Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jan;19(1):95-105.
doi: 10.5217/ir.2019.09167. Epub 2020 Jul 10.

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

Hiroyuki Okamoto  1 , Nathanael L Dirks  2 , Maria Rosario  3 , Tetsuharu Hori  4 , Toshifumi Hibi  5
Affiliations

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

Hiroyuki Okamoto et al. Intest Res. 2021 Jan.

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).

Keywords: Asian; Colitis, ulcerative; Crohn disease; Population pharmacokinetics; Vedolizumab.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

Okamoto H is an employee of Takeda PRA Development Center, KK, Osaka, Japan. Rosario M is an employee of Takeda Development Center Americas Inc, Cambridge, MA, USA and holds equity stake in Takeda. Hori T is an employee of Takeda Pharmaceutical Company Limited, Osaka, Japan and holds equity stake in Takeda. Dirks NL is an employee of Metrum Research Group, Tariffville, CT, USA and was a paid consultant to Takeda for this work. Hibi T is an employee of Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Japan, and has received honoraria from Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, AbbVie GK, Zeria Pharmaceutical, JIMRO, Aspen Japan K.K, Ferring, Gilead Sciences, Kissei Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Janssen Pharmaceutical and Pfizer Japan; has received scholarship grants from EA Pharma, Abbvie, JIMRO, Zeria Pharmaceutical and Otsuka Holdings. No other potential conflict of interest relevant to this article was reported.

Hibi T is an editorial board member of the journal but did not involve in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Figures

Fig. 1.
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.
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.
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).
See this image and copyright information in PMC

References

    1. Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330:864–875. - PubMed
    1. U.S. Food and Drug Administration Takeda Pharmaceuticals America Inc. Entyvio (vedolizumab) prescribing information [Internet] c2014 [cited 2019 May 10]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125476s000lbl.pdf.
    1. European Medicine Agency Takeda Pharma A/S. Entyvio (vedolizumab) summary of product characteristics [Internet] 2019 c2018 [cited 2019 May 10]. https://www.ema.europa.eu/en/documents/product-information/entyvio-epar-....
    1. Rosario M, Dirks NL, Gastonguay MR, et al. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;42:188–202. - PMC - PubMed
    1. Zhu Y, Hu C, Lu M, et al. Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis. J Clin Pharmacol. 2009;49:162–175. - PubMed

Associated data

LinkOut - more resources