Assessment of Vedolizumab Disease‐Drug‐Drug Interaction Potential in Patients With Inflammatory Bowel Diseases

Abstract

Disease‐drug‐drug interactions (DDDIs) have been identified in some inflammatory diseases in which elevated proinflammatory cytokines can downregulate the expression of cytochrome P450 (CYP) enzymes, potentially increasing systemic exposure to drugs metabolized by CYPs. Following anti‐inflammatory treatments, CYP expression may return to normal, resulting in reduced drug exposure and diminished clinical efficacy. Vedolizumab has a well‐established positive benefit‐risk profile in patients with ulcerative colitis (UC) or Crohn's disease (CD) and has no known systemic immunosuppressive activity. A stepwise assessment was conducted to evaluate the DDDI potential of vedolizumab to impact exposure to drugs metabolized by CYP3A through cytokine modulation. First, a review of published data revealed that patients with UC or CD have elevated cytokine concentrations relative to healthy subjects; however, these concentrations remained below those reported to impact CYP expression. Exposure to drugs metabolized via CYP3A also appeared comparable between patients and healthy subjects. Second, serum samples from patients with UC or CD who received vedolizumab for 52 weeks were analyzed and compared with healthy subjects. Cytokine concentrations and the 4β‐hydroxycholesterol‐to‐cholesterol ratio, an endogenous CYP3A4 biomarker, were comparable between healthy subjects and patients both before and during vedolizumab treatment. Finally, a medical review of postmarketing DDDI cases related to vedolizumab from the past 6 years was conducted and did not show evidence of any true DDDIs. Our study demonstrated the lack of clinically meaningful effects of disease or vedolizumab treatment on the exposure to drugs metabolized via CYP3A through cytokine modulation in patients with UC or CD.

Risk assessment of drug–drug interaction potential for bintrafusp alfa with cytochrome P4503A4 substrates: A totality of evidence approach

“…In this data set, baseline cytokine or 4β‐hydroxycholesterol levels (Tables S2 and S3 ) appeared to overlap with the ranges reported in healthy patients. 13 , 20 , 21 The only cytokine with evidence of transient (2.4‐fold) increase was IFN‐ɣ, which had decreased toward the baseline by 2 weeks after the dose. No modulation of any other inflammatory cytokines was observed with bintrafusp alfa.…”

“…11 Studies of other therapeutic proteins have used profiling of proinflammatory cytokines to exclude potential perpetrator DDIs and eliminate the need for clinical DDI assessment. 12,13 Clinical safety data, together with population PK assessments, have indicated a low risk of victim DDI for bintrafusp alfa as monotherapy or in combination with chemotherapeutics, thus enabling the design of multiple combination phase II and III clinical trials NCT02517398, NCT04066491, and NCT03840915. 14,15 Bintrafusp alfa has a unique mechanism of action and is a direct cytokine modulator via neutralization of TGFβ.…”

The Role of CYP3A in Health and Disease

“…In colon biopsy samples from patients with ulcerative colitis and patients with Crohn’s disease, a DNA microarray analysis has uncovered broad suppression of genes involved in drug metabolism; this dysregulation is accompanied by pronounced downregulation of PXR [ 418 ]. Some authors have compared serum levels of proinflammatory cytokines and pharmacokinetic parameters of drugs–substrates of CYP3A enzymes between healthy individuals and patients with ulcerative colitis or Crohn’s disease [ 419 , 420 ]; it has been demonstrated there that higher baseline serum levels of proinflammatory cytokines (TNF, IL-1β, IL-6, and IL-8) in the patients do not cause a change in CYP3A4 activity, as evidenced by the pharmacokinetic parameters of the drugs–substrates of CYP3A enzymes in such patients. Those researchers concluded that inflammatory bowel disease does not elevate the production of proinflammatory cytokines to the clinically significant levels that could alter pharmacokinetics of drugs–substrates of CYP3A enzymes [ 419 , 420 ].…”

“…Some authors have compared serum levels of proinflammatory cytokines and pharmacokinetic parameters of drugs–substrates of CYP3A enzymes between healthy individuals and patients with ulcerative colitis or Crohn’s disease [ 419 , 420 ]; it has been demonstrated there that higher baseline serum levels of proinflammatory cytokines (TNF, IL-1β, IL-6, and IL-8) in the patients do not cause a change in CYP3A4 activity, as evidenced by the pharmacokinetic parameters of the drugs–substrates of CYP3A enzymes in such patients. Those researchers concluded that inflammatory bowel disease does not elevate the production of proinflammatory cytokines to the clinically significant levels that could alter pharmacokinetics of drugs–substrates of CYP3A enzymes [ 419 , 420 ]. Nonetheless, examination of intestinal biopsy samples from people with and without Crohn’s disease and quantification of CYP3A4 expression by Western blotting indicate a significant decrease in protein expression of CYP3A4 in the ileum (by 45%) and colon (by 78%) in subjects with Crohn’s disease relative to subjects without it [ 421 ].…”

Not your usual drug‐drug interactions: Monoclonal antibody–based therapeutics may interact with antiseizure medications

“…In one study, CYP3A4 activity was not modulated in patients with inflammatory bowel diseases treated with vedolizumab. 62…”