PI-080 - PHARMACOKINETICS OF NERANDOMILAST IN HEALTHY VOLUNTEERS

Y. Yu¹, D. Jappar¹, J. Wu¹, U. Burkard², C. Coeck³, D. Zoz¹; ¹Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA, ²Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach and der Riss, Germany, ³Boehringer Ingelheim SComm., Brussels, Belgium.

Background: Nerandomilast (BI 1015550) is a preferential phosphodiesterase 4B (PDE4B) inhibitor under investigation for treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. The single- and multiple-dose PK of nerandomilast have been evaluated in healthy subjects following oral administration in single-rising-dose (SRD) and multiple-rising-dose (MRD) trials. In addition, metabolism and excretion pathways were investigated in a mass balance study.

Methods: In SRD and MRD studies, nerandomilast (as a powder for oral solution) was administered to healthy subjects as a single dose in a 0.02 mg to 24 mg dose range and as twice-daily (b.i.d.) multiple doses of 1 mg and 6 mg for 14 days, respectively. In the mass balance study, each subject received a single dose of 18 mg nerandomilast (C-14) as oral solution (0.5 ml/mL), which consisted of 17.16 mg non-labeled nerandomilast and 0.84 mg radiolabeled [14C]nerandomilast-EQ (equivalent).
In each study, PK blood samples were collected for determination of nerandomilast concentrations. In the mass balance study, additional urine and feces samples were collected and [14C]-radioactivity was also quantified from blood samples. PK parameters were calculated via non-compartmental analysis. Descriptive statistical methods were used to summarize PK parameters.

Results: After oral administration, nerandomilast was rapidly absorbed with peak plasma concentrations (Cmax) occurring between 0.5-1.25 h post-dose and declining in a biphasic manner afterwards. Nerandomilast exposure (Cmax and AUC0-∞) increased dose proportionally following single- and multiple-dose administration. Steady state was reached by 7 days after b.i.d. dosing with up to 1.69-fold drug accumulation. Following a single oral dose administration of [14C]nerandomilast, 58.0% of drug was excreted in feces and 36.4% was excreted in urine. 11.9% of the administered nerandomilast dose was excreted as unchanged parent compound in urine.

Conclusion: Nerandomilast was rapidly absorbed following oral administration and showed a biphasic decline. Nerandomilast exposure increased proportionally with dose. Nerandomilast was excreted via both urine and feces.