Mar 2026
Early clinical pharmacology evaluation of the novel anti-inflammatory macrolide, glasmacinal (EP395): tolerability, pharmacokinetics and drug interactions
Dave Singh, Kate Hanrott, Olof Breuer, Johan Bylund, Björn Schultze, Virginia Norris
Br J Clin Pharmacol
Br J Clin Pharmacol
Abstract
Aims
This work assessed the pharmacokinetics (PK), safety and tolerability of glasmacinal (EP395, an oral anti-inflammatory macrolide with negligible antimicrobial activity in development for COPD treatment) in two healthy participant trials: ‘first-in-human’ (FIH) and ‘drug–drug-interaction’ (DDI).
Methods
The FIH trial was a randomized, double-blind, placebo-controlled trial of single (20–750 mg) and multiple (120–375 mg daily for 28 days) doses of glasmacinal. The DDI trial was an open-label assessment of the effect of verapamil (moderate CYP3A4 inhibitor and P-gp inhibitor) on the PK of glasmacinal, and the effect of glasmacinal on the PK of midazolam (CYP3A4 substrate) and digoxin (P-gp substrate).
Results
No SAEs or severe AEs occurred, and no AEs considered related to glasmacinal led to withdrawal. Glasmacinal was rapidly absorbed, reaching peak plasma concentrations at ~4 h post-dose and a terminal half-life ~70 h. Glasmacinal systemic exposure (Cmax and AUC0–inf) was reduced by one third when administered after food (300-mg single dose, parallel group comparison). Co-administration of glasmacinal with verapamil increased glasmacinal exposure (Cmax 1.70-fold [90% CI: 1.52, 2.39], AUC0–inf 2.41-fold [90% CI: 2.18, 2.82]). Glasmacinal modestly increased exposure to midazolam (Cmax 1.26-fold [90% CI: 1.12, 1.49], AUC0–inf 1.54-fold [90% CI: 1.33, 1.89]) and digoxin (Cmax 1.38-fold [90% CI: 1.22, 1.81] and AUC0–inf 1.37-fold [90% CI: 1.26, 1.52]).
Conclusions
Glasmacinal was well tolerated in single doses up to 750 mg and repeat doses up to 375 mg. Glasmacinal may be a victim of selected drugs that impact CYP3A4 and/or P-gp but is unlikely to be a perpetrator of clinically relevant DDIs.