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.