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Combination of cassette-dosing and microsampling for reduced animal usage for antibody pharmacokinetics in cynomolgus monkeys, wild-type mice, and human FcRn transgenic mice

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Abstract

Purpose

The aim of this study was to develop a useful antibody PK evaluation tool using a combination of cassette-dosing and microsampling in mice and monkeys in order to reduce the number of animals used.

Methods

Cetuximab, denosumab, infliximab, and a mixture of the three antibodies, i.e., cassette-dosing, were administered intravenously to cynomolgus monkeys, C57BL/6J mice, and homozygous human neonatal Fc-receptor transgenic (Tg32) mice. Mouse blood was collected from one animal continuously via the jugular vein at nine points.

Results

In cynomolgus monkeys, infliximab showed faster elimination in the cassette-dosing group than in the single-dose group. Anti-drug antibody production was observed, but the PK parameters of the clearance and distribution volume were similar in both groups. In C57BL/6J and Tg32 mice, each of the plasma concentrations–time profiles after cassette-dosing were similar to those after single dosing. PK evaluation using a combination of cassette-dosing and microsampling in mice may reduce the number of mice used by approximately 90% compared with the conventional method.

Conclusions

The combination of antibody cassette-dosing and microsampling is a promising PK evaluation method as a high-throughput and reliable with reduced numbers of mice and cynomolgus monkeys.

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Abbreviations

ABTS:

2,2-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid

ADA:

Anti-drug antibody

C0 :

Concentration at time 0

CL:

clearance

FcRn:

Neonatal Fc-receptor

hEGFR:

Human epidermal growth factor receptor

hFcRn:

Human neonatal Fc-receptor

hRANKL:

Human receptor activator of nuclear factor-κB ligand

HRP:

Horseradish peroxidase

hTNFα:

Human tumor necrosis factor alpha

IV:

Intravenous

IVIG:

Intravenous immunoglobulin

LCMS:

Liquid chromatography–mass spectrometry

LLOQ:

lower limit of quantitation

mAb:

monoclonal antibody

NCA:

Non-compartmental analysis

PBS-T:

phosphate-buffered saline with 0.05% Tween® 20, pH 7.4

PK:

Pharmacokinetics

SA-MTP:

Streptavidin-coated microtiter plates

t½ :

half-life

Tg32:

homozygous hFcRn transgenic

Vss :

Volume of distribution at steady state

WT:

Wild-type

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Authors and Affiliations

  1. Research Division, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba-shi, Shizuoka, 412-8513, Japan

    Miho Nagayasu & Kazuhisa Ozeki

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  1. Miho Nagayasu
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  2. Kazuhisa Ozeki
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Correspondence to Kazuhisa Ozeki.

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Nagayasu, M., Ozeki, K. Combination of cassette-dosing and microsampling for reduced animal usage for antibody pharmacokinetics in cynomolgus monkeys, wild-type mice, and human FcRn transgenic mice. Pharm Res 38, 583–592 (2021). https://doi.org/10.1007/s11095-021-03028-6

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  • DOI: https://doi.org/10.1007/s11095-021-03028-6

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