A novel in silico model and algorithm for refining therapeutic treatment of retinal disease

Researchers at the Institute of Mathematics, Kassel University and the Department of Ophthalmology, Heidelberg University, have reported a novel in silico model and algorithm for the drug distribution of a therapeutic in the vitreous body to enable personalized therapy treating retinal disease.  The study suggested that the drug distribution and the amount of drug on the macula may be influenced by the choice of drug and the manner of its administration. Based on the models and simulation results, the researchers recommended a refined age-related macular degeneration (AMD) therapy in terms of injecting drug location, orientation, diffusion and concentration.

The German researchers were aimed to improve mathematical modelling and in silico simulations for AMD, one of the most common cause of vision loss in industrialized countries affecting 10% of those over 65 years of age, and potentially 25% of those over 75 years of age.  As reported in the medical literature, there has been no standard treatment for dry AMD to date however, a recent approval for a treatment for geographic atrophy (GA) secondary to AMD is expected to be marketed shortly in the US. For wet AMD, several treatments have been on the market for almost 20 years with the introduction of the first anti-VEGF agent (Macugen) around 2004, laser photocoagulation and photodynamic therapy.  Thereafter, anti-VEGF agents include Lucentis (ranibizumab), Avastin (bevacizumab), Eylea (aflibercept), and Beovu (brolucizumab, 2020).  While these treatments are not fixed, these approaches include differing regimens, monthly or bimonthly injections, a pro-re-nata strategy and a treat-and-extend regimen as “a personalized” treatment. Regardless, the current researchers and many others have reported a number of unresolved issues in terms of frequency, dosage, location of injection, effectiveness, choice of drug and more. Consequently, a long-lasting optimized therapy solution for patients with AMD is yet to be accepted and therefore one experimental approach to use mathematical modelling may provide some impact on improving outcomes for both clinicians and their patients.

In the current study, researchers used a transport-diffusion equation to describe drug distribution in the vitreous coupled with the Darcy equation for vitreous humor flow.  The experiments showed that gravity should play a role in drug distribution and the results from the work suggested that a number of recommendations were presented for a “Refined Therapy”, including:

  • “When the drug is injected centrally into the vitreous, a certain amount of the drug reaches the macula the longest. This can be interesting for longer acting drugs, e.g., aflibercept. Otherwise, a large portion of the drug escapes through the retina.
  • If the drug is injected closer to the macula, a higher concentration arrives there, but for a shorter period of time. This can be interesting for an intensified initial treatment, e.g., for the treatment of a thick edema.
  • The needle should be oriented in the direction of the macula. An unfavourable insertion angle can lead to a loss of up to 38% of the drug at the macula.
  • A larger diffusion coefficient for the drug, a lighter molecule, results in a higher drug concentration at the macula, but on average over 30 days, it results in a lower drug concentration at the macula because more drug also escapes through the retina more quickly”.