P533 Assessment of disease-related therapeutic protein drug-drug interaction (TP-DDI) for etrolizumab in patients with moderately to severely active ulcerative colitis (UC)
X.T. Wei*, J. Kenny, L. Dickmann, R. Maciuca, C. Looney, C. Khojasteh-Bakht, M.T. Tang
Genentech, Clinical Pharmacology, South San Francisco, United States
UC is an inflammatory bowel disease (IBD) representing a chronic inflammatory condition of the colon associated with a dysregulated mucosal immune system. Etrolizumab is a humanized IgG1 monoclonal antibody (mAb) that specifically binds the beta(β)7 subunit of alpha(α)4β7 and αEβ7 integrins. The efficacy and safety of etrolizumab has been evaluated in patients with moderate to severely active UC in a Phase 2 trial (EUCALYPTUS). The objective of this analysis was to evaluate the TP-DDI risk for etrolizumab, a mAb not directly targeting cytokines, in patients with moderately to severely active UC.
This TP-DDI assessment focused on the effect on cytochrome P450 3A (CYP3A), since among the few commonly used medications in IBD that involve CYP metabolic pathways, most are CYP3A substrates. First, the IBD disease effect on CYP-mediated drug metabolism was evaluated by comparing literature pharmacokinetic (PK) data of CYP3A substrate drugs from patients with IBD (UC or Crohn's disease) with that of healthy participants. Second, the etrolizumab effect on CYP3A4 messenger RNA (mRNA) expression level (via quantitative polymerase chain reaction) was evaluated in the colonic biopsy samples collected before and after etrolizumab or placebo treatment in patients with UC from EUCALYPTUS.
Review of the literature data showed similar drug exposure and PK parameters between patients with IBD and healthy participants for prednisolone, budesonide, and cyclosporine. These drugs are substrates of CYP3A and conventionally used as treatment options for patients with IBD. These literature data suggest a low risk of an IBD-related disease-drug interaction for CYP3A substrates. Treatment with etrolizumab did not result in a consistent change in colonic CYP3A4 mRNA expression compared with patients receiving placebo. Additionally, etrolizumab did not show significant treatment effect on C-reactive protein at the targeted therapeutic dose level in patients with UC from the EUCALYPTUS study.
The results from these assessments indicate a low TP-DDI risk for etrolizumab in patients with UC, and in particular, a low impact on the colonic CYP3A4 enzyme.