Plasma drug-concentrations in patients with pulmonary arterial hypertension on combination treatment

Introduction: Combination therapy of the phosphodiesterase-type 5 inhibitors (PDE-5i) sildenafil or tadalafil and endothelin receptor antagonists bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH). The objective of this study was to analyse plasma drug concentrations in PAH-patients during different combination treatments. Methods: PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least one month were routinely assessed, including clinical parameters and plasma drug concentrations. Plasma concentrations were measured at trough before the second daily dose was taken. Time, type and dosage of last medication intake were documented. Plasma concentrations were normalised considering dose and time from last medication intake and presented as multiples of the expected mean (MOM) of the respective monotherapies. Differences in plasma concentrations between each treatment group were analysed by Wilcoxon rank sum test. Results: 125 patients (84 female, 57% idiopathic/heritable, mean pulmonary arterial pressure 47 ± 15 mmHg) were included. Mean PDE-5i plasma concentrations were significantly lower when co-administered with bosentan than with ambrisentan or macitentan (both p < 0.001). Patients receiving sildenafil-bosentan who performed clinically indicated transition to macitentan or ambrisentan showed a significant increase in sildenafil concentrations (p < 0.001). Conclusions: Only the combination with macitentan or ambrisentan treatment led to sufficient mean PDE-5i plasma concentrations and should therefore be preferred to bosentan. The study was not powered to analyse if lower PDE-5i concentrations cause unsatisfying clinical response or clinical worsening. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.