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 mu M 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 (C-max) and 1.9 (1.5-2.3) for area under the plasma concentration-time curve from 0 to 12 h (AUC(0-12h)). Midazolam PK showed GMRs (90% CI) of 1.1 (1.1-1.2) for C-max and 1.5 (1.4-1.6) for AUC(0-24) 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Various auto-inflammatory diseases are triggered by inadequately controlled complement activity. ACT-1014-6470 is a novel orally available complement factor 5a receptor 1 (C5aR1) antagonist, which was well-tolerated and exhibited favorable pharmacokinetic (PK) properties in single-and multiple-ascending dose studies. WHAT QUESTION DID THIS STUDY ADDRESS? The cytochrome P450 (CYP)-inhibition potential of ACT-1014-6470 was assessed in vitro and in a clinical study simultaneously investigating the effect of a single dose of 100 mg ACT-1014-6470 on the PK of the CYP2C19 and CYP3A4-sensitive substrates omeprazole, midazolam, and their metabolites, respectively, in healthy male subjects. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? In vitro, the strongest inhibition was measured for CYP2C19 with an inhibition constant (Ki) of 4.3 mu M ACT-1014-6470. In accordance, the compound was a weak inhibitor of CYP2C19 and CYP3A4 in healthy subjects, as indicated by 1.9-and 1.5-fold increases in omeprazole and midazolam area under the plasma concentration--time curve, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? As ACT-1014-6470 is intended to be administered in auto-inflammatory diseases, in which combination therapies might be indicated to improve remission, its inhibition potential at two of the most prominent metabolizing enzymes, CYP2C19 and CYP3A4, was characterized as weak. Because CYP2C19 showed the lowest Ki value in vitro, inhibition of other CYPs by ACT-1014-6470 is not considered clinically relevant, further reducing the risk of drug-drug interactions in patients with auto-inflammatory diseases.