Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: The pharmacokinetics (PK) of canakinumab (CAN) and total interleukin (IL)-1β kinetics have been well investigated in CAPS patients (pts).1 Here we present the PK and pharmacodynamics (PD) of CAN (solution for injection-liquid in vial [LIVI]) from the randomized treatment epoch (primary analysis up to Week 16) of a Phase III study (NCT02059291
Methods: The study comprised 3 disease cohorts (crFMF, HIDS/MKD, and TRAPS). Each cohort followed the same study design across 4 epochs (screening epoch [up to 12 weeks], randomized treatment epoch [16 weeks], randomized withdrawal epoch [24 weeks] and open-label treatment epoch [72 weeks]). Pts (age, ≥2 years) with crFMF, HIDS/MKD, or TRAPS who had a flare during Epoch 1 were randomized (1:1) in Epoch 2 to receive subcutaneous (sc) CAN 150 mg (or 2 mg/kg for pts weighing ≤40 kg) every 4 weeks (q4w) or placebo. Blinded uptitration (up to 300 mg) was allowed for pts not resolving the index flare by Day 15. Serum samples for CAN concentrations and total IL-1β were collected at baseline (Day 1), and trough samples, at weeks 2, 4, 8, 12, and 16.
Results: In crFMF, HIDS/MKD, and TRAPS pts, the serum clearance and steady-state volume of distribution of CAN varied according to body weight, and were estimated to be 0.14±0.04 L/day and 4.96±1.35 L, respectively. The estimated half-life of CAN was 25.6±6.4 days. CAN minimal concentration at Week 16 following 150 mg sc q4w dosing was estimated to be 15.3±6.6 μg/mL. The estimated steady-state area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUCtau) was 648±202 μg.day/mL. Similar results were obtained in all 3 diseases. CAN binding to circulating IL-1β was demonstrated by increase in total IL-1β following CAN dosing in all 3 diseases. In pts requiring uptitration to 300 mg, levels of total IL-1β were higher, suggesting higher production of IL-1β, and therefore the need for a higher dose.
Conclusion: This was the first study to evaluate the PK of canakinumab given in the LIVI form. The results observed in crFMF, HIDS/MKD, and TRAPS pts were similar to those observed in other indications (CAPS and SJIA) using the lyophilisate form. These data suggested that the new formulation did not affect the PK/PD of canakinumab and similar to CAPS, patients with higher levels of IL-1β require canakinumab uptitration to achieve optimal disease control. Reference: 1.Chakraborty A, et al. Clin Pharmacokinet. 2012;51:e1–18.
To cite this abstract in AMA style:Frenkel J, Anton J, Livneh A, Ben-Chetrit E, Brogan P, Bujan-Rivas S, Constantin T, De Benedetti F, Gattorno M, Gül A, Hoffman HM, Kone-Paut I, Lachmann H, Ozen S, Simon A, Van der Hilst J, Zeft A, Speziale A, Junge G, Xu L. Pharmacokinetic and Pharmacodynamic Characteristics of Canakinumab in Patients with Periodic Fever Syndromes: Results from a Phase III Pivotal Umbrella Trial [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/pharmacokinetic-and-pharmacodynamic-characteristics-of-canakinumab-in-patients-with-periodic-fever-syndromes-results-from-a-phase-iii-pivotal-umbrella-trial/. Accessed March 26, 2019.
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