PII-054 - EFFECT OF COMPLEMENT FACTOR 5A RECEPTOR 1 (C5AR1) ANTAGONIST ACT-1014-6470 ON THE CYTOCHROME P450 2C19 AND 3A4 SUBSTRATES OMEPRAZOLE AND MIDAZOLAM IN A COCKTAIL STUDY IN HEALTHY SUBJECTS.

M. Anliker-Ort^1,2, B. Berger¹, P. Kaufmann¹, L. Janů³, J. van den Anker⁴, J. Dingemanse¹; ¹Idorsia Pharmaceuticals Ltd,, Allschwil, Switzerland, ²University Children's Hospital, Basel, Switzerland, ³CEPHA s.r.o., Pilsen, Czech Republic, ⁴University of Basel Children's Hospital, Basel, Switzerland.

Background: In autoinflammatory diseases, the complement factor 5a receptor 1 (C5aR1) is inadequately activated, leading to tissue damage [1]. Single- and multiple-ascending doses of the selective, orally-available C5aR1 antagonist ACT-1014-6470 were well tolerated in healthy subjects [2,3], while its cytochrome P450 (CYP) 2C19 and 3A4 perpetrator potential was not yet known.

Methods: This was an open-label, two-period, fixed-sequence Phase 1 cocktail study investigating the effect of a single oral dose of 100 mg ACT-1014-6470 on the pharmacokinetics (PK) of concomitantly administered single oral doses of 20 mg omeprazole and 2 mg midazolam in 20 healthy male subjects under fed conditions. PK blood sampling and safety assessments were performed regularly. PK parameters of all analytes were determined by non-compartmental analysis and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of Treatment B (omeprazole and midazolam administered concomitantly with ACT-1014-6470) vs Treatment A (omeprazole and midazolam administered alone) were calculated.

Results: ACT-1014-6470 PK were in line with previous studies. For omeprazole, the GMRs (90% CI) were 1.9 (1.5–2.5) for maximum plasma concentrations (Cmax), 1.9 (1.5–2.3) for area under the plasma-concentration time curve (AUC) from 0 to 12 h, and 1.0 (0.9–1.2) for terminal half-life (t½). For midazolam, the GMRs (90% CI) were 1.1 (1.1–1.2) for Cmax, 1.5 (1.4–1.6) for AUC from 0 to 24 h, and 1.3 (1.2–1.4) for t½. All treatments were well tolerated, 5 adverse events were reported by 3 subjects, and all subjects completed the study.

Conclusion: An increased exposure to omeprazole and midazolam after concomitant administration with a single dose of 100 mg ACT-1014-6470 suggests a weak inhibition of CYP2C19 and CYP3A4.

[1] Ort, M., Dingemanse, J., van den Anker, J. & Kaufmann, P. Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. Front. Immunol.2020;11(December):1-20.
[2] Anliker‐Ort, M., Dingemanse, J., Hsin, C., Richard, M., Huehn, E., Sabattini, G. et al. First‐in‐human study with ACT‐1014‐6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients. Basic Clin. Pharmacol. Toxicol.2022;131(2):114-128.
[3] Anliker‐Ort, M., Dingemanse, J., Farine, H., Groenen, P., Kornberger, R., van den Anker, J. et al. Multiple‐ascending doses of ACT‐1014‐6470, an oral complement factor 5a receptor 1 (C5a1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement. Br. J. Clin. Pharmacol. 2022:1–10.