Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease

M Rosario, N L Dirks, M R Gastonguay, A A Fasanmade, T Wyant, A Parikh, W J Sandborn, B G Feagan, W Reinisch, I Fox, M Rosario, N L Dirks, M R Gastonguay, A A Fasanmade, T Wyant, A Parikh, W J Sandborn, B G Feagan, W Reinisch, I Fox

Abstract

Background: Vedolizumab, an anti-α(4)β(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing.

Aims: To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling.

Methods: Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data.

Results: Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L).

Conclusions: Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).

© 2015 Takeda Pharmaceuticals International Co published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Median (interquartile range) of observed vedolizumab trough serum concentration vs. nominal sampling time in patients with UC (GEMINI 1) and patients with CD (GEMINI 2) during maintenance treatment with placebo or vedolizumab 300 mg every 4 weeks (Q4W) or every 8 weeks (Q8W). All patients (including those in the placebo group) received 2 doses of vedolizumab 300 mg during induction (at weeks 0 and 2). The median value is shown as a point and the interquartile range is represented by a vertical bar.
Figure 2
Figure 2
Diagrammatic representation of the population pharmacokinetic model of vedolizumab. Conc, vedolizumab concentration; Km, concentration at half‐maximum elimination rate; Vmax, maximum elimination rate.
Figure 3
Figure 3
Distribution of individual vedolizumab linear clearance (CLL) estimates from the final population pharmacokinetic model in patients with UC and patients with CD.
Figure 4
Figure 4
Goodness‐of‐fit plots: observed vedolizumab serum concentration vs. population and individual predicted vedolizumab concentration from the final population pharmacokinetic model. Values are shown as points with a dashed pink loess trend line through the data. A line of identity (solid black) is shown for reference.
Figure 5
Figure 5
Effect of covariates on vedolizumab linear clearance (CLL). Each point and line represent the median and 95% credible interval, respectively, of the Bayesian posterior distribution of normalised samples of vedolizumab CLL adjusted for the covariate. The reference individual weighs 70 kg; is 40 years old; has an albumin level of 4 g/dL, a faecal calprotectin level of 700 mg/kg, a CDAI score of 300 (for patient with CD), a partial Mayo score of 6 (for patient with UC), and no concomitant therapy use; and is ADA negative and TNF‐α antagonist therapy naïve. Albumin: 2.7, 3.2, 3.7, 4.2 and 4.7 g/dL represent the 6th, 18th, 70th, 85th, and 98.5th percentiles, respectively, of baseline albumin levels for patients in GEMINI 1, 2, and 3. Weight: 40, 60, 80, 100, and 120 kg represent the 1.5th, 30th, 71st, 92nd and 98th percentiles, respectively, of baseline weight values for patients in GEMINI 1, 2, and 3. The vertical black line is drawn at the reference point estimate, and the shaded region is ± 25% of the reference point estimate chosen to represent an uncertainty range of clinical unimportance.
Figure 6
Figure 6
Individual vedolizumab linear clearance (CLL) estimates by Mayo endoscopic subscore at the end of induction (week 6) for patients with UC (GEMINI 1). Midlines represent medians. Box limits represent 25th and 75th percentiles. Whiskers (error bars) represent highest and lowest points within 1.5 × interquartile range. Individual points represent outliers.
Figure 7
Figure 7
Receptor (α4β7) saturation plot: observed MAdCAM‐1 vs. observed vedolizumab serum concentration in patients with UC (GEMINI 1) and patients with CD (GEMINI 2). Baseline data are included.
Figure 8
Figure 8
Observed MAdCAM‐1 vs. time for patients with UC (GEMINI 1) and patients with CD (GEMINI 2). Upper left panel: patients received placebo during induction and maintenance; upper right panel: patients received 2 doses of vedolizumab 300 mg during induction and vedolizumab 300 mg every 4 weeks (Q4W) during maintenance; lower left panel: patients received 2 doses of vedolizumab 300 mg during induction and vedolizumab 300 mg every 8 weeks (Q8W) during maintenance; lower right panel: patients received 2 doses of vedolizumab 300 mg during induction and placebo during maintenance.

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