Pharmacokinetic and pharmacodynamic properties of canakinumab, a human anti-interleukin-1ß monoclonal antibody.
Clin Pharmacokinet
; 51(6): e1-18, 2012 Jun 01.
Article
en En
| MEDLINE
| ID: mdl-22550964
ABSTRACT
Canakinumab is a high-affinity human monoclonal anti-interleukin-1ß (IL-1ß) antibody of the IgG1/κ isotype designed to bind and neutralize the activity of human IL-1ß, 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-1ß. 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-1ß was observed in both healthy subjects and all patient populations following canakinumab dosing, reflecting the ability of canakinumab to bind circulating IL-1ß. The kinetics of total IL-1ß 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-1ß, 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Interleucina-1beta
/
Síndromes Periódicos Asociados a Criopirina
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Anticuerpos Monoclonales
Límite:
Animals
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Humans
Idioma:
En
Revista:
Clin Pharmacokinet
Año:
2012
Tipo del documento:
Article