Combination Therapy of Pulmonary Arterial Hypertension with Vardenafil and Macitentan Assessed in a Human Ex Vivo Model.

Purpose: Treatment of pulmonary arterial hypertension (PAH) by vasodilator drug monotherapy is often limited in its effectiveness. Combination therapy may help to improve treatment and to reduce drug toxicity. This study assessed the combination of the endothelin receptor antagonist macitentan and the phosphodiesterase-5 inhibitor vardenafil in a human ex vivo model.

Methods: Study patients did not suffer from PAH. Human pulmonary arteries (PA) and veins (PV) were harvested from resected pulmonary lobes. Contractile forces of blood vessel segments in the presence and absence of the vasodilator drugs macitentan, its main metabolite ACT-132577, and vardenafil were determined isometrically in an organ bath.

Results: Macitentan 1E-7 M was sufficient to significantly abate endothelin-1-induced vasoconstriction in PA. A concentration of 1E-6 M was required for significant effects of macitentan on PV and of ACT-132577 on both vessel types. Combination of 1E-7 M macitentan and 1E-6 M vardenafil inhibited sequential constriction with endothelin-1 and norepinephrine of PA significantly more than either compound alone. Effects of 3E-7 M and 1E-6 M macitentan and effects of all doses of ACT-132577 were not further enhanced by 1E-6 M vardenafil.

Conclusions: These data suggest that vasodilator effects of macitentan and vardenafil combined may surpass monotherapy in vivo if drug doses are adjusted properly. Vasodilation by the longer-acting metabolite ACT-132577 was not further enhanced by vardenafil.