title: Assessment of Disease-Related Therapeutic Protein Drug-Drug Interaction for Etrolizumab in Patients With Moderately to Severely Active Ulcerative Colitis.
abstract: The efficacy and safety of etrolizumab, a humanized IgG1 mAb, were evaluated in patients with ulcerative colitis (UC) in a phase 2 study (EUCALYPTUS). The current study assessed the risk of therapeutic protein drug-drug interaction (TP-DDI) of etrolizumab on CYP3A activity in patients with UC. Literature review was performed to compare serum proinflammatory cytokine levels and pharmacokinetic (PK) parameters of CYP3A substrate drugs between patients with inflammatory bowel disease (IBD) and healthy subjects. Treatment effect of etrolizumab on CYP3A activity was evaluated by measuring colonic CYP3A4 mRNA expression and serum C-reactive protein (CRP) in EUCALYPTUS patients. Literature data suggested similar levels between IBD patients and healthy subjects for serum proinflammatory cytokines and PK parameters of CYP3A substrate drugs. Additionally, treatment with etrolizumab did not change colonic CYP3A4 mRNA expression or serum CRP levels in UC patients. In conclusion, our results indicate a low TP-DDI risk for etrolizumab in UC patients, particularly on medications metabolized by CYP3A.
authors.affiliation: Clinical Pharmacology, Genentech, Inc, South San Francisco, CA, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wei
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc, South San Francisco, CA, USA.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.affiliation: Clinical Pharmacology, Genentech, Inc, South San Francisco, CA, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Dickmann
authors.affiliation: Biometrics, Genentech, Inc, South San Francisco, CA, USA.
authors.forename: Romeo
authors.initials: R
authors.lastname: Maciuca
authors.affiliation: Biomarkers, Genentech, Inc, South San Francisco, CA, 94080, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Looney
authors.affiliation: Clinical Pharmacology, Genentech, Inc, South San Francisco, CA, USA.
authors.forename: Meina T
authors.initials: MT
authors.lastname: Tang
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism* / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D038622:Internationality; D011485:Protein Binding / Q000502:physiology; D012720:Severity of Illness Index
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D002097:C-Reactive Protein; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C559198:etrolizumab
keywords: etrolizumab; therapeutic protein drug-drug interaction; ulcerative colitis