Eyeworld CME Supplements

EW JUL 2013 - Supported by Bausch + Lomb

This is a supplement to EyeWorld Magazine that doctors can take a test after reading and receive CME credits for.

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ders, Dr. Chang and his colleagues were able to identify two factors significantly associated with IOP response. First was age. The mean age of the steroid responders was significantly lower than the mean age of the non-responders, 61.3±11.8 years vs. 71.8±11.7 years, respectively (p<0.01). Second was axial length. The responders had significantly longer eyes than the non-responders, 25.59±3.0 mm vs. 24.33±1.75 mm, respectively (p<0.01). The significance of these risk factors becomes even clearer when the data is stratified (Figures 4 and 5). In terms of age, patients 40-54 years old are four times more likely to be steroid responders than patients ≥65 years old. In terms of myopia, the risk of steroid response rose with increasing axial length. Compared to eyes <25.0 mm long, eyes longer than 27 mm had a more than 5-fold increase in risk and those longer than 29.0 mm had more than a 14-fold increase in risk (Figures 4 and 5). Taken together, the youngest patients (40-54 years old) with the longest eyes (≥29.0 mm) have a markedly greater 46-fold increase in steroid response risk compared to older patients (≥65 years old) with normal axial length (<25.0 mm)—35.7% vs. 0.7%, respectively. Interestingly, these ratios were the same across the spectrum of steroid responders regardless of the severity of IOP increase—meaning these risk factors do not appear to influence the severity of the response. This risk stratification has given Dr. Chang the opportunity to customize his approach to postoperative steroid use following cataract surgery, particularly in light of published studies that suggest steroid responders may be more tolerant of loteprednol etabonate 0.5% than of other corticosteroids.8,9 Where patients have a significantly higher odds ratio of a steroid response —i.e., patients less than 65 years old with an axial length of 25.0-29.0 mm (red box in Figure 5)—he uses loteprednol, avoids difluprednate, and monitors the IOP more closely. For patients at highest risk— i.e., patients of all ages with axial lengths >29.0 mm (green box in Figure 5)—he uses topical NSAIDs only, opting to add loteprednol only if necessitated by factors such as greater inflammation, with the addition of prophylactic topical glaucoma medication to prevent an IOP spike. This study is the first to correlate steroid response to high myopia and the first to tie steroid response to younger age in terms of topical as opposed to intravitreal medication. The two risk factors combined result in a very high percentage of steroid responders. For these eyes, loteprednol etabonate 0.5% offers a possibly safer alternative, and Dr. Chang's subsequent clinical experience bears this out. Medication vehicles: Strategies to prevent edema and relieve pain "Medications, as we all know, are a little bit more than just the active ingredients," said Francis S. Mah, MD, director, cornea and external disease, and co-director, refractive surgery, Scripps Clinic, La Jolla, Calif. Every bottle of medication includes other components, such as preservatives, drug delivery systems, viscosity increasing agents, buffers, stabilizers, and carrier vehicles. "It's a very special scenario that we have with the eye because we put these eye drops directly onto the place of therapy," said Dr. Mah. The medication vehicle thus "plays a huge role in terms not only of efficacy, but of safety and tolerability as well." In fact, safety is a major part of the design of newer formulations of steroids and NSAIDs, particularly in terms of medication vehicles. "We want to reduce as much as possible the baggage that comes along with medications," he said. "In general, we try to have the lowest concentrations that will provide the efficacy of the drug, and we try to optimize the preservatives so that we reduce any potential for toxicity." In addition to safety, medication vehicles provide opportunities to enhance efficacy through increased penetration and tissue concentrations. Medication vehicles can, for instance, increase the solubility of drugs. The cornea, said Dr. Mah, provides a strong barrier to the entry of these drugs into the eye due to its biphasic structure, with lipophilic epithelial and endothelial layers combined with a hydrophilic stroma. Medication vehicles provide ways to overcome that barrier, thus helping to optimize dosing, ideally reducing dose frequency, resulting in improved patient compliance. Figure 6. Topical ocular drug deposition Improving drug delivery The basic challenge, said Dr. Mah, is that typically out of an average of 50 microliters of medication dropped onto the eye and through various mechanisms including spillage, lacrimation and blinking, tear film turnover, and conjunctival and scleral absorption, only about 5% of the total dose actually enters the eye to work as intended10,11,12 (Figure 6). Attaining an optimal drug concentration at the site of action thus presents a major problem in ocular therapeutics. Strategies to improve drug delivery focus on overcoming two basic challenges: minimizing precorneal drug loss and maximizing corneal drug absorption. This is achieved by increasing the effective dose, utilizing molecular design, and/or utilizing formulation science (Figure 7). The first strategy, increasing the effective dose, may mean increasing the concentration of the active drug, such as with the latest formulation of nepafenac (0.3% from 0.1%), and/or decreasing the size of the suspension particles such as the 40% reduction of the new nepafenac formulation. Although increasing the dosing frequency may also increase the effective dose, Dr. Mah said, increasing the dosing frequency is not a very favorable approach since it also decreases patient compliance. Reducing drug concentrations may seem counter to increasing the effective dose, if the efficacy can be optimized using other methods, the advantage is the potential to reduce unwanted side effects. This was the strategy for the new formulation of bromfenac (0.07% from 0.09%). The second strategy uses molecular design to increase lipophilicity and solubility.

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