ACT-1014-6470 is an orally available complement factor 5a receptor 1 antagonist and a novel treatment option in auto-inflammatory diseases. The in vitro inhibition potential of ACT-1014-6470 on cytochrome P450 isozymes (CYPs) and its effect on the pharmacokinetics (PK) of the CYP2C19 and CYP3A4 substrates omeprazole and midazolam, respectively, in humans were assessed. In vitro assays were conducted with isoform-specific substrates in human liver microsomes. In an open-label, two-period, fixed-sequence cocktail study, single doses of 20 mg omeprazole and 2 mg midazolam were administered concomitantly to 20 healthy male subjects alone (treatment A) and after a single dose of 100 mg ACT-1014-6470 (treatment B) under fed conditions. Safety and PK assessments were performed. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of noncompartmental PK parameters of treatment B versus treatment A were calculated. In vitro, no time-dependent inhibition was observed and the lowest inhibition constant of 4.3 μM ACT-1014-6470 was recorded for CYP2C19. In humans, GMRs (90% CI) of omeprazole PK were 1.9 (1.5-2.5) for maximum plasma concentration (Cmax ) and 1.9 (1.5-2.3) for area under the plasma concentration-time curve from 0 to 12 h (AUC0-12 h ). Midazolam PK showed GMRs (90% CI) of 1.1 (1.1-1.2) for Cmax and 1.5 (1.4-1.6) for AUC0-24 h . All treatments were well-tolerated. In line with in vitro results and regulatory risk factor calculation, the increased exposure to omeprazole and midazolam in humans after concomitant administration with a single dose of 100 mg ACT-1014-6470 reflected a weak inhibition of CYP2C19 and CYP3A4.

• MeSH
• Cytochrome P-450 CYP3A * MeSH
• Cytochrome P-450 CYP2C19 MeSH
• Factor Va * MeSH
• Drug Interactions MeSH
• Humans MeSH
• Midazolam pharmacokinetics   MeSH
• Omeprazole pharmacokinetics   MeSH
• Cytochrome P-450 Enzyme System MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Anticoagulants administration & dosage   MeSH
• Bronchopneumonia diet therapy   drug therapy   MeSH
• Factor Va antagonists & inhibitors   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pulmonary Embolism diagnosis   etiology   drug therapy   MeSH
• Activated Protein C Resistance diagnosis   MeSH
• Venous Thrombosis diagnosis   drug therapy   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH

• MeSH
• Factor Va physiology   MeSH
• Protein C diagnostic use   physiology   MeSH
• Protein S diagnostic use   physiology   MeSH
• Thrombophilia diagnosis   MeSH
• Publication type
• Congress MeSH
• Review MeSH

• MeSH
• Factor Va metabolism   MeSH
• Factor VIIIa metabolism   MeSH
• Protein C metabolism   MeSH
• Thrombophilia etiology   MeSH
• Publication type
• Review MeSH