Assessment of potential drug-drug interactions in patients with hereditary angioedema from the ITACA cohort: simulations from a real-life dataset considering Danazol versus Berotralstat

Mauro Cancian^1*Andrea Zanichelli^2,3Dario Cattaneo⁴Antonio Gidaro⁵Riccardo Senter¹Francesco Arcoleo⁶Pietro Andrea Accardo⁶Donatella Bignardi⁷Paolo Borrelli⁸Caterina Colangelo⁹Tiziana De Pasquale¹⁰Davide Firinu¹¹Francesca Perego¹²Massimo Triggiani¹³Giuseppe Spadaro¹⁴Chiara Cogliati⁵Emanuele Bizzi¹⁵Valentina Popescu Janu⁵Maria Domenica Guarino¹⁶Paolina Quattrocchi¹⁷Luisa Brussino¹⁸Oliviero Rossi¹⁹Paola Triggianese²⁰Stefano Agolini²¹FRANCESCO GIARDINO²²Vincenzo Montinaro²³

• ¹Department of Systems Medicine, Allergy Division, University Hospital of Padua, Padua, Italy, Padova, Italy
• ²Department of Biomedical Sciences for Health, University of Milan, Milan, Italy, Milan, Italy
• ³UO di Medicina, Centro Angioedema, I.R.C.C.S. Policlinico San Donato, Milan, Italy, Milano, Italy
• ⁴Unit of Clinical Pathology, Luigi Sacco University Hospital, Milan, Italy, milano, Italy
• ⁵Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy, Milano, Italy
• ⁶UOC di Patologia Clinica e Immunologia, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy, Palermo, Italy
• ⁷Allergology Unit, IRCCS San Martino Polyclinic Hospital, Genoa, Italy, Genova, Italy
• ⁸SSD Dermatologia e Allergologia, Ospedale Beauregard, Aosta, Italy, Aosta, Italy
• ⁹Azienda Sanitaria Locale Di Pescara, Pescara, Italy, Pescara, Italy
• ¹⁰Department of Allergology, University Hospital “Maggiore della Carità” of Novara, Novara, Italy, novara, Italy
• ¹¹Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy, cagliari, Italy
• ¹²Department of Internal Medicine, Istituti Clinici Scientifici Maugeri IRCCS, Milan, Italy, milano, Italy
• ¹³Department of Internal Medicine, Istituti Clinici Scientifici Maugeri IRCCS, Milan, Italy, Salerno, Italy
• ¹⁴Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy, napoli, Italy
• ¹⁵Internal medicine department, Fatebenefratelli and Sacco hospitals, Milan, Italy., Milano, Italy
• ¹⁶Allergy Unit, Hospital of Civitanova Marche, Civitanova Marche, Italy, Civitanova Marche, Italy
• ¹⁷Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, Messina, Italy, Messina, Italy
• ¹⁸Allergy and Clinical Immunology Unit, Department of Medical Sciences, University of Torino & Mauriziano Hospital, Torino, Italy, Torino, Italy
• ¹⁹Immunoallergology Unit, University Hospital of Careggi, Florence, Italy, Firenze, Italy
• ²⁰Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Roma Tor Vergata, Rome, Italy, Roma, Italy
• ²¹Department of Clinical Immunology, Azienda Ospedaliera Universitaria Ospedali Riuniti di Ancona, Ancona, Italy, Ancona, Italy
• ²²Azienda Ospedaliero-Universitaria Policlinico "G.Rodolico-San Marco", Catania, Italy, Catania, Italy
• ²³U.O.C. di Nefrologia e Dialisi, Ospedale Generale Regionale "F. Miulli", Acquaviva delle Fonti (BA)., Acquaviva delle Fonti (BA), Italy

BackgroundDanazol is regularly used as a prophylactic treatment in patients with Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH). However, this drug is characterized by a risk of drug-drug interactions (DDIs). Berotralstat, the first oral kallikrein inhibitor, has been recently approved for the prevention of HAE attacks. Here, we sought to compare the risk of potential DDIs in real-life HAE patients hypothetically given Danazol or Berotralstat.MethodsOur clinic's database was retrospectively reviewed to identify patients diagnosed with HAE who were treated with at least one concomitant medication. The DDIs were assessed using three freely available drug interaction checkers and scored based on their severity. The agreement between the three drug checkers was evaluated using weighted Cohen’s kappa coefficient. Results75 HAE patients (64% female, mean age 56±21 years) were considered. They were mainly treated with antihypertensives (37%), hypoglycemic (19%), and hypolipemic agents (17%). Significant discrepancies among the three-drug interaction checkers were found. The first checker identified 18 potential DDIs, all involving Danazol and a statin (simvastatin). The second checker identified, respectively, 66 and 14 DDIs for Danazol (20% severe, regarding Simvastatin and Rivaroxaban) and Berotralstat (0% severe). The third checker identified 49 and 43 DDIs for Danazol (22% severe, regarding Simvastatin) and Berotralstat (0%).