179: Phase 1 Study Evaluating the Bioequivalence of the Dispersible Final Market Image Macitentan Tablet & the Opsumit® Tablet in Fasted Conditions

Statement of Purpose: Macitentan is an orally active, nonpeptide, potent dual endothelin A and B receptor antagonist (ERA). It is approved as a film-coated Opsumit® tablet for treatment in adult pulmonary arterial hypertension (PAH) patients as a 10 mg once daily dose. A phase 3 study in children (TOMORROW) aged 6 months to 18 years is ongoing, and a new dispersible to-be-marketed formulation, final market image (FMI), for the pediatric use was developed. The aim of this study was to evaluate the bioequivalence of the FMI tablet to the Opsumit® tablet in healthy adults.

Description of Methods & Materials: A single-center, open-label, randomized, 2-way crossover Phase 1 study was conducted in healthy adults in fasted conditions to evaluate the bioequivalence of the FMI (4 tablets x 2.5 mg) with the marketed Opsumit® (10 mg) tablet. Full PK profile of macitentan and its metabolite aprocitentan were determined based on plasma samples from venous blood up to 216 hours after the study intervention administration in each period. Plasma macitentan and aprocitentan were determined by validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays. Primary PK parameters (C_max, AUC_last, and AUC_inf) of macitentan were calculated using the NCA method, and bioequivalence was determined based on the 90% confidence interval (CIs) of geometric mean ratios (GMR) of the primary PK parameters. Safety and tolerability were also evaluated throughout the study.

Data & Results: A total of 28 healthy adult subjects received at least 1 dose of study intervention and had at least 1 plasma concentration. One subject was excluded from the PK analysis, and all subjects were included in the safety analysis. Macitentan plasma C_max and AUCs were comparable after both treatments with a GMR of 94.56%, 103.54%, and 104.1% for C_max, AUC_last, and AUC_inf, respectively. The 90% CIs for the GMRs of the 3 primary PK parameters were contained within the predefined 80.00% to 125.00% bioequivalence limits. Study interventions were well tolerated, and there were no adverse events leading to study discontinuation.

Interpretation, Conclusion or Significance: Bioequivalence was demonstrated on the primary PK parameters between two formulations of macitentan administered as the dispersible FMI macitentan tablets (4 x 2.5 mg) and the film-coated Opsumit® tablet (10 mg) in healthy adult participants in fasted conditions. The administration of a single oral dose of 10 mg macitentan in fasted condition was generally safe and well tolerated in these subjects when administered as either formulation.

Disclosures: