Phase 1 Studies to Assess Inhaled Seralutinib as a Perpetrator or a Victim of Drug-Drug Interactions in Healthy Participants.

Abstract

Seralutinib, an inhaled, small-molecule tyrosine kinase inhibitor in clinical development for the treatment of pulmonary arterial hypertension (PAH), was evaluated for its potential as a perpetrator or victim of a metabolic and transporter-based drug-drug interactions in 2 phase 1 studies. In study 1, 24 participants received a cocktail of probe substrates: caffeine (CYP1A2), montelukast (CYP2C8), flurbiprofen (CYP2C9), midazolam (CYP3A), and pravastatin (OATP1B1/1B3), plus digoxin (P-gp) with or without seralutinib. In study 2, 19 participants received seralutinib with/without itraconazole, a strong CYP3A inhibitor, or fosaprepitant, a weak CYP3A inhibitor. Geometric least-squares mean ratios and 90% confidence intervals for maximum observed concentration (C_max) and area under the plasma concentration-time curve (AUC) were obtained. Safety was monitored throughout the studies. All adverse events were mild or moderate in severity. Seralutinib coadministration increased AUC for midazolam 3.03-fold and caffeine 1.32-fold. The coadministration increased digoxin C_max 1.28-fold. Seralutinib did not meaningfully alter C_max and AUC for montelukast, flurbiprofen, or pravastatin. Fosaprepitant and itraconazole increased seralutinib AUC 1.08- and 1.84-fold, respectively. Seralutinib is a moderate CYP3A inhibitor and a weak CYP1A2 inhibitor; it slightly inhibits P-gp. Seralutinib exposure is minimally affected by a weak CYP3A inhibitor but is substantially increased by a strong CYP3A inhibitor.