While not necessary for most systemic preclinical toxicology studies, the addition of supplemental specialized ocular endpoints may be warranted if a compound belongs to a class known for potential ocular side effects. Supplemental endpoints may also be warranted in the early screening phase in order to weed out the most problematic compounds.

The key is to identify compounds early and then include the appropriate supplementary endpoints which will enhance the probability of detecting an adverse ocular effect.

CNS-Active and Metabolic-Altering Compounds
It is well-known that compounds which can cross the blood brain barrier can also reach the retina. Also, if a compound can alter metabolic processes, it may have secondary effects in the eye. Ultimately, if a compound’s target or off-target receptors are also present in ocular tissue there is the potential for adverse ocular effects.

The development of CNS-active and metabolic-altering compounds is becoming more prevalent, which begs the question: Should we include ocular parameters in early screenings or MTD studies? Two technologies, electroretinography (ERG) and optical coherence tomography (OCT), can evaluate functional or structural ocular changes in vivo, respectively.

Two Technologies for Evaluating the Retina
The ERG is a functional evaluation which measures the retina’s response to a light stimulus. The resulting waveform is a composite of various cells responding to and/or transmitting an electronic signal to the optic nerve. Not only is the ERG sensitive to transient functional changes, it can detect retinal cell damage too. Because it can detect changes due to damage before they are visible in an ophthalmology examination, it may be useful in early screening.

High-resolution OCT, such as SD-OCT, provides a non-invasive structural evaluation of the retina. Images produced from this examination show individual micron-level cross-sections of retinal cell layers. These 3-dimensional volume scans are used to evaluate the retina’s overall structure. It takes less than five minutes for this test to serially image a retina, representing an enormous monetary advantage compared to standard serial histopathology sections.

An Example: Phosphodiesterase (PDE) Inhibitor
Let’s for example consider a fictitious phosphodiesterase 51 inhibitor. The screening of this potentially suspect molecule was uneventful. We’re out of the woods, right? Not quite. An acute or short-term (4-7 day) dose may not result in enough ocular exposure for adverse changes to manifest. Since this PDE inhibitor is in a class which has demonstrated ocular side effects in animals and humans, inclusion of additional ocular endpoints such as ERG and/or OCT at intervals throughout the 28-day and/or 3-month studies may help elucidate potential adverse ocular changes and help determine how to deal with them.

To Include or Not to Include…
So, is there an advantage to including ocular endpoints in the preclinical development of products not targeted to the eye? Probably, if they are used judiciously. Like all technologies, they have their strengths and weaknesses and represent a snapshot in time.

In early studies, there may not be enough time or exposure to cause a degenerative change which is detectable by the above mentioned tests. However, if the compound’s class and action is considered, selective screening may preclude an unexpected issue further down the development road. As it is not time or cost-effective to include them by default, in order to be effective, this approach requires preset criteria to determine which compounds will be subjected to the additional evaluations.