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.