BI 1015550

Breast Feeding; Lactation; Milk, Human; Phosphodiesterase 4 Inhibitors

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

In the two large pre-registration trials of nerandomilast in idiopathic and progressive pulmonary fibrosis (each enrolling roughly 1,180 patients treated for at least 52 weeks with 9 or 18 mg twice daily or placebo), serum aminotransferase elevations were not identified as a notable adverse event, and hepatic adverse reactions did not appear among the events reported more often with nerandomilast than with placebo. Serum ALT elevations above 3 times the upper limit of normal (ULN) arose in 0% to 1.5% of both the nerandomilast- and placebo-treated subjects, and there were no instances of clinically apparent liver injury attributable to nerandomilast. The product label does not list hepatic laboratory abnormalities among the adverse reactions, gives no recommendation for routine liver test monitoring, and requires no dose adjustment for mild or moderate hepatic impairment. Since its approval, there have been no published reports of liver injury attributed to nerandomilast, but clinical experience with the drug has been limited.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Nerandomilast exerts antifibrotic and immunomodulatory effects. In animal models, it decreased the levels and activities of pro-inflammatory factors and mediators, such as tumour necrosis factor-α (TNF-α) and cytokines. In patients with IPF, nerandomilast was shown to inhibit the proliferation of primary lung fibroblasts. Increases in nerandomilast steady-state trough concentrations were associated with better efficacy, as indicated by a smaller reduction in forced vital capacity (FVC) from baseline over 52 weeks.

Nerandomilast is a phosphodiesterase 4 (PDE4) inhibitor. PDE4 is an enzyme that regulates inflammatory processes. PDE4 has been implicated in the driving the inflammation and fibrosis of the lungs in IPF. Nerandomilast preferentially inhibits the PDE4B isoenzyme over PDE4A, PDE4C, and PDE4D. PDE4 inactivates cyclic adenosine monophosphate (cAMP) by hydrolyzing it. Nerandomilast elevates intracellular cAMP levels through PDE4B inhibition, which reduces the expression of pro-fibrotic growth factors and inflammatory cytokines overexpressed in IPF, such as mitogen-activated protein kinase (MAPK) and transforming growth factor beta (TGFβ).

Nerandomilast is primarily metabolized by CYP3A and to a lesser extent by multiple UGT enzymes. After oral administration of nerandomilast, chiral inversion from the pharmacologically active R-enantiomer to the pharmacologically inactive S-enantiomer occurs via metabolism. The S-enantiomer was identified as a minor metabolite of nerandomilast. The R-enantiomer is the predominant circulating enantiomer.