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

Hiroyuki Okamoto, Nathanael L Dirks, Maria Rosario, Tetsuharu Hori, Toshifumi Hibi, Hiroyuki Okamoto, Nathanael L Dirks, Maria Rosario, Tetsuharu Hori, Toshifumi Hibi

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.

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

Fig. 3.

Distribution of individual vedolizumab linear…

Fig. 3.

Distribution of individual vedolizumab linear clearance (CLL) estimates from the final population pharmacokinetic…

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).
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).

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Source: PubMed

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