Aurélie Gautier, Andrej Skerjanec, Olivier Luttringer, Phil McKernan, Philip Lowe
Novartis Pharma AG, Basel, Switzerland
Objectives: Canakinumab is a high-affinity fully human monoclonal antibody of the IgG1/k isotype, designed to bind and functionally neutralize the bioactivity of IL-1B, which is recognized as one of the principal pro-inflammatory cytokines in cryopyrin associated periodic syndromes (CAPS). The objectives of the study were to describe the kinetics of canakinumab and dynamics of binding IL-1B in CAPS patients; to determine if these are different in 2- and 3-year-old children versus older children and adults; and to explore the impact of CAPS phenotype (Muckle-Wells Syndrome [MWS], Familial Cold Autoinflammatory Syndrome [FCAS], Neonatal-Onset Multisystem Inflammatory Disease [NOMID]) on the kinetics of canakinumab and dynamics of binding to IL-1B.
Methods: A pharmacokinetics (PK)-binding model was used to describe the kinetic and binding parameters of canakinumab and IL-1B in CAPS patients, and in other populations relative to CAPS. The subgroup of 7 CAPS patients who were 2 and 3 years of age at baseline was also compared to the overall CAPS population.
Results: The 7 CAPS patients did not show any difference in terms of PK. However, they showed a higher IL-1B turnover including IL-1B clearance and production. IL-1B levels were linked with the severity of the CAPS phenotype. In the pediatric population, MWS and especially NOMID patients had higher concentrations of the inert canakinumab/IL-1B complexes after administration of canakinumab, indicating more cytokine in the body to be captured.
Conclusions: Correlation with clinical responses suggested that these increased levels of IL-1B may explain why younger and NOMID phenotype patients require higher doses or escalation to higher doses.
Reference: PAGE 22 (2013) Abstr 2731 [www.page-meeting.org/?abstract=2731]
Poster: Other Drug/Disease Modelling