Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor 1 antagonist ACT‐1014‐6470 in vitro and in vivo

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.