Pneumologie 2016; 70 - P393
DOI: 10.1055/s-0036-1572030

Change of sildenafil plasma concentrations after transition from bosentan to macitentan in pulmonary arterial hypertension

J Ohnesorge 1, B Egenlauf 2, N Benjamin 1, C Fischer 3, Y Enderle 4, J Burhenne 4, A Huppertz 4, A Carls 4, WE Haefeli 4, E Grünig 1
  • 1Zentrum für Pulmonale Hypertonie, Thoraxklinik am Universitätsklinikum Heidelberg
  • 2Pneumologie und Beatmungsmedizin, Thoraxklinik am Universitätsklinikum Heidelberg; Zentrum für Pulmonale Hypertonie
  • 3Institut für Humangenetik, Universität Heidelberg
  • 4Abteilung Klinische Pharmakologie und Pharmakoepidemiologie, Universitätsklinikum Heidelberg

Introduction: Combination therapy of the phosphodiesterase-type 5 (PDE-5) inhibitor sildenafil and the endothelin receptor antagonist (ERA) bosentan may cause drug interactions in patients with pulmonary arterial hypertension (PAH). The objective of this study was to analyse plasma drug concentrations in PAH-patients during bosentan-sildenafil combination treatment and its changes after transition from bosentan to macitentan.

Methods: Patients receiving a stable combination treatment of bosentan and sildenafil for at least one month were routinely assessed in our PAH centre. Routine assessments included demographics, blood collection for assessment of drug plasma concentrations, and clinical data such as WHO functional class (FC). Patients whose ERA treatment was changed were reassessed at their next visit. Plasma concentrations were normalised considering dose and time from last medication intake and presented as multiples of the previously published mean of sildenafil monotherapy with “values < 1” denoting lower and “> 1” higher values than the expected mean. Changes in sildenafil plasma concentrations were analysed by Wilcoxon signed rank test. The study was submitted to the Ethic committee of the University of Heidelberg which had no objections against the trial.

Results: Twenty-one PAH patients (14 females, 53% idiopathic/heritable, 61% WHO FC III, mean pulmonary arterial pressure 57 ± 16 mmHg) receiving bosentan-sildenafil at baseline were switched to macitentan for clinical reasons. Sildenafil plasma concentrations were lower than the expected mean when co-administered with bosentan (0.43 ± 0.32). After transition to macitentan, sildenafil plasma concentrations significantly increased 3.7-fold to 1.6 ± 1.4 (p < 0.001).

Conclusions: This study indicates that transition from bosentan to macitentan leads to significantly higher sildenafil plasma concentrations. Further investigations are needed to detect correlations between plasma concentrations and clinical parameters.