Effect of Pharmacologic Interaction Between ERAs and PDE-5 Inhibitors on Medication Serum Levels and Clinical Disease Status in Patients With PAH

The development of disease-targeted medication for the treatment of pulmonary arterial hypertension (PAH) has significantly improved within the last years, leading to the development of 10 approved agents. Combination treatment with Endothelin-Receptor-Antagonists (ERA) and Phosphodiesterase-Type-5-Inibitors (PDE-5-Inhibitor) has become increasingly important for the treatment of PAH. In a recent press release, the results of the AMBITION study reported that an upfront combination treatment immediately after diagnosis leads to a delayed disease progression \[4\]. Thus, the question if there is a clinically relevant pharmaco-dynamic drug-drug interaction is of rising interest.

Mechanisms of action Three ERAs have been approved for the treatment of PAH including the dual inhibitors Bosentan and Macitentan and the selective Endothelin Receptor type A inhibitor (ETA-Inhibitor) Ambrisentan. The dual antagonists inhibit both ETA- and the type B (ETB)-receptor, while the selective antagonist only affects the ETA-receptor \[2\]. The physiologic ligand of the receptors is Endothelin-1, which binds to the ETA-receptor and causes vasoconstriction and proliferation of the vascular smooth muscle cells. The binding to the ETB-receptor leads to an endogenous production of NO and prostacyclin in the endothelial cells.

PDE-5-Inhibitors include the two substances Sildenafil and Tadalafil. They inhibit the degradation of cyclic guanosine monophosphate (cGMPs), which triggers the vasodilative effect of endothelial NO.

Interaction There is evidence for the pharmacokinetic interaction (inhibition / induction of critical targets of drug metabolism and drug distribution) of both substance classes: the PDE-5-Inhibitors Sildenafil and Tadalafil are mainly eliminated in the liver by the hepatic enzyme Cytochrom-P450-Oxygenase type 3A4 (CYP3A4). The dual inhibitor Bosentan is both a substrate and an inductor of the Cytochrom-P450-Oxydase type 3A4 and type 2C9 \[5,6\].

It has already been shown in an in vivo-study, that simultaneous application of PDE-5-Inhibitors and Bosentan leads to a systemic reduction of the PDE-5-Inhibitor concentration of 40%, due to the CYP3A4-inducing effect of Bosentan \[5\]. Sildenafil, in contrast, leads to a decreased degradation of Bosentan in the liver with an approximately 50% increase in plasma leves. An anticipated result, especially when higher dosages of Sildenafil are applied, is the accumulation of Bosentan and reduction of Sildenafil levels.

A recent in vitro-study has shown that Tadalafil may also serve as CYP3A4-inductor, while this effect has not been detected for Sildenafil \[7\].

In contrast Macitentan which has been approved in 2013, has no clinically relevant CYP3A4-inducing effects. \[8\]. The in vitro-study has also detected a further interaction between ERAs and PDE-5-Inhibitors. Both PDE-5-Inhibitors Sildenafil and Tadalafil affect the transport molecules organic anion transporting polypeptides (OATPs), which are responsible for the hepatocellular intake of the dual ERA Bosentan. They also had a mild effect on the intake of Ambrisentan.

Sildenafil is a potent inhibitor of OATPs, whereas Tadalafil shows only minor inhibition of OATPs \[7\]. Both Sildenafil and Tadalafil significantly reduce the intracellular concentration of Bosentan in the liver, leading to a reduced degradation of Bosentan. For Ambrisentan this effect seemed to be less pronounced \[7\]. Consequently, this mechanisms of action lead to higher ERA-levels and to decreased PDE-5-Inhibitor plasma concentrations in patients receiving combination treatment. The most distinct interaction is expected for the combination of Sildenafil (PDE-5-Inhibitor) and Bosentan (ERA).

Up to now, the prevalence and role of this pharmacokinetic interaction for the clinical status and progression of the disease is not clear. Respective combination treatments have only been investigated in healthy male volunteers so far \[5,9\].

Eligibility Criteria:
Inclusion Criteria:

1. Men and women ≥ 18 years old
2. Diagnosis of PAH according to ESC/ERS-guidelines: patients with manifest pulmonary arterial hypertension, mean pulmonary arterial pressure ≥25mmHg, measured by right heart catheterization.
3. Combination treatment with ERA (Bosentan, Ambrisentan or Macitentan) and PDE-5-Inhibitor (Sildenafil or Tadalafil) for more than 3 months.

Exclusion Criteria:

1. Underage patients
2. Pregnancy or lactation