Bioequivalence of Macitentan and Tadalafil Given as Fixed-dose Combination or Single-component Tablets in Healthy Subjects.

AIMS: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects.

METHODS: Studies AC-077-101 and AC-077-103 were single-center, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic (PK) sampling over 216 h was conducted, and PK parameters were derived using non-compartmental methods.

RESULTS: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single-component was sourced from the United States (US) and European Union (EU), respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve, and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000 to 1.2500). No subject died and no serious adverse events were reported in either studies.

CONCLUSIONS: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU-sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.