062: Absolute Oral Bioavailability of Nerandomilast in Healthy Male Study Participants

Statement of Purpose, Innovation or Hypothesis: Nerandomilast (BI 1015550), a preferential inhibitor of phosphodiesterase 4B, is being investigated in the Phase 3 FIBRONEER^TM clinical trials as a potential treatment for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. To support further understanding of the pharmacokinetics of nerandomilast, this study aimed to assess the absolute oral bioavailability of a single oral dose of nerandomilast by simultaneously administering an intravenous ¹⁴C microtracer in healthy male study participants.

Description of Methods & Materials: This non-randomized, open-label, single-period, single-arm, Phase 1 study examined the absolute bioavailability of 18 mg nerandomilast as a tablet formulation for oral administration using an intravenous microtracer approach in healthy male participants aged 18–65 yrs with a body mass index (BMI) of 18.5–29.9 kg/m². A microtracer of 10 μg ¹⁴C-labeled nerandomilast mixed with 90 µg unlabeled nerandomilast in 10 mL solution (Reference: R) was administered intravenously 1.5h (assumed time to maximum concentration after oral administration) after the administration of a single oral dose of 18 mg unlabeled nerandomilast in tablet form (Test: T). Concentrations of unlabeled nerandomilast in plasma were determined using a validated liquid chromatography tandem mass spectrometry assay, and concentrations of ¹⁴C‑nerandomilast were determined using accelerator mass spectrometry analysis. Primary pharmacokinetic parameters were area under the concentration–time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC_0-∞) of nerandomilast following oral administration of the tablet formulation and AUC_0-∞ of ¹⁴C‑nerandomilast following intravenous administration. The absolute bioavailability of the oral dose was estimated by the ratio of adjusted geometric means for the dose-normalized AUC_0-∞ (T/R) using a statistical model of an analysis of variance on the logarithmic scale, including the ‘formulation’ as fixed effect and ‘subject’ as random effect.

Data & Results: Eight healthy male participants (six White, one Asian, one multiple race) received trial medication and completed the trial. Mean (standard deviation [SD]) age was 28.9 yrs (13.9) and mean (SD) BMI was 22.6 kg/m² (1.9). Upon dose normalization,
AUC_0-∞ of the oral dose was 118.27 h∙mmol/L/kg, and AUC_0-∞ of the intravenous dose was 161.69 h∙mmol/L/kg. The absolute bioavailability of a single oral dose of 18 mg nerandomilast was estimated as 73.15% (90% confidence interval [CI]: 67.32%, 79.48%) (see Table 1). The plasma concentration–time profiles of the 18 mg oral dose and the ¹⁴C-labeled microtracer (normalized to oral dose) are shown in Figure 1. No on-treatment adverse events or other clinically relevant safety findings were reported for any participant.

Interpretation, Conclusion or Significance: The absolute bioavailability of nerandomilast administered as an 18 mg oral tablet, which is the dose administered twice daily in Phase II and III trials, was 73.15% (90% CI: 67.32%, 79.48%).

Disclosures: XT and NW are employed by Boehringer Ingelheim. SB and RT are contracted to Boehringer Ingelheim for this study. This study was supported and funded by Boehringer Ingelheim. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment related to the development of the Abstract. Cindy Macpherson, PhD of Nucleus Global provided writing, editorial support and formatting assistance, which was contracted and funded by Boehringer Ingelheim. Boehringer Ingelheim was given the opportunity to review the abstract for medical and scientific accuracy as well as intellectual property considerations.

Citations/References:

Additional Information/Authors: The authors would like to acknowledge the contributions of Anne Regelin and David Joseph to the design of the study, Anne Regelin and Jocelyn Courville to study conduct and execution, Anna-Marie Schuknecht to data analysis and Yichao Yu, Dilara Jappar, and Donald Zoz to scientific oversight of the study.