4. Discussion
De novo discovery and development of new therapeutics is an
extremely costly and time-consuming process that is rarely conducted for
neglected tropical diseases, including onchocerciasis, where drug
discovery is notoriously under-funded. Since emodepside is a registered
product in animal health, the present studies confirm the usefulness of
drug repurposing as a strategy for identifying and developing new
therapeutic agents. Its safety and efficacy profiles are well
established after nearly 15 years of use in the veterinary setting. As
expected, the early development results in healthy male subjects from
the three Phase I studies reported here show promising safety profiles.
Across all three Phase I clinical studies, emodepside was found to be
rapidly absorbed under fasting conditions. Dose-proportional increases
in plasma emodepside concentrations were observed with increasing doses
from 1 mg to 40 mg after oral administration of the LSF. Conventional IR
tablets containing 5 mg or 20 mg crystalline emodepside were somewhat
more slowly and poorly absorbed as compared to the LSF.
The half-life during the first 24 hours after dosing, i.e. during the
distribution-elimination phase, was short at around 11 hours, and was
followed by a very long terminal elimination half-life, estimated at
> 500 hours. Owing to the long terminal elimination
half-life, steady state was not reached after repeated dosing with
emodepside for 10 days in the MAD study. In all three studies, plasma
concentration-time profiles for emodepside showed a distinct biphasic
pattern in the descending part of the curve, which is postulated to
reflect initial rapid distribution of the compound followed by very slow
terminal elimination. This finding is particularly promising since rapid
distribution of emodepside in the tissues suggests that exposure of the
parasites may be high, given that microfilariae reside mainly in the
skin and adult worms in subcutaneous tissue. This hypothesis is backed
up by preclinical findings with radio-labelled emodepside, showing that
radioactivity levels were higher in most tissues than in the blood, the
highest concentrations being detected in the fat at all time-points. In
addition, the long terminal half-life is expected to be advantageous in
maintaining patient exposure to pharmacodynamically active drug levels.
The long half-life is not expected to raise any safety issues, based on
the available toxicological data and the safety profile of emodepside
across the three studies.
In both studies comparing dosage forms, the LSF showed consistently
higher bioavailability than the tablet formulations. Indeed, in the SAD
study, the conventional IR tablet containing crystalline emodepside had
insufficient bioavailability compared to the LSF and was considered
unsuitable for further study. This is due to the biopharmaceutical
properties of emodepside, and optimisation of the dosage form was
required to improve the dissolution kinetics. New ASD tablets containing
5 mg emodepside in amorphous form were developed and showed markedly
better bioavailability. The gastrosoluble ASD tablet was more
bioavailable than the gastroresistant ASD tablet. With both ASD tablets,
intake under fed conditions slowed the rate of absorption of emodepside
and reduced its bioavailability. Based on data from the RBA study, a 15
mg dose with the gastrosoluble ASD tablet is predicted to provide
equivalent exposure to 10 mg LSF.
From the outset it was known that, for logistical reasons, the liquid
formulation would not be practical for use in the field in Phase II and
III studies in countries where onchocerciasis is endemic. Nevertheless,
as these Phase I studies showed, the LSF leads to higher exposure as
compared to the tablet formulations, making it useful in assessing the
safety profile. Overall, TEAEs were more frequent with the LSF,
particularly at higher doses.
No important safety risks, either potential or identified, have been
identified with emodepside to date. Safety data accrued in the three
Phase I studies indicate that potential effects on the central nervous
system and vision will require close monitoring in future studies.
Lastly, in the MAD study, the increase in plasma emodepside
concentration after the final dose of the LSF on Day 9 was lower after
10 mg BID than after 10 mg OD, with
Cmax/Ctrough ratios of 1.9 and 3.0,
respectively (data on file). Although the total daily dose in the 10 mg
BID dosing group was twice as high as that in the 10 mg OD dosing group
on Days 0–8, geometric mean Cmax on Day 9 was only
1.2-fold higher in the 10 mg BID dosing group compared to the 10 mg OD
group. This suggested that twice-daily dosing might be beneficial in
mitigating any adverse effects related to Cmax, thereby
improving tolerability.
Thus, the three Phase I studies provided invaluable information on the
safety, PK profile and relative bioavailability of emodepside in healthy
humans. The LSF is not suitable for easy and accurate clinical use under
the conditions expected for patients treated for onchocerciasis, and the
Phase I data enabled us to select a field-adapted tablet formulation
compatible with the biopharmaceutical properties of emodepside. We also
identified a dose and dosing regimen that will achieve the target
effective concentration in humans, i.e. 100 ng/mL
(10-7 M) of emodepside, and open the way for Phase II
and III studies in individuals infected with O. volvulus .