Pharmacokinetic interactions in different combinations of specific pulmonary arterial hypertension treatment

Introduction: Combination therapy of the phosphodiesterase-type 5 inhibitors (PDE-5I) sildenafil (SIL) or tadalafil (TAD) and endothelin receptor antagonists (ERA) bosentan (BOS), ambrisentan (AMB), or macitentan (MAC) may cause mutual interactions in patients with pulmonary arterial hypertension (PAH). Aim of this study was to compare plasma concentrations in PAH patients according to different combination treatments and to identify combinations that cause relevant interactions. Methods: PAH patients receiving a stable combination treatment with ERA and PDE-5I for at least one month were routinely assessed, including demographics, clinical status, and plasma drug concentrations. 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 with values < 1 denoting lower and > 1 higher values than the expected mean. Differences in plasma concentrations between each treatment group were analysed by Wilcoxon rank sum test. Results: 110 patients (75 female, 34% idiopathic/heritable, 57% ≥WHO FC III, mean pulmonary arterial pressure 47 ± 15 mmHg) were included in the study. Results for mean and 95% confidence intervals (CI) of plasma concentrations were BOS-SIL 0.41 CI 0.32 – 0.50 (n = 35), BOS-TAD 0.85 CI 0.51 – 1.2 (n = 8), AMB-SIL 1.23 CI 0.78 – 1.68 (n = 19), AMB-TAD 1.61 CI 1.36 – 1.87 (n = 21), MAC-SIL 1.36 CI 0.97 – 1.74 (n = 22) and MAC-TAD 1.43 CI 0.55 – 2.3 (n = 5). The MOM SIL plasma concentrations were significantly lower when co-administered with BOS than with AMB or MAC (both p < 0.001). MOM plasma concentrations were significantly higher in TAD than in SIL in combination with BOS (p = 0.002) and AMB (0.014), but not with MAC (p = 0.79). Conclusions: The study results suggest that specific combinations of PAH-specific therapies lead to decreased PDE-5I plasma concentrations. The lowest levels were detected in the combination of BOS-SIL treatment. Further, larger scaled investigations are needed to analyse the association with clinical data.