Pharmacokinetic interactions in different combinations of pulmonary arterial hypertension treatment

Introduction: 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 Endothelin-Receptor-Antagonists (ERA) and Phosphodiesterase-type-5 inhibitors (PDE-5I) for ≥1 month were routinely assessed, including demographics, clinical status, and plasma drug concentrations. Plasma concentrations were normalised for dose and time from last medication intake and presented as multiples of the expected mean (MOM) of the respective monotherapies with values 1 higher values than the expected mean. Results: 125 patients (67% female, 34% idiopathic, 57% ≥WHO FC III, mean pulmonary arterial pressure 47±15mmHg) were included in the study. Results for mean and standard deviation of plasma concentrations were Bosentan (BOS)-Sildenafil (SIL) 0.44±0.42 (n=39), BOS-Tadalafil (TAD) 0.89±0.53 (n=7), Ambrisentan (AMB)-SIL 1.3±0.97 (n=19), AMB-TAD 1.67±0.63 (n=21), Macitentan (MAC)-SIL 1.16±0.87 (n=33) and MAC-TAD 1.59±0.99 (n=6). SIL plasma concentrations were significantly lower when co-administered with BOS than with AMB or MAC (both p 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.