean IOP post-treatment, change in IOP, target IOP, percent change in IOP, effect on diurnal IOP, ‘clinical success,’ percent subjects achieving a specified target IOP, and ‘nonresponders’ (Figure 2). Important considerations to interpret the drug effect properly include: IOP at drug peak and trough effect, contralateral effect in monocular placebo-controlled trials, regression to the mean, placebo effect, and definitions of ‘clinical success’ and ‘nonresponders.’ In pharmacology trials, the safety and efficacy data of a drug are based on a biased population of ‘homogeneous subjects’ who met specific inclusion and exclusion criteria. Although these criteria are important to minimize confounding effects of various ocular conditions, systemic diseases and medications, such study designs explain why unusual and infrequent drug reactions are identified in a ‘post-marketing’ setting when the drug is widely used in patients who deviate The Pharmacogenomics Journal (2003) 3, 197–201 & 2003 Nature Publishing Group All rights reserved 1470-269X/03 $25.00