On this episode of Retina Mentor Moments, John W. Kitchens, MD, and Michael W. Stewart, MD, discuss transitioning from private practice to academia and retinal disease management, with a focus on pharmacokinetics and iodine allergies.
Dr. Stewart is a consultant ophthalmologist and professor of ophthalmology at Mayo Clinic in Jacksonville, Florida. He researches ophthalmic conditions and publishes on the cornea, glaucoma, oculoplastics, and neuro-ophthalmology.
His main interests include chorioretinal vascular diseases such as age-related macular degeneration, diabetic retinopathy, retinal vein occlusion, and macular telangiectasia. He also works on infectious retinitis, vitreoretinal surgery for retinal detachments, and studies mathematical modeling of ocular pharmacology and vitreoretinal diseases.
Transitioning from private practice to academia
Many doctors often move from academia to private practice, but Dr. Stewart chose the opposite path. He initially returned to Florida for family reasons and joined a private practice, where he worked for 10 years after finishing his fellowship in vitreoretinal disease.
After some reflection, he realized that transitioning into an academic institution would be a great change for him, and with his position at the Mayo Clinic, he didn't have to uproot his life.
The Mayo Clinic in Jacksonville was established in 1986 as the first Mayo Clinic destination medical center. It is expanding, and over the next 3 years, it is expected that retina fellowships and residencies will be introduced at this location.
In academia, Dr. Stewart is deeply involved in research. Although he has been involved in academia for 26 years, aspects of private practice, such as clinical practice, productivity, and revenue generation, are just as important.
A quick review of intravitreal drug pharmacokinetics
At present, intravitreal injection is the favored approach for delivering drugs to the retina. Notably, anti-VEGF therapies can be administered monthly or bimonthly because these antibodies and soluble receptors have extended intravitreal half-lives—approximately a week—and remain effective at low concentrations, tolerating relatively high doses.
However, most of these treatments result in sub-therapeutic drug levels in the retina.1 Dr. Stewart states that directly comparing drug binding affinities can be a useful way to discuss how well drugs perform when comparing them to each other; however, mathematically, such comparisons are not entirely accurate.
A 100x increase in binding affinity does not mean there is a 100x increase in binding within the eye. Although a drug may work well in the vitreous, these medications typically target the retina and suprachoroidal space.
The volume of distribution is a pharmacokinetic parameter that indicates how extensively a drug distributes and binds after administration. Following an intravitreal injection, the eye acts like an isolated tissue because blood circulation functions as a sink, diluting the drug to such an extent that plasma drug concentrations do not significantly influence ocular drug profiles.1
Therefore, within those tissues, we lack a reliable model for how binding affinity translates to effectiveness in these areas.
How potency and clearance shape anti-VEGF treatment outcomes
The best way to evaluate this is to focus on potency, Dr. Stewart says. When retinal vascular endothelial cells are plated with vascular endothelial growth factor (VEGF), it stimulates migration by releasing calcium ions. The question becomes: what concentration is needed to halt 50% of the calcium release?
The lower the concentration required to reduce calcium release, the more effective the drug will be on capillary endothelial cells, as the migration and proliferation of endothelial cells are integral to the angiogenesis process.
According to Dr. Stewart, within a pharmacokinetic model, clearance can help explain why some patients need injections less frequently than others. Evaluating serum concentrations and determining how quickly it leaves the eye helps calculate the half-life. In patients with a history of vitrectomy, they appear to have higher clearance rates, as the vitreous has been removed, and they may require more injections.
Dr. Stewart notes that subretinal fluid may be protective for visual acuity, and clinicians need to understand how different fluid compartments impact vision. Following initial treatment, anti-VEGF therapies that allow for stable subretinal fluid but not intraretinal fluid may enable patients to achieve optimal visual outcomes.2
Check out Decreasing Treatment Burdens with Second Generation Anti-VEGF Agents for pearls and data on the efficacy of next-generation anti-VEGF drugs.
Watch the interview to dive into pharmacokinetics in retinal disease management with Dr. Stewart!
Demystified: Iodine allergy
Betadine is an antiseptic containing povidone-iodine (PVI). It is a widely used antiseptic in ophthalmic surgery with strong evidence of effectiveness. True iodine allergies are rare; most reactions are caused by toxicity, especially with repeated procedures. Inadequate pre-operative antisepsis in patients who self-report iodine allergy has led to many cases of endophthalmitis.3
High antiseptic concentrations can be toxic to the corneal epithelium, with the degree of toxicity depending on the concentration. At low concentrations, PVI is tolerated by most people, even without anesthesia. Allergic contact dermatitis is a rare side effect, but clinicians may mistake it for an allergic reaction.
For individuals with poor PVI tolerance, lower concentrations of PVI or chlorhexidine, such as 0.05% or 0.1%, are recommended.3 However, obtaining these concentrations through compounding pharmacies can be difficult, as they may not have good quality control compared to commercially available products in Europe, according to Dr. Stewart.
