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

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).

• Authors: 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
• Journal: Alimentary pharmacology & therapeutics (Aliment Pharmacol Ther) Vol. 42 Issue 2 Pg. 188-202 (Jul 2015) ISSN: 1365-2036 [Electronic] England
• PMID: 25996351 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Takeda Pharmaceuticals International Co published by John Wiley & Sons Ltd.

Chemical References

• Albumins
• Antibodies, Monoclonal, Humanized
• Gastrointestinal Agents
• vedolizumab

Topics

• Adolescent
• Adult
• Aged
• Albumins (therapeutic use)
• Antibodies, Monoclonal, Humanized (pharmacokinetics, therapeutic use)
• Body Weight
• Colitis, Ulcerative (drug therapy)
• Crohn Disease (drug therapy)
• Female
• Gastrointestinal Agents (pharmacokinetics, therapeutic use)
• Half-Life
• Healthy Volunteers
• Humans
• Inflammatory Bowel Diseases (drug therapy)
• Male
• Metabolic Clearance Rate
• Middle Aged
• Young Adult