Pharmacokinetics
Following single doses of mesdopetam AUCt, AUC0-∞ and Cmax showed a
dose-linear relationship indicating dose proportionality for mesdopetam.
Urine recovery analysis showed that renal excretion amounted to around
30% of the dose administered, indicating renal excretion of unchanged
compound as one of the mayor pathways for the elimination of mesdopetam.
The mean t1/2 of the parent compound mesdopetam ranged
from 6.4 to 7.1 hours. The plasma concentration-time profile of the
metabolite IRL902 was similar to the profile for the parent compound
which points to formation rate limited pharmacokinetics while the plasma
concentration profiles for metabolite IRL872 were markedly different
with a mean t1/2 of more than 20 hours indicating
elimination rate limited pharmacokinetics for this metabolite. Since
both IRL902 and IRL872 are pharmacologically inactive, no untoward
pharmacological effects are expected from metabolites formed from
mesdopetam.
A small food interaction suggesting slightly higher exposures under fed
conditions was observed for mesdopetam. After multiple dose
administration the pharmacokinetic profile was similar to single dose
pharmacokinetics, with rapid absorption for the parent compound and a
t1/2 of ~7 hours. The mean AR for
mesdopetam and was close to 1 for both 40 mg and 80 mg dose level
indicating virtually no accumulation from the first to the last dose.
One possible explanation for the supra-proportional increases of IRL902
levels between the two MAD doses could be capacity limited metabolism to
IRL872 (acetylation), which showed little change in exposure between the
doses. The significance of the finding is however limited since only two
dose levels were studied and was only observed in part 2 of the study.
The overall pharmacokinetics of mesdopetam supports twice daily use in
patients.
In conclusion, mesdopetam was generally safe and well tolerated in
healthy male subjects up to 120 mg single dose and to 80 mg in the MAD
part. There were no notable safety findings or indications of a safety
risk. Mesdopetam displayed rapid absorption and linear pharmacokinetics
with an apparent terminal elimination half-life around 7 hours upon
single as well as repeated administration.