Intest Res.  2021 Jan;19(1):95-105. 10.5217/ir.2019.09167.

Population pharmacokinetics of vedolizumab in Asian and non-Asian patients with ulcerative colitis and Crohn’s disease

Affiliations
  • 1Takeda PRA Development Center KK, Osaka, Japan
  • 2Metrum Research Group, Tariffville, CT, USA
  • 3Takeda Development Center Americas Inc, Cambridge, MA, USA
  • 4Takeda Pharmaceutical Company Limited, Osaka, Japan
  • 5Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan

Abstract

Background/Aims
Vedolizumab is indicated for moderately-to-severely active ulcerative colitis (UC) and Crohn’s disease (CD). Because multiple factors may result in different pharmacokinetics and clinical efficacies, understanding determinants of vedolizumab clearance may enhance dose and treatment strategies. The aim was to characterize vedolizumab pharmacokinetics in Asian and non-Asian UC and CD patients.
Methods
Population pharmacokinetic analysis for repeated measures, using data from 5 studies, was conducted using nonlinear mixed-effects modeling. A Bayesian estimation approach in NONMEM 7.3 was utilized to leverage the predominantly sparse data available for this analysis with results from a prior population pharmacokinetic analysis of vedolizumab.
Results
Vedolizumab pharmacokinetics were described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half life of vedolizumab was 24.7 days for anti-vedolizumab antibody (AVA)-negative patients and 18.1 days for AVA-positive patients; linear clearance (CLL) was 0.165 L/day for AVA-negative patients and 0.246 L/day for AVA-positive patients; central (Vc) and peripheral compartment volumes of distribution were 3.16 L and 1.84 L, respectively. Interindividual variabilities (percent coefficient of variation) were 30.8% for CLL and 19% for Vc; interoccasion variability on CLL was 20.3%; residual variance was 17.8%. For albumin, body weight and AVA, only extreme values were identified as potentially clinically important predictors of CLL. The effect of race (Asian/non-Asian) and diagnosis (UC/CD) on CLL was negligible and likely not of clinical importance.
Conclusions
Pharmacokinetic parameters were similar in Asian and non-Asian patients with moderately-to-severely active UC and CD. This analysis supports use of vedolizumab flat-fixed dosing in these patients. (Clinicaltrials.gov Identifiers: NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2). CCT 101; NCT02039505 and CCT-001; NCT02038920)

Keyword

Population pharmacokinetics; Vedolizumab; Colitis, ulcerative; Crohn disease; Asian

Figure

  • Fig. 1. Diagrammatic representation of the final population pharmacokinetic model of vedolizumab. CLL, linear clearance; CLNL, nonlinear clearance; Vmax, maximum elimination rate; Km, half-maximum elimination rate; Conc, vedolizumab concentration. This figure is reproduced with permission from John Wiley & Sons.

  • Fig. 2. Covariate effects on vedolizumab linear clearance (CLL). CLL relative to the typical reference subject (body weight: 70 kg, albumin: 4 g/dL, race: non-Asian, diagnosis: UC, AVA: negative [titer <10]) is plotted by covariate value. Covariates were fixed to the reference values except when they were the subject of perturbation. Body weight and albumin were evaluated at the 5th, 25th, 75th, and 95th percentiles in the dataset. Positive AVA was evaluated at titer values with the highest incidence in the dataset. The closed circles represent the effect for that covariate at the median covariate parameter estimate derived from the Bayesian posterior probability distribution. The horizontal line represents the evaluation of the effect at the extremes of the posterior derived 95% credible interval (CDI) for that covariate parameter estimate. Median and 95% CDI values for the covariate effect are shown above the distribution. The vertical line at x=1 represents the typical reference subject, and the grey shaded region represents a parameter change of ±25% from the reference value of 1 (null effect).

  • Fig. 3. Distribution of individual vedolizumab linear clearance (CLL) estimates from the final population pharmacokinetic model in Asian (A) and non-Asian patients (B) with ulcerative colitis (UC) and Crohn’s disease (CD).


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