DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



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 window

Frequency 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

Page last updated: August 23, 2015

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017