WO2004017993A1 - Combinaison de prostacycline ou d'analogues de la prostacycline, et d'antagonistes du recepteur de l'endotheline pour le traitement de l'hypertension arterielle pulmonaire - Google Patents

Combinaison de prostacycline ou d'analogues de la prostacycline, et d'antagonistes du recepteur de l'endotheline pour le traitement de l'hypertension arterielle pulmonaire Download PDF

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Publication number
WO2004017993A1
WO2004017993A1 PCT/EP2003/008122 EP0308122W WO2004017993A1 WO 2004017993 A1 WO2004017993 A1 WO 2004017993A1 EP 0308122 W EP0308122 W EP 0308122W WO 2004017993 A1 WO2004017993 A1 WO 2004017993A1
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WO
WIPO (PCT)
Prior art keywords
prostacyclin
epoprostenol
bosentan
endothelin receptor
pulmonary arterial
Prior art date
Application number
PCT/EP2003/008122
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English (en)
Inventor
Frederic Bodin
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2004017993A1 publication Critical patent/WO2004017993A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention relates to pharmaceutical compositions for the treatment of pulmonary arterial hypertension one containing a prostacyclin or a prostacyclin analogue and the other an endothelin receptor antagonist, characterised in that the side effects of the prostacyclin or the prostacyclin analogue are strongly reduced by the concomitant administration of the prostacyclin or the prostacyclin analogue and the endothelin receptor antagonist.
  • Pulmonary hypertension is a disease defined by a progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right ventricular failure and death. Pulmonary hypertension is associated with endothelial dysfunction, characterized by a decreased expression of the vasodilators nitric oxide and prostacyclin, and by an increased expression of the growth factor and vasoconstrictive substance endothelin-1 and its receptors.
  • Prostacyclin and prostacyclin analogues such as epoprostenol, treprostinil, iloprost, beraprost significantly improve hemodynamic parameters and clinical cyrr.ptoms in patients with pulmonary arterial hypertension.
  • the major mechanism of action of prostacyclin and prostacyclin analogues is vasodilation, whereas improvement in pulmonary vascular hypertrophy and inhibition of platelet aggregation may also play a role.
  • the use of prostacyclin or prostacyclin analogues is associated with a number of side effects such as jaw pain, headaches, flushing, tachycardia and systemic hypotension.
  • Endothelin receptor antagonists such as bosentan (4-tert-butyl-N-[6-(2- hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzene- sulfonamide) are also efficacious in the treatment of pulmonary arterial hypertension.
  • Bosentan improves hemodynamic parameters (cardiac index, pulmonary artery pressure, pulmonary vascular resistance), increases exercise capacity, improves WHO functional class, and decreases the rate of clinical worsening in patients with pulmonary arterial hypertension.
  • Bosentan does not significantly modify heart rate or mean arterial blood pressure in patients with pulmonary arterial hypertension.
  • Endothelin receptor antagonists are competitive antagonism of the binding of ET-1 on ET receptors, thereby decreasing pulmonary vasoconstriction and vascular remodelling.
  • Endothelin receptor _ ⁇ tagonists by their inhibition of the endothelin system, further inhibit the activation of other neurohormonal systems, and in particular reduce sympathetic nerve activity, decrease catecholamine concentrations and blunt reactive tachycardia in response to a decrease in blood pressure.
  • bosentan and a prostacyclin especially epoprostenol (5Z, 9 alpha, 11alpha, 13E, 15S)-6,9-Epoxy-11 ,15-dihydroxyprosta-5,13-dien-1-oic acid, sodium salt [compare also US Patent 4,539,333], has been evaluated in a clinical study.
  • the authors, (compare Am J Respir Crit Care Med Vol 165. pp1209-1216, 2002), who were running on behalf of Actelion Pharmaceuticals Ltd the clinical trials of the combination of these two drugs, speculated that tnis combination may have additional efficacy. The outcome of the trial was, however, entirely unexpected.
  • the basis of the present application is the unexpected finding in the clinical trial initiated and supervised by Actelion Pharmaceuticals Ltd that the combination of bosentan with epoprostenol not only has additional efficacy, but also decreases the risk of side effects related to epoprostenol considerably. Indeed, in patients treated with bosentan and epoprostenol, there were fewer reported cases of jaw pain, headaches and systemic hypotension, a lesser decrease in blood pressure and a lesser increase in heart rate as compared to patients treated with epoprostenol alone.
  • compositions for the treatment of pulmonary arterial hypertension one containing epoprostenol and the other bosentan, characterised in that the side effects of epoprostenol are strongly reduced by the concomitant administration of epoprostenol and bosentan or by preferably administering bosentan within a time frame of ninety six hours after epoprostenol has been administered.
  • the dose of the prostacyclin may vary between 1 ng/kg/min and 250 ng/kg/min depending on the length it has been already administered.A preferred dose range is 2 ng/kg/min. With increasing time the dose is increased.
  • a preferred use of the pharmaceutical compositions resides in administering for two days 2 ng/kg/min, then increasing every two weeks the dose by 2 ng/kg/min up to the preferred target dose of 14 ⁇ 2 ng/kg/min. After the first two days of treatment with prostacyclin or an analogue bosentan is administered twice a day at a dose of either 62,5 mg or 125 mg.
  • a dose range for the prostacyclin of 0,01 to 200 mg per kilogram bodyweight, conveniently 0,01 to 10 mg per kilogram, is used.
  • the dose range for the endothelin antagonist may be 0,01 mg to 10 mg per kilogram bodyweight, conveniently 0,5 mg to 3,0 mg per kilogram bodyweight.
  • the preparation of a pharmaceutical composition containing a prostacyclin has been described in US Patent No. 4,539,333 and is incorporated by reference.
  • Study design The duration of the study was 16 weeks, 2:1 bosentan:placebo randomization. All patients received the starting epoprostenol dose of 2 ng/kg/min for 2 days, then they were randomized i ⁇ either bosentan or placebo. Every 2 weeks thereafter, epoprostenol was increased 2 ng/kg/min up to the target dose of 14 ⁇ 2 ng/kg/min by week 16. All patients received epoprostenol together with either bosentan or placebo for 16 weeks. Hemodynamic assessments were performed at baseline (prior to start of therapy) and again after 16 weeks of therapy. Safety monitoring was performed throughout the study duration.
  • TPR total pulmonary resistance
  • Secondary endpoints Changes from baseline to week 16 in Cl (Cardiac Index), PVR (Pulmonary Vascular Resistance), mPAP (mean pulmonary arterial pressure), and mRAP (mean right atrial pressure); changes from baseline to week 16 in walk distance (6-min walk test), dyspnea fatigue rating, WHO functional class; and safety and tolerability.
  • the results show a positive trend toward an improvement in hemodynamic parameters, specifically increase in Cardiac Index (Cl) and decreases in Total Pulmonary Resistance (TPR), mean Pulmonary Arterial Pressure (mPAP) and mean Right Atrial Pressure (mRAP), in patients who received bosentan with epoprostenol compared to those who received epoprostenol alone.
  • TPR Total Pulmonary Resistance
  • mPAP mean Pulmonary Arterial Pressure
  • mRAP mean Right Atrial Pressure
  • HYPOTENSION 2 18.2% - The combination of bosentan with epoprostenol or any other prostacyclin analogs leads to an additional efficacy and less prostanoid-related side effects.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques pour le traitement de l'hypertension artérielle pulmonaire. Une de ces compositions contient une prostacycline ou un analogue de prostacycline, de préférence de l'époprosténol, et l'autre contient un antagoniste du récepteur de l'endothéline, de préférence du bosentane. L'invention concerne également l'utilisation concomitante de ces compositions pour réduire les effets secondaires de la prostacycline ou des analogues de la prostacycline.
PCT/EP2003/008122 2002-08-12 2003-07-24 Combinaison de prostacycline ou d'analogues de la prostacycline, et d'antagonistes du recepteur de l'endotheline pour le traitement de l'hypertension arterielle pulmonaire WO2004017993A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP02/09024 2002-08-12
EP0209024 2002-08-12

Publications (1)

Publication Number Publication Date
WO2004017993A1 true WO2004017993A1 (fr) 2004-03-04

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/008122 WO2004017993A1 (fr) 2002-08-12 2003-07-24 Combinaison de prostacycline ou d'analogues de la prostacycline, et d'antagonistes du recepteur de l'endotheline pour le traitement de l'hypertension arterielle pulmonaire

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WO (1) WO2004017993A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008088617A1 (fr) * 2006-12-04 2008-07-24 Regents Of The University Of Colorado Traitement de la broncho-pneumopathie chronique obstructive
WO2009009561A1 (fr) * 2007-07-11 2009-01-15 Lexicon Pharmaceuticals, Inc. Procédés et compositions de traitement d'hypertension pulmonaire et de maladies et de troubles apparentés
WO2009152160A1 (fr) * 2008-06-10 2009-12-17 Gilead Sciences, Inc. Promédicaments inhalés à base de carbaprostacyclines et de prostacyclines destinés au traitement de l'hypertension artérielle pulmonaire
WO2010018549A2 (fr) * 2008-08-13 2010-02-18 Actelion Pharmaceuticals Ltd Compositions thérapeutiques contenant du macitentan
US8071596B2 (en) 2007-01-12 2011-12-06 Concert Pharmaceuticals, Inc. Endothelin receptor antagonists
US8080549B2 (en) 2007-01-12 2011-12-20 Concert Pharmaceuticals, Inc. Endothelin receptor antagonists
US8623917B2 (en) 2005-06-02 2014-01-07 The Regents Of The University Of Colorado, A Body Corporate Uses of prostacyclin analogs
US11069054B2 (en) 2015-12-30 2021-07-20 Visiongate, Inc. System and method for automated detection and monitoring of dysplasia and administration of immunotherapy and chemotherapy

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHANNICK, R.N.; RUBIN, J.L.: "New and experimental therapies for pulmonary hypertension", CLINICS IN CHEST MEDICINE, vol. 22, no. 3, 1 September 2001 (2001-09-01), pages 539 - 545, XP009017847 *
CHANNICK, R.N.; RUBIN, L.J.: "Combination therapy for pulmonary hypertension: a glimpse into the future?", CRITICAL CARE MEDICINE, vol. 28, no. 3, 2000, pages 896 - 897, XP009017850 *
HOEPER, M.M.; NAZZARENO, G.; SIMONNEAU, G.; RUBIN, J.L.: "New treatments for pulmonary hypertension", AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 165, 1 May 2002 (2002-05-01), pages 1209 - 1216, XP002255303 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8623917B2 (en) 2005-06-02 2014-01-07 The Regents Of The University Of Colorado, A Body Corporate Uses of prostacyclin analogs
WO2008088617A1 (fr) * 2006-12-04 2008-07-24 Regents Of The University Of Colorado Traitement de la broncho-pneumopathie chronique obstructive
US8071596B2 (en) 2007-01-12 2011-12-06 Concert Pharmaceuticals, Inc. Endothelin receptor antagonists
US8080549B2 (en) 2007-01-12 2011-12-20 Concert Pharmaceuticals, Inc. Endothelin receptor antagonists
AU2008275179B2 (en) * 2007-07-11 2013-09-12 Lexicon Pharmaceuticals, Inc. Methods and compositions for treating pulmonary hypertension and related diseases and disorders
US8410121B2 (en) 2007-07-11 2013-04-02 Lexicon Pharmaceuticals, Inc. Methods of treating pulmonary hypertension
WO2009009561A1 (fr) * 2007-07-11 2009-01-15 Lexicon Pharmaceuticals, Inc. Procédés et compositions de traitement d'hypertension pulmonaire et de maladies et de troubles apparentés
US7875622B2 (en) 2007-07-11 2011-01-25 Lexicon Pharmaceuticals, Inc. Methods and compositions for treating pulmonary hypertension and related diseases and disorders
WO2009152160A1 (fr) * 2008-06-10 2009-12-17 Gilead Sciences, Inc. Promédicaments inhalés à base de carbaprostacyclines et de prostacyclines destinés au traitement de l'hypertension artérielle pulmonaire
WO2010018549A2 (fr) * 2008-08-13 2010-02-18 Actelion Pharmaceuticals Ltd Compositions thérapeutiques contenant du macitentan
WO2010018549A3 (fr) * 2008-08-13 2010-07-29 Actelion Pharmaceuticals Ltd Compositions thérapeutiques contenant du macitentan
US20110136818A1 (en) * 2008-08-13 2011-06-09 Martine Clozel Therapeutic compositions containing macitentan
TWI446911B (zh) * 2008-08-13 2014-08-01 Actelion Pharmaceuticals Ltd 含美西特田（ｍａｃｉｔｅｎｔａｎ）之治療組合物
US8809334B2 (en) * 2008-08-13 2014-08-19 Actelion Pharmaceuticals Ltd. Therapeutic compositions containing macitentan
AU2009280843B2 (en) * 2008-08-13 2015-03-05 Actelion Pharmaceuticals Ltd Therapeutic compositions containing macitentan
US9173881B2 (en) 2008-08-13 2015-11-03 Actelion Pharmaceuticals Ltd. Therapeutic compositions containing macitentan
US9597331B2 (en) 2008-08-13 2017-03-21 Actelion Pharmaceuticals Ltd. Therapeutic compositions containing macitentan
EP2315587B1 (fr) 2008-08-13 2017-10-25 Actelion Pharmaceuticals Ltd. Compositions thérapeutiques contenant du macitentan
EP3300729A1 (fr) 2008-08-13 2018-04-04 Actelion Pharmaceuticals Ltd Compositions thérapeutiques contenant du macitentan
US11069054B2 (en) 2015-12-30 2021-07-20 Visiongate, Inc. System and method for automated detection and monitoring of dysplasia and administration of immunotherapy and chemotherapy

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