Model-informed Entyvio dosing increases remission in Crohn's
Click Here to Manage Email Alerts
Model-informed dosing of Entyvio provided data to maximize endoscopic remission rates among patients with Crohn’s disease, according to research published in Inflammatory Bowel Diseases.
“Rates of endoscopic remission in patients with CD rarely exceed 30% and it remains unknown whether dosing escalation based on therapeutic drug monitoring could lead to higher rates of endoscopic remission,” Jurij Hanzel, MD, University of Ljubliana Medical Center, Ljubljana, Slovenia, and colleagues wrote. “Although concentrations associated with endoscopic remission have been suggested in real-world studies, an integrated pharmacokinetic-pharmacodynamic (PK-PD) model describing the relationship between dose, concentration and outcome offers the opportunity of individualizing dosing based on patient characteristics and simulating intensified dosing regimens to assess the magnitude of increases in endoscopic remission rates.”
In a prospective, open-label study, researchers assessed endoscopic outcomes of 110 patients with CD dosed every 8-weeks with Entyvio 330 mg (vedolizumab, Takeda); they further measured serum concentrations and vedolizumab antibodies before each infusion and performed ileocolonoscopies at baseline, week 26 and week 52. A first-order Markov model described the relationship between PK exposure metrics and remission probability. Researchers noted linear clearance was 0.215 L per day and the volume of distribution was 4.92 L.
According to study results, higher concentrations of vedolizumab increased the probability of achieving endoscopic remission where linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of vedolizumab antibodies and among patients with previous biologic therapy exposure. Specifically, a week 22 individual-predicted vedolizumab concentration of 20 mg/L yielded a 35% probability of remission at week 26. Further, model-based simulations suggested every 4-week dosing may yield an endoscopic remission rate of 46.5% and 40% in biologic-naive patients and patients previously exposed to biologic therapy, respectively.
“We have developed the first PK-PD model of vedolizumab to target endoscopic remission in CD. Higher vedolizumab exposure may be needed to achieve endoscopic remission. Patients previously treated with anti-TNF agents and those with low serum albumin concentrations are more likely to have insufficient vedolizumab exposure,” Hanzel and colleagues concluded. “Prospective trials of intensified vedolizumab dosing regimens may be warranted to assess strategies to maximize rates of endoscopic remission.”
Perspective
Back to Top
Benjamin Cohen, MD, MAS
The authors present a population PK-PD model derived from an analysis of the LOVE-CD study that was a prospective open-label multicenter trial designed to assess endoscopic outcomes in Crohn’s disease patients treated with vedolizumab. PK-PD models offer the opportunity to perform precision medicine with tailored dosing to improve endoscopic outcomes.
Dashboard-driven dosing of infliximab using similar Bayesian models have shown reductions in the incidence of loss of response and a large randomized clinical trial comparing dashboard-based infliximab dosing to standard of care dosing is about to begin.
In the study by Hanzel et al., factors associated with high clearance of vedolizumab included low albumin concentration, prior TNFi exposure and the presence of antibodies to vedolizumab. These are similar to what we see with TNFi monoclonal antibodies. It is important to note that this study is based on data collected in patients enrolled shortly after the approval of vedolizumab who may be a more treatment-refractory population than the patients typically treated with vedolizumab now. Given the treatment gaps that currently exist in IBD, the potential of precision dosing based on predictive modeling to optimize therapeutic outcomes is exciting. However, it is still early days with respect to vedolizumab dosing, and studies such as this are more hypothesis generating than ready for primetime in clinical care.
Collapse
Read more about
Click Here to Manage Email Alerts