In both fed and fasted healthy volunteers, an ambrisentan and tadalafil fixed-dose combination (FDC) is bioequivalent to concurrently administered monotherapies, with tolerability and safety consistent with the individual monotherapies, according to a study published in Clinical Therapeutics.
Combination therapy with ambrisentan and tadalafil has been shown to be more effective for the prevention of clinical failure events in patients with pulmonary arterial hypertension than either drug alone. The aim of this randomized, 3-part, single-dose, open-label, 5-way crossover study was to evaluate the bioequivalence of 4 FDC formulations of ambrisentan and tadalafil compared with the coadministration of the 2 monotherapies. The first part of the study assessed the bioavailability of 4 candidate FDCs and the reference monotherapies. The second part assessed the bioavailability of 3 different granulation sizes (FG1-FG3). The third part of the study assessed whether the FDC candidate from part 2 (FG1) was bioequivalent to co-administered 10-mg ambrisentan + 40-mg tadalafil monotherapies taken in both the fasted and fed states. Safety and tolerability were also assessed.
Of the 174 screened study participants, 112 were randomly assigned to treatment across all 3 parts of the study, and 100 completed the full scope of assigned treatments. In part 1, all 4 FDC formulations yielded similar pharmacokinetic parameters (Cmax, AUC0e∞, and AUC0—t) to the reference treatments. Granulation size was shown to not affect relative bioavailability in part 2 of the study. In part 3, the coadministration of the monotherapies in both the fasted and fed states produced pharmacokinetic parameters within the bioequivalence range (90% CI) of the selected ambrisentan/tadalafil FDC. A total of 99 participants (88%) reported an adverse event, and all but one were of mild to moderate intensity, with headaches being the most common (reported by 82% of participants).
Study investigators concluded, “This study showed that the proposed ambrisentan and tadalafil FDC formulation is bioequivalent to concurrently administered monotherapies, under both fed and fasted states in healthy volunteers. The safety and tolerability of the FDC are consistent with those of the individual monotherapies. The FDC is therefore a viable alternative to combination therapy with individual agents.”
Disclosures: These studies were all funded by GlaxoSmithKline.
Okour M, Puri A, Chen G, et al. A phase I study to show the relative bioavailability and bioequivalence of fixed-dose combinations of ambrisentan and tadalafil in healthy subjects [published online May 3, 2019]. Clin Ther. doi:10.1016/j.clinthera.2019.04.007