Session Type: Abstract Submissions (ACR)
Canakinumab (CAN), a human, selective anti-interleukin-1β monoclonal antibody, has demonstrated rapid and sustained efficacy in systemic juvenile idiopathic arthritis (SJIA) patients,1and is approved in >30 countries including USA, EU, Canada, UK and Russia. Given the nature of the disease (pediatric population, rare condition), the phase III program only included limited placebo data. In such a context, the safety profile of CAN has been characterized via a model-based analysis of the dose-exposure-safety event relationship. The purpose of the study is to explore the relationship between CAN concentration and the occurrence of adverse events of special interest (ESI) and related laboratory abnormalities.
The analysis considered the open-label, part I of phase III trial wherein SJIA patients received CAN 4mg/kg (300 mg max.) every 4 weeks for a maximum of 8 consecutive doses (n=188). Individual CAN concentration time-profiles have been predicted for those patients, by combining the patients’ CAN and IL-1β concentration-time data and an established population PK model. This model is a PK-binding model parameterized in terms of clearance of drug and ligand (IL-1β), central and peripheral volume for the drug, interstitial flow rate, ligand production rate and binding affinity which has been developed using all the data available from the entire CAN program. The average serum CAN concentration (Cavg) was calculated from the concentration time profiles for each patient and dosing interval. In each dosing interval, Cavg were compared between patients with and without the following safety events of special interest: AEs of abdominal pain, cough, headache, infection, serious AE infection, pyrexia, and vomiting, as well as lab abnormalities of thrombocytopenia (>3XULN [upper limit normal]), leucopenia (≤0.8 XLLN [lower limit normal]), >20g/L decrease from baseline hemoglobin, neutropenia (<0.9 X LLN), transaminases elevation (>3XLLN), elevated total cholesterol (≥1.5XULN), triglycerides (≥5.7 mmol/L), and >25% decrease from baseline estimated glomerular filtration rate for 2 consecutive visits.
For all adverse ESIs and related laboratory abnormalities, except neutropenia, Cavg was not different for patients who experienced an event compared with those who did not. The mean Cavg for patients with neutropenia was comparable to the 74thpercentile of those patients without neutropenia, however this higher Cavg was not found to be associated with more infection.
A pharmacometric based analysis in SJIA patients treated with a therapeutic dose of CAN, did not find, in the range of CAN exposure observed, any relationship between average CAN exposure and the occurrence of any safety ESI, except for neutropenia. This increased Cavg in patients with neutropenia was not associated with increased infections. These data support the effective and safe use of CAN4mg/kg every 4 week for the treatment of SJIA in patients >2 years old.
1Ruperto N. et al. N Engl J Med 2012; 367 (25):2396-406
Novartis Pharmaceutical Corporation,
Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company,
Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Roche, Wyeth/Pfizer,
H. H. Brunner,
Novartis, Roche, BMS, Pfizer, Biogen, Boehringer-Ingelheim, Jannsen, Astrazeneca,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-pharmacometric-based-analysis-of-the-occurrence-of-selected-safety-events-of-special-interest-and-canakinumab-exposure-in-systemic-juvenile-idiopathic-arthritis-patients/