Key result
Combination therapy with bosentan resulted in lower sildenafil (MoM 0.44; 95% CI 0.30-0.57) and tadalafil concentrations compared to combinations with ambrisentan or macitentan in PAH patients.
Why the study?
How do different combinations of PDE-5 inhibitors and endothelin receptor antagonists affect plasma drug concentrations in patients with pulmonary arterial hypertension?
Observational (n=125)
How do different combinations of PDE-5 inhibitors and endothelin receptor antagonists affect plasma drug concentrations in patients with pulmonary arterial hypertension?
Combination of PDE-5 inhibitors with macitentan or ambrisentan achieves targeted mean plasma concentrations and avoids the significant pharmacokinetic interactions seen with bosentan.
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.
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Grünig et al. (2017) conducted an observational in Pulmonary arterial hypertension (PAH) (n=125). Combination therapy with PDE-5i (sildenafil or tadalafil) and ERA (bosentan, ambrisentan, or macitentan) vs. Respective monotherapies (expected mean) was evaluated on Plasma drug concentrations presented as multiples of the expected mean (MoM) of the respective monotherapies. Combination therapy with bosentan resulted in lower sildenafil (MoM 0.44; 95% CI 0.30-0.57) and tadalafil concentrations compared to combinations with ambrisentan or macitentan in PAH patients.
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