Pharmacokinetic-Pharmacodynamic Model of Vedolizumab for Targeting Endoscopic Remission in Patients With Crohn Disease: Posthoc Analysis of the LOVE-CD Study

Jurij Hanzel, Erwin Dreesen, Séverine Vermeire, Mark Löwenberg, Frank Hoentjen, Peter Bossuyt, Esmé Clasquin, Filip J Baert, Geert R D'Haens, Ron Mathôt, Jurij Hanzel, Erwin Dreesen, Séverine Vermeire, Mark Löwenberg, Frank Hoentjen, Peter Bossuyt, Esmé Clasquin, Filip J Baert, Geert R D'Haens, Ron Mathôt

Abstract

Background: Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedolizumab exposure to endoscopic remission in CD.

Methods: Data were obtained from the first 110 patients participating in a phase 4 prospective multicenter trial (LOVE-CD; ClinicalTrials.gov identifier: NCT02646683), where vedolizumab was dosed at 300 mg every 8 weeks and serum concentrations and antibodies to vedolizumab were measured before each infusion. Concentration-time profiles were described by a 2-compartment model with parallel linear and nonlinear elimination. A first-order discrete-time Markov model was used to describe the relationship between pharmacokinetic exposure metrics and the probability of endoscopic remission (Simple Endoscopic Score for CD < 4).

Results: Linear clearance was 0.215 L/d, and the volume of distribution of the central compartment was 4.92 L. Linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab, and in patients with previous exposure to other biologic therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggested that endoscopic remission rates of 46.5% or 40.0% could be reached with every-4-weeks dosing in patients who were naïve or previously exposed to biologic therapy, respectively.

Conclusions: Model-informed dosing of vedolizumab in CD provides a foundation for future research aiming to maximize endoscopic remission rates.

Keywords: exposure-response; inflammatory bowel disease; pharmacometrics; therapeutic drug monitoring.

© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.

Figures

Figure 1.
Figure 1.
Prediction-corrected visual predictive check of the final population PK model. Observed vedolizumab concentrations are represented by empty blue circles. The solid line connects the observed median prediction-corrected vedolizumab serum concentrations (mg/L) per bin. The dashed lines connect the fifth and 95th percentiles of the prediction-corrected observations. Shaded areas denote the 95% confidence interval of the median, fifth, and 95th percentiles of the simulated values (n = 1000).
Figure 2.
Figure 2.
Goodness-of-fit plots for the Markov model. Observed (tiles) and predicted (lines) of patients achieving endoscopic remission (full line) or dropping out (dashed line) at week 26 as a function of individual predicted vedolizumab concentrations at week 22. Numbers indicate the number of patients in each quantile. Only patients with a SES-CD > 3 at baseline are shown (n = 106).

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