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

被引：222

作者：

Rosario, M. ^{[1
]}

Dirks, N. L. ^{[2
]}

Gastonguay, M. R. ^{[2
]}

Fasanmade, A. A. ^{[1
]}

Wyant, T. ^{[1
]}

Parikh, A. ^{[3
]}

Sandborn, W. J. ^{[4
]}

Feagan, B. G. ^{[5
]}

Reinisch, W. ^{[6
,7
]}

Fox, I. ^{[1
]}

机构：

[1] Takeda Pharmaceut Int Co, Cambridge, MA 02139 USA

[2] Metrum Res Grp LLC, Tariffville, CT USA

[3] Takeda Pharmaceut Int Inc, Deerfield, IL USA

[4] Univ Calif San Diego, Div Gastroenterol, La Jolla, CA 92093 USA

[5] Univ Western Ontario, Robarts Res Inst, London, ON, Canada

[6] Med Univ Vienna, Dept Internal Med 3, Vienna, Austria

[7] McMaster Univ, Dept Internal Med, Hamilton, ON, Canada

来源：

ALIMENTARY PHARMACOLOGY & THERAPEUTICS | 2015年 / 42卷 / 02期

关键词：

MAINTENANCE THERAPY; HUMANIZED ANTIBODY; INDUCTION THERAPY; INFLIXIMAB; ASSOCIATION; ADALIMUMAB; MODERATE;

D O I：

10.1111/apt.13243

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BackgroundVedolizumab, an anti-(47) 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. AimsTo 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. MethodsData 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. ResultsVedolizumab 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 25.5days; linear clearance (CLL) was 0.159L/day for UC and 0.155L/day for CD; central compartment volume of distribution (V-c) was 3.19L; and peripheral compartment volume of distribution was 1.66L. 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 CLL. ConclusionsPopulation 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).

引用

页码：188 / 202

页数：15

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