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Population pharmacokinetics‐pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease
Author(s) -
Rosario M.,
Dirks N. L.,
Gastonguay M. R.,
Fasanmade A. A.,
Wyant T.,
Parikh A.,
Sandborn W. J.,
Feagan B. G.,
Reinisch W.,
Fox I.
Publication year - 2015
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.13243
Subject(s) - vedolizumab , medicine , ulcerative colitis , pharmacokinetics , volume of distribution , population , pharmacodynamics , dosing , inflammatory bowel disease , gastroenterology , pharmacology , disease , environmental health
Summary Background Vedolizumab, an anti‐α 4 β 7 integrin monoclonal antibody ( mA b), is indicated for treating patients with moderately to severely active ulcerative colitis ( UC ) and Crohn's disease ( CD ). As higher therapeutic mA b 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 CL L 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: NCT 01177228; NCT 00783718 ( GEMINI 1); NCT 00783692 ( GEMINI 2); NCT 01224171 ( GEMINI 3).