Effect of Pharmacologic Interaction Between ERAs and PDE-5 Inhibitors on Medication Serum Levels and Clinical Disease Status in Patients With PAH
Information source: Heidelberg University
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pulmonary Arterial Hypertension
Intervention: no intervention, only observation of different groups (Other)
Phase: N/A
Status: Recruiting
Sponsored by: Heidelberg University Official(s) and/or principal investigator(s): Ekkehard Grünig, MD, Principal Investigator, Affiliation: Thoraxclinic at the University Hospital Heidelberg
Overall contact: Ekkehard Grünig, MD, Phone: +496221396, Ext: 8053, Email: ekkehard.gruenig@med.uni-heidelberg.de
Summary
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.
Clinical Details
Official title: Effect of Pharmacologic Interaction Between Endothelin-Receptor-Antagonists and Phosphodiesterase-5 Inhibitors on Medication Serum Levels and Clinical Disease Status in Patients Wih Pulmonary Arterial Hypertension
Study design: Observational Model: Cohort, Time Perspective: Prospective
Primary outcome: Characterisation of medication levels
Secondary outcome: Frequency of borderline medication serum levels or medication levels out of the therapeutic windowFrequency of borderline medication serum levels or medication levels out of the therapeutic window Impact of medication adjustment Subgroup analysis: analysis of medication serum levels in patients with pulmonary arterial hypertension associated with connective tissue disease Clinical relevance WHO functional class Clinical relevance 6 minute walking distance Clinical relevance NTproBNP Clinical relevance Echocardiography systolic pulmonary arterial pressure Clinical relevance Echocardiography right ventricular area Clinical relevance Echocardiography right atrial area Clinical relevance Echocardiography tricuspid annular plane systolic excursion Clinical relevance Echocardiography Tei-index Clinical relevance Echocardiography left ventricular excentricity index Clinical relevance Echocardiography right ventricular pump function Clinical relevance blood gas analysis oxygen partial pressure Clinical relevance blood gas analysis carbon dioxide partial pressure Clinical relevance blood gas analysis oxygen saturation Clinical relevance blood gas analysis oxygen supply Clinical relevance diffusion capacity DLCO Clinical relevance diffusion capacity DLCO/VA Clinical relevance clinical symptoms Clinical relevance adverse events
Detailed description:
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].
Literature
1. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of
pulmonary hypertension. The task force for the diagnosis and treatment of pulmonary
hypertension of the European Society of Cardiology (ESC) and the European Respiratory
Society (ERS), endorsed by the International Society of Heart and Lung Transplantation
(ISHLT). Eur Respir J 2009;34: 1219-63.
2. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. The New
England journal of medicine 2004;351: 1425-36.
3. Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ, Nicolls MR. Pathobiology of pulmonary
arterial hypertension and right ventricular failure. Eur Respir J 2012;40: 1555-65.
4. First-Line Combination of Ambrisentan and Tadalafil Reduces Risk of Clinical Failure
Compared to Monotherapy in Pulmonary Arterial Hypertension Outcomes Study. Gilead
Sciences Inc., 2014. (Accessed 2014-10-13, 2014, at
http://www. gilead. com/news/press-releases/2014/9/firstline-combination-of-ambrisentan-and-tadalafil-reduces-risk-of-clinical-failure-compared-to-monotherapy-in-pulmonary-arterial-hypertension-outcomes-study.)
5. Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic
interaction between tadalafil and bosentan in healthy male subjects. Journal of
clinical pharmacology 2008;48: 610-8.
6. Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma
concentration of sildenafil when coprescribed in pulmonary hypertension. British
journal of clinical pharmacology 2005;60: 107-12.
7. Weiss J, Theile D, Spalwisz A, Burhenne J, Riedel KD, Haefeli WE. Influence of
sildenafil and tadalafil on the enzyme- and transporter-inducing effects of bosentan
and ambrisentan in LS180 cells. Biochemical pharmacology 2013;85: 265-73.
8. Weiss J, Theile D, Ruppell MA, Speck T, Spalwisz A, Haefeli WE. Interaction profile of
macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. European
journal of pharmacology 2013;701: 168-75.
9. Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions
between steady-state bosentan and sildenafil. European journal of clinical pharmacology
2008;64: 43-50.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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
Locations and Contacts
Ekkehard Grünig, MD, Phone: +496221396, Ext: 8053, Email: ekkehard.gruenig@med.uni-heidelberg.de
Centre for pulmonary hypertension, Thoraxclinic at the University Hospital Heidelberg, Heidelberg 69126, Germany; Recruiting Ekkehard Grünig, MD, Phone: +496221396, Ext: 8053, Email: ekkehard.gruenig@med.uni-heidelberg.de
Additional Information
First-Line Combination of Ambrisentan and Tadalafil Reduces Risk of Clinical Failure Compared to Monotherapy in Pulmonary Arterial Hypertension Outcomes Study. Gilead Sciences Inc., 2014. (Accessed 2014-10-13, 2014
Related publications: Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008 Jan;64(1):43-50. Epub 2007 Nov 27.
Starting date: May 2015
Last updated: June 29, 2015
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