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THU0569 Pharmacokinetics and Pharmacodynamics of Canakinumab in Patients with Autoinflammatory Periodic Fever Syndromes (Colchicine Resistant FMF, HIDS/MKD and TRAPS)
  1. F. De Benedetti1,
  2. J. Anton2,
  3. M. Gattorno3,
  4. H. Lachmann4,
  5. I. Kone-Paut5,
  6. S. Ozen6,
  7. J. Frenkel7,
  8. A. Simon8,
  9. A. Zeft9,
  10. E. Ben-Chetrit10,
  11. H. Hoffman11,
  12. Y. Joubert12,
  13. K. Lheritier12,
  14. A. Speziale12,
  15. G. Junge12,
  16. X. Xu13
  1. 1IRCCS Ospedale Pediatrico Bambino Gesú, Rome, Italy
  2. 2Hospital Sant Joan de Déu, Barcelona, Spain
  3. 3Pediatric Rheumatology, G. Gaslini Institute, Genoa, Italy
  4. 4UK National Amyloidosis Centre, University College London Medical School, London, United Kingdom
  5. 5Hôpital Kremlin Bicetre, University of Paris SUD, Paris, France
  6. 6Hacettepe University Children's Hospital, Ankara, Turkey
  7. 7University Medical Center Utrecht, Utrecht
  8. 8Radboud University Medical Centre, Nijmegen, Netherlands
  9. 9Pediatrics Rheumatology, Cleveland Clinic, Cleveland, United States
  10. 10Rheumatology Unit, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
  11. 11University of California, La Jolla, United States
  12. 12Novartis Pharma AG, Basel, Switzerland
  13. 13Novartis Pharmaceuticals Corporation, East Hanover, United States

Abstract

Background Periodic fever syndromes are a group of rare autoinflammatory conditions that includes, among others, cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD) and TNF receptor-associated periodic syndrome (TRAPS). The pharmacokinetics (PK) of canakinumab (CAN) and total interleukin (IL)-1β kinetics have been well characterised in CAPS patients (pts).1 Here we present the PK and pharmacodynamics (PD) of CAN in colchicine resistant/intolerant (crFMF), HIDS/MKD and TRAPS pts.

Objectives To evaluate the PK and PD of CAN (solution for injection-liquid in vial [LIVI]) from the phase III study in crFMF, HIDS/MKD and TRAPS pts at Week 16.

Methods The study (NCT02059291) comprised of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS). Each cohort followed the same study design across 4 epochs (screening epoch [up to 12 weeks], randomised treatment epoch [16 weeks], randomised 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 randomised (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 day15. 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 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 up titration to 300 mg, levels of total IL-1β were higher suggesting higher production of IL-1β.

Conclusions This was first study to evaluate the PK characteristics of canakinumab given in the LIVI form. The results observed in crFMF, HIDS/MKD and TRAPS patients were similar to those observed in other indications (CAPS and SJIA) using the lyophilisate form. These data suggested that new formulation did not affect PK/PD of the drug and similarly to CAPS, patients with higher levels of IL-1β may require canakinumab up-titration to have an optimal disease control.

  1. Chakraborty A, et al. Clin Pharmacokinet. 2012;51:e1–18.

Disclosure of Interest F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS, J. Anton Grant/research support from: Novartis, Pfizer, Abbvie, Roche, SOBI, Consultant for: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, Abbvie, Chugai, S. Ozen Consultant for: Novartis, Speakers bureau: SOBI, J. Frenkel Grant/research support from: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, A. Zeft: None declared, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: BMS, Consultant for: Novartis, SOBI, Regeneron, Speakers bureau: Novartis, Y. Joubert Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, A. Speziale Employee of: Novartis, G. Junge Employee of: Novartis, X. Xu Employee of: Novartis

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