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. 2020 Dec;86(12):2424-2434.
doi: 10.1111/bcp.14347. Epub 2020 May 29.

Bioequivalence of macitentan and tadalafil given as fixed-dose combination or single-component tablets in healthy subjects

Simon Grill  1 , Shirin Bruderer  1 , Patricia N Sidharta  2 , Mariya Antonova  3 , Susanne Globig  2 , James Carlson  4 , Armin Schultz  5 , Dénes Csonka  1
Affiliations

Bioequivalence of macitentan and tadalafil given as fixed-dose combination or single-component tablets in healthy subjects

Simon Grill et al. Br J Clin Pharmacol. 2020 Dec.

Abstract

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-centre, 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 sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental 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 USA and 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 (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies.

Conclusion: 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.

Keywords: bioequivalence; fixed-dose combination; macitentan; pulmonary arterial hypertension; tadalafil.

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Conflict of interest statement

Si.G., S.B. and D.C. are employees of Actelion Pharmaceuticals Ltd. Su.G. and P.N.S. are employees of Idorsia Pharmaceuticals Ltd. M.A. is an employee of Aixial s.r.o. J.C. is an employee of Reven, LLC.

Figures

FIGURE 1
FIGURE 1
Study AC‐077‐101: Arithmetic mean plasma concentration vs time profiles for macitentan, ACT‐132577 and tadalafil during the first 24 hours after administration of fixed‐dose combination (FDC) or free combination of macitentan and US‐sourced tadalafil in group 1 and group 2, pharmacokinetics analysis set. Data are plotted on a linear scale
FIGURE 2
FIGURE 2
Study AC‐077‐101: Arithmetic mean plasma concentration vs time profiles for macitentan, ACT‐132577 and tadalafil over 216 hours after administration of fixed‐dose combination (FDC)‐1 or free combination of macitentan and US‐sourced tadalafil in group 1, pharmacokinetics analysis set. Data are plotted on a linear scale
FIGURE 3
FIGURE 3
Study AC‐077‐101: Arithmetic mean plasma concentration vs time profiles for macitentan, ACT‐132577 and tadalafil over 216 hours after administration of fixed‐dose combination (FDC)‐2 or free combination of macitentan and US‐sourced tadalafil in group 2, pharmacokinetic analysis set. Data are plotted on a linear scale
FIGURE 4
FIGURE 4
Study AC‐077‐103: Arithmetic mean plasma concentration vs time profiles of fixed‐dose combination (FDC)‐2 for macitentan, ACT‐132577 and tadalafil over 216 hours after administration of FDC‐2 or free combination of macitentan and EU‐sourced tadalafil, pharmacokinetic analysis set. Data are plotted on a linear scale
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