Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment

Respiration. 2017;94(1):26-37. doi: 10.1159/000470916. Epub 2017 May 12.

Abstract

Background: Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH).

Objective: The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments.

Methods: PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations. Concentrations were normalized considering dose and time from last medication intake and presented as multiples of the expected mean (MoM) of the respective monotherapies.

Results: A total of 125 PAH patients (84 female, 41 male, 57% idiopathic/heritable) were included. Sildenafil and tadalafil concentrations were lowest in combination with bosentan (MoM 0.44 ± 0.42, 95% confidence interval [CI] 0.30-0.57, and MoM 0.89 ± 0.53, 95% CI 0.50-1.28, respectively) compared to the combination with ambrisentan (MoM 1.3 ± 0.97, 95% CI 0.86-1.73, and MoM 1.67 ± 0.63, 95% CI 1.40-1.94, respectively) and macitentan (MoM 1.16 ± 0.87, 95% CI 0.86-1.46, and MoM 1.59 ± 0.99, 95% CI 0.80-2.38, respectively). The combination of sildenafil and bosentan led to more than twice the expected bosentan concentrations in 53.8%. Patients switching from sildenafil-bosentan to macitentan showed a significant increase in sildenafil concentrations (p < 0.001).

Conclusions: Only the combination with macitentan or ambrisentan led to targeted mean PDE-5i plasma concentrations and should therefore be preferred to combination with bosentan. Sildenafil-bosentan showed the strongest interaction, with low sildenafil and high bosentan concentrations. The study was not powered to analyze whether lower PDE-5i concentrations cause unsatisfying clinical response. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.

Keywords: Ambrisentan; Bosentan; Combination therapy; Macitentan; Pulmonary arterial hypertension; Sildenafil; Tadalafil.

MeSH terms

  • Adult
  • Aged
  • Bosentan
  • Case-Control Studies
  • Drug Interactions
  • Drug Therapy, Combination
  • Endothelin Receptor Antagonists / blood*
  • Endothelin Receptor Antagonists / therapeutic use
  • Female
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Male
  • Middle Aged
  • Phenylpropionates / blood*
  • Phenylpropionates / therapeutic use
  • Phosphodiesterase 5 Inhibitors / blood*
  • Phosphodiesterase 5 Inhibitors / therapeutic use
  • Pyridazines / blood*
  • Pyridazines / therapeutic use
  • Pyrimidines / blood*
  • Pyrimidines / therapeutic use
  • Sildenafil Citrate / blood*
  • Sildenafil Citrate / therapeutic use
  • Sulfonamides / blood*
  • Sulfonamides / therapeutic use
  • Tadalafil / blood*
  • Tadalafil / therapeutic use

Substances

  • Endothelin Receptor Antagonists
  • Phenylpropionates
  • Phosphodiesterase 5 Inhibitors
  • Pyridazines
  • Pyrimidines
  • Sulfonamides
  • Tadalafil
  • Sildenafil Citrate
  • ambrisentan
  • Bosentan
  • macitentan