DISCUSSIONS
This study was the first-in-human study to evaluate the safety/tolerability, and PK of rhEGF eyedrops after single and multiple administrations in healthy male subjects. There were some published EGF eyedrops in corneal injury including dry eye syndrome, however, there has been no PK studies of EGF eyedrops. [14] Therefore, this study was the first published PK study for rhEGF eyedrops.
The one of the primary goals of first-in-human study were to determine safety/tolerability. Considering the safety profiles, rhEGF eyedrops at doses ranging from 10 μg/mL to 100 μg/mL in SAD and MAD studies were well tolerated. No subjects experienced serious adverse events. Among subjects who received rhEGF, corneal erosion was the most common ADR. The incidences of corneal erosion showed similar among dose groups including placebo. In addition, corneal erosions occurred in medioinferior side in which tear sampling was commonly conducted. Therefore, corneal erosion may be caused by tear sampling procedures rather than rhEGF eyedrops.
After administrations of rhEGF eyedrops, there were numerous peaks in time-serum EGF concentration profiles. Serum EGF levels show high variability through numerous causes including circadian rhythm, ultradian rhythm, and venous puncture. [15, 16] In addition, normal serum EGF levels are 0.1-1.281 μg/L. [16, 17] In this study, all of the serum EGF levels were within the normal serum EGF levels. Therefore, the numerous peaks are thought to be due to ultradian rhythm rather than rhEGF eyedrops, and rhEGF eyedrops did not affect serum EGF levels. Given that high serum EGF level is associated with numerous toxicities including esophageal adenocarcinoma and non-small lung cancer, rhEGF eyedrops can be administered without systemic toxicity. [17-20]
In this study, tear EGF was rapidly absorbed, then, tear EGF concentrations became similar compared to those of baseline and placebo after 4 hours without accumulation. The rapid decline of tear EGF concentrations may result from precorneal fluid drainage including nasolacrimal drainage and blinking despite the lack of clear mechanisms of rhEGF binding to ocular tissue.[21] Further study may be needed to find the mechanism of corneal binding of rhEGF after administration of rhEGF eyedrops. The absence of tear EGF accumulation means that the possibility of toxicity due to the accumulation of rhEGF eyedrops is low during long-term administration.
There has been no published data of therapeutic tear EGF concentrations for corneal injury in human. Some in vitro studies reported that the therapeutic EGF concentrations was 1–10 μg/L.[22, 23] In our study, the average tear EGF concentrations among dose groups were 0.74-18.8 μg/L and 2.6-12.4 μg/L in SAD and MAD studies, respectively. Therefore, 50 μg/mL of rhEGF eyedrop twice a day may be considered a therapeutic dose because the average tear EGF concentrations in the dose group of 50 μg/mL were 5.8 μg/L and 4.1 μg/L in SAD and MAD studies, respectively.
In this study, tear EGF exposure did not show dose-linearity although tear EGF exposure increased by dose. The amount of tear may affect the tear EGF concentration, which is thought to have influenced the PK variability of EGF after administration of rhEGF eyedrops. Considering the PK variability and lack of accumulation of rhEGF eyedrops, trough tear EGF concentration is not thought a suitable biomarker for the evaluation of the efficacy of rhEGF eyedrops.
Although rhEGF eyedrops have been emerging as a good treatment option for corneal injury, no appropriate dose of rhEGF eyedrops has been known. There are some studies showing that higher dose of EGF eyedrops might be inappropriate for the treatment of the corneal injury because auto-inhibition may occur by high dose of EGF, however, these studies did now show any dose-tear EGF concentration relathionships. [22, 24, 25] Therefore, further study for corneal injury patients may be needed considering tear PK variability and safety profile of rhEGF eyedrops.
In this study, no anti-EGF antibodies were detected except for a subject in placebo before rhEGF administration. Generally, there are numerous soluble proteins which bind with EGF including human EGF receptor 1, human EGF receptor 2, and arginine esterase. [26-28] Therefore, rhEGF eyedrops might be administered without decrease in the efficacy due to anti-EGF antibody formation even if administered for a long time.
There are some limitations in this study. This study was performed in healthy subjects to minimize confounding factors that could influence the study results. Further study for corneal injury patients is needed to evaluate the efficacy of the drug. There were missing values of tear PK sampling due to the difficulty of the sample collection. Nevertheless, the PK profile could be observed in all dose groups.
In conclusion, dose range from 10-100 μg/mL solution of rhEGF eyedrops in single and multiple administration was safe and well tolerated in healthy male subjects. All ADRs were mild and transient. rhEGF eyedrops increased tear EGF level without effect on systemic exposure. The results of this study justifies further evaluation of the efficacy and safety of rhEGF eyedrops for corneal injury patients.