Prophylaxis and treatment of angioedema
The invention relates to a bradykinin (BK) B2-receptor antagonist having structural formula (I) for use in prophylactic treatment of angioedema (AE) or in a method of treating AE, wherein said compound is at least once orally administered in a therapeutically effective dose to prevent, alleviate or treat AE symptoms. This invention also provides a method of prophylactic treatment of a human patient suffering from AE or a method for on-demand treatment of a human patient who has experienced an acute AE attack, comprising orally administering to the human patient a therapeutically effective dose of the compound of formula (I) at least once to thereby alleviate or treat AE symptoms of the patient.
1 . A method of treating or preventing a bradykinin-mediated disorder in a human comprising orally administering to the human with a bradykinin-mediated disorder a compound having the following structural formula (I):
or a pharmaceutically acceptable salt, or solvate thereof:
at a dose of 10 to 50 mg of the compound having structural formula (I), wherein the bradykinin-mediated disorder is angioedema (AE), and wherein the compound is administered on-demand, daily, or both.
2 . The method of claim 1 , wherein the angioedema (AE) is hereditary angioedema (HAE), acquired angioedema (AAE), bradykinin-mediated non-histaminergic idiopathic angioedema, allergic angioedema, or drug-induced angioedema, or bradykinin-mediated angioedema of unidentified cause.
3 . The method of claim 2 , wherein treating or preventing HAE comprises reducing the frequency of HAE attacks, reducing the severity of HAE attacks, the prevention of recurrent attacks of HAE, improving the quality of life, reducing or eliminating the need for additional standard of care treatments for HAE, reducing the need to discontinue other treatment due to HAE, or combinations thereof.
4 . The method of claim 3 , wherein preventing HAE comprises the prevention of recurrent attacks of HAE and the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered daily.
5 . The method of claim 4 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered once per day or two times daily.
6 . The method of claim 4 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered two times daily, wherein each dose is spaced at least 4 hours apart, at least 6 hours apart, at least 8 hours apart, at least 10 hours apart, or at least 12 hours apart.
7 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered at a daily dose that provides a C 12h blood or blood plasma level of the compound of at least 10 ng/ml, at least 15 ng/mL, at least 20 ng/ml, at least 25 ng/ml, at least 30 ng/ml, at least 35 ng/ml, at least 40 ng/ml, at least 45 ng/ml or at least 50 ng/mL.
8 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered at a daily dose that provides a threshold blood plasma level of at least 10 ng/ml, at least 15 ng/ml, at least 20 ng/ml, at least 25 ng/mL, at least 30 ng/ml, at least 30 ng/ml, at least 35 ng/ml, or at least 50 ng/ml; and a trough blood plasma level greater than 10 ng/ml, 15 ng/mL, or 20 ng/mL.
9 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily at dose equivalent to an amount of the compound of 10 to 50 mg.
10 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered at least two times daily, wherein each dose comprises an amount of the compound equivalent to 10 to 30 mg.
11 . The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt, or solvate thereof, is administered in the form of an oral solution, oral dispersion, oral suspension or a solid oral dosage form.
12 . The method of claim 1 , wherein the method further comprises co-administration of at least one additional therapeutic agent.
13 . The method of claim 12 , wherein the at least one additional therapeutic agent is co-administered concurrently, sequentially, alternatingly or separately.
14 . The method of claim 12 , wherein the additional therapeutic agent is a CYP3A4 inhibitor, or a pharmaceutically acceptable salt, or solvate thereof.
15 . The method of claim 14 , wherein the CYP3A4 inhibitor is selected from the group comprising itraconazole, clarithromycin, erythromycin, telithromycin, nefazodone, voriconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, cobicistat, troleandomycin, telaprevir, danoprevir, elvitegravir, mifepristone, mibefradil, LCL161, posaconazole, grapefruit juice DS, ceritinib, conivaptan, tucatinib, ribociclib, idelalisib and boceprevir, or a pharmaceutically acceptable salt, or solvate thereof.
16 . A kit containing: (i) a pharmaceutical unit dosage composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt, or solvate thereof; and (ii) a pharmaceutical unit dosage composition comprising a therapeutically effective amount of a CYP3A4 CYP34A inhibitor, or a pharmaceutically acceptable salt, or solvate thereof.
17 . The kit of claim 16 , wherein the CYP3A4 inhibitor is selected from the group comprising itraconazole, clarithromycin, erythromycin, telithromycin, nefazodone, voriconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, cobicistat, troleandomycin, telaprevir, danoprevir, elvitegravir, mifepristone, mibefradil, LCL161, posaconazole, grapefruit juice DS, ceritinib, conivaptan, tucatinib, ribociclib, idelalisib and boceprevir, erythromycin, fluconazole, atazanavir/ritonavir, darunavir, ACT-539313, duvelisib diltiazem, darunavir/ritonavir, dronedarone, crizotinib, atazanavir, fedratinib, letermovir, GSK2647544, aprepitant, lefamulin, casopitant, amprenavir, faldaprevir, imatinib, verapamil, ravuconazole, netupitant, nilotinib, istradefylline, grapefruit juice tofisopam, cyclosporine, ACT-178882, ciprofloxacin, voxelotor, Magnolia vine ( Schisandra sphenanthera ), isavuconazole, cimetidine,FK1706, fenebrutinib, tabimorelin, amlodipine, rimegepant, ranolazine, breviscapine, lomitapide, fosaprepitant (IV), Seville orange ( Citrus aurantium ) juice, amiodarone, larotrectinib, diosmin, chlorzoxazone, M100240, fluvoxamine, ranitidine, goldenseal, clotrimazole, olaparib, tacrolimus,ASP8477, palbociclib, cilostazol, ticagrelor, peppermint oil, ivacaftor, GSK2248761, Guan Mai Ning, entrectinib, osilodrostat, AZD2327, piperine resveratrol, roxithromycin, suvorexant, propiverine, isoniazid, berberine, hormonal contraceptives, delavirdine, daclatasvir, simeprevir, SCY-078 (MK-3118), atorvastatin, tolvaptan, rucaparib, almorexant, GSK1292263, evacetrapid, linagliptin, grazoprevir (ingredient of Zepatier), lacidipine, cranberry juice, pazopanib, fostamatinib, everolimus, blueberry juice, flibanserin, lapatinib, brodalumab, AMD070, alprazolam, Tong Xin Luo, glecaprevir and pibrentasvir, bicalutamide, sitaxentan, azithromycin, lumateperone, obeticholic acid, ginkgo, teriflunomide, or a pharmaceutically acceptable salt, or solvate thereof.