Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1β monoclonal antibody

被引：147
作者：
Abhijit Chakraborty
Stacey Tannenbaum
Christiane Rordorf
Philip J. Lowe
David Floch
Hermann Gram
Sandip Roy
机构：
[1] Novartis Institutes for BioMedical Research, East Hanover, NJ 07936-1080, One Health Plaza
[2] Novartis Pharmaceuticals Corporation, East Hanover, NJ
[3] Novartis Pharma AG, Postfach, Basel
来源：
Clinical Pharmacokinetics | 2012年 / 51卷 / 6期
关键词：
Canakinumab; Cryopyrin-associated-periodic-syndromes; Interleukin-1-beta; Monoclonal-antibodies; Pharmacokinetics; Pharmacology;
D O I：
10.2165/11599820-000000000-00000
中图分类号：
学科分类号：
摘要：
Canakinumab is a high-affinity human monoclonal anti-interleukin-1β (IL-1β) antibody of the IgG1κ isotype designed to bind and neutralize the activity of human IL-1β, a pro-inflammatory cytokine. Canakinumab is currently being investigated on the premise that it would exert anti-inflammatory effects on a broad spectrum of diseases, driven by IL-1β. This paper focuses on the analysis of the pharmacokinetic and pharmacodynamic data from the canakinumab clinical development programme, describing results from the recently approved indication for the treatment of cryopyrin-associated periodic syndromes (CAPS) under the trade name ILARIS®, as well as diseases such as rheumatoid arthritis, asthma and psoriasis.Canakinumab displays pharmacokinetic properties typical of an IgG1 antibody. In a CAPS patient weighing 70kg, slow serum clearance (0.174Lday) was observed with a low total volume of distribution at steady state (6.0L), resulting in a long elimination half-life of 26 days. The subcutaneous absolute bioavailability was high (70). Canakinumab displays linear pharmacokinetics, with a dose-proportional increase in exposure and no evidence of accelerated clearance or time-dependent changes in pharmacokinetics following repeated administration was observed. The pharmacokinetics of canakinumab in various diseases (e.g. CAPS, rheumatoid arthritis, psoriasis or asthma) are comparable to those in healthy individuals. No sex-or age-related pharmacokinetic differences were observed after correction for body weight.An increase in total IL-1β was observed in both healthy subjects and all patient populations following canakinumab dosing, reflecting the ability of canakinumab to bind circulating IL-1β. The kinetics of total IL-1β along with the pharmacokinetics of canakinumab were characterized by a population-based pharmacokinetic-binding model, where the apparent in vivo dissociation constant, signifying binding affinity of canakinumab to circulating IL-1β, was estimated at 1.07±0.173nmolL in CAPS patients.During development of canakinumab a cell line change was introduced. Pharmacokinetic characterization was performed in both animals and humans to assure that this manufacturing change did not affect the pharmacokineticpharmacodynamic properties of canakinumab. © 2012 Springer International Publishing AG. All rights reserved.
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页码：e1 / e18
页数：17
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