Effects of nerandomilast, a preferential PDE4B inhibitor, on metabolism of midazolam, a sensitive CYP3A substrate

<bold>Introduction</bold> Nerandomilast (BI 1015550), an oral preferential phosphodiesterase-4B (PDE4B) inhibitor, is being developed for the treatment of patients with Idiopathic Pulmonary Fibrosis and Progressive Pulmonary Fibrosis. Based on in vitro evaluation, nerandomilast has the potential to induce CYPs 3A4, 2C8 and 2C9 enzymes, therefore potentially impacting the efficacy of drugs that are mainly metabolized by these enzymes. <bold>Aims and objectives</bold> The main objective of this trial was to investigate the potential of nerandomilast to induce the CYP3A4 enzyme by evaluating the effect of multiple oral doses of 18 mg nerandomilast on the pharmacokinetic of the sensitive CYP3A4 substrate, midazolam. <bold>Methods</bold> The trial had an open-label, two-period, fixed sequence crossover study design in healthy male subjects to compare the relative bioavailability of midazolam with and without nerandomilast co-administration. A single oral dose of 2 mg midazolam was administered alone in reference treatment period R and was given after 14 days of twice daily treatment with 18 mg nerandomilast in test treatment period T. <bold>Results</bold> Co-administration of 18 mg nerandomilast reduced midazolam peak plasma concentration (Cmax) and the total exposure (AUC) by 22% and 8%, respectively, compared to when midazolam was administered alone. <bold>Conclusions:</bold> Nerandomilast is not considered to be a CYP3A inducer. Induction of CYP2C enzymes by nerandomilast is also not expected since both CYP3A and CYP2C enzymes are induced via activation of the same pathway, pregnane X receptor. Therefore, nerandomilast is not expected to affect the systemic exposure of drugs that are mainly metabolized by CYP3A and CYP2C enzymes.