Article

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

Novartis Institutes for BioMedical Research,One Health Plaza, East Hanover, NJ 07936-1080,
Clinical Pharmacokinetics (impact factor: 5.4). 06/2012; 51(6):e1-18. DOI:10.2165/11599820-000000000-00000 pp.e1-18
Source: PubMed

ABSTRACT Canakinumab is a high-affinity human monoclonal anti-interleukin-1β (IL-1β) antibody of the IgG1/κ 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 70 kg, slow serum clearance (0.174 L/day) was observed with a low total volume of distribution at steady state (6.0 L), 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 ± 0.173 nmol/L 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 pharmacokinetic/pharmacodynamic properties of canakinumab.

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Keywords

age-related pharmacokinetic differences
 
anti-inflammatory effects
 
canakinumab clinical development programme
 
Canakinumab displays linear pharmacokinetics
 
Canakinumab displays pharmacokinetic properties typical
 
cell line change
 
cryopyrin-associated periodic syndromes
 
elimination half-life
 
healthy subjects
 
high-affinity human monoclonal anti-interleukin-1β
 
low total volume
 
manufacturing change
 
pharmacokinetic/pharmacodynamic properties
 
population-based pharmacokinetic-binding model
 
rheumatoid arthritis
 
signifying binding affinity
 
slow serum clearance
 
subcutaneous absolute bioavailability
 
trade name ILARIS®
 
vivo dissociation constant
 

Abhijit Chakraborty