S0876 Assessment of Vedolizumab Disease-Drug-Drug Interaction in Patients With Inflammatory Bowel Diseases

Abstract

INTRODUCTION: Disease-drug-drug interactions (DDIs) have been identified in some inflammatory diseases where elevated proinflammatory cytokines can downregulate the expression of cytochrome P450 (CYP) enzymes, potentially increasing the systemic exposure of drug substrates metabolized by CYPs. Several monoclonal antibodies for treating inflammatory conditions that impact cytokines have been reported to normalize CYP expression and thereby reduce exposure to drug substrates. Vedolizumab (VDZ) has a well-established, positive benefit-risk profile in patients with ulcerative colitis (UC) or Crohn’s disease (CD). VDZ has no known systemic immunosuppressive activity and is not regarded as a direct cytokine modulator. METHODS: A stepwise assessment was conducted to evaluate the DDI potential for VDZ to impact exposure to CYP substrates through cytokine modulation. First, a literature review was performed to assess cytokine concentrations and the exposure of commonly used medications metabolized by CYPs (corticosteroids and immunosuppressants) in patients with UC or CD vs healthy controls. Next, concentrations of cytokines and a surrogate biomarker of CYP3A4 activity (ratio of 4β-hydroxycholesterol to cholesterol [4β-OHC/C]) were analyzed in VDZ-treated patients vs healthy controls. Finally, a medical review of the Takeda VDZ global safety database was conducted on 5 years of VDZ postapproval data to evaluate any evidence of true DDI. RESULTS: The literature review showed that patients with UC or CD had statistically significantly elevated cytokine concentrations relative to healthy controls; however, these concentrations remained below published levels that could impact CYP expression. Exposure to medications metabolized via CYP3A was comparable between patients and healthy controls. Cytokine concentrations—except for IFN-γ, which was used to verify the active disease status of patients—and 4β-OHC/C were comparable between healthy controls and patients both before and during VDZ treatment (Tables 1 and 2). A total of 22 adverse event reports of suspected DDIs were identified in the VDZ global safety database search. Medical adjudication of these cases did not reveal any relationship to VDZ DDIs. CONCLUSION: There is a lack of clinically meaningful effect of UC or CD on the exposure of CYP substrate drugs resulting from cytokine modulation. VDZ treatment also did not affect CYP activity, indicating minimal risk of DDIs with VDZ in patients with UC or CD.Table 1.: Cytokine Concentrations With 24-Month Expiry in Patients With UC or CD and Healthy ControlsTable 2.: Cytokine Concentrations With 19-Month Expiry in Patients With CD and Healthy Controls