Pharmacokinetics and Pharmacodynamics of Canakinumab in Patients With Systemic Juvenile Idiopathic Arthritis

Abstract

The characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) properties in pediatric patients is essential in supporting the recommended dosage of canakinumab in the relevant population. Here the PK and PD properties of canakinumab-a monoclonal antibody-in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) are presented. Blood samples were obtained from 4 phase 2/3 clinical studies in patients with SJIA. Canakinumab PK properties and total interleukin (IL)-1β kinetic properties were characterized by a population-based PK-binding model. On administration, canakinumab increased total IL-1β complex in SJIA patients. Canakinumab clearance and volume of distribution were not impacted by age in pediatric patients after correction for the patient's body weight. The estimated serum clearance of canakinumab was 0.106 ± 0.00689 L/day, with a corresponding volume of distribution at steady state of 3.2 L and an estimated half-life of 22 days, based on a model typical body weight of 33 kg. Body-weight-based dosing provided comparable canakinumab exposure across the age groups in patients 2 to <20 years with SJIA. In younger children, a modest increase in the turnover rate of IL-1β was observed. Compared to other indications, IL-1β production rate was higher and clearance was slower in patients with SJIA. Low immunogenicity incidence of 3.1% was observed, and none of the patients had neutralizing antibodies. In conclusion, the PK/PD findings further support dose selection of canakinumab in patients with SJIA.

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

“…In studies where free (C) or total (CT) mAb concentrations and R or RT were available, three approximations were made: -data transformation or model parameterization that avoid the estimation of ksyn, as made for etrolizumab [39] (anti-integrins), domagrozumab [40] (anti-mysotatin) and denosumab [41] (anti-RANKL); -total target amount assumed to be constant. This necessitates, to set kdeg = kint, as made for canakinumab [42][43][44][45] (anti-IL-1β), bevacizumab [46] (anti-VEGF) and volociximab [47] (anti-integrins); -binding of mAb to its target assumed irreversible (figure 1C), i.e. koff = 0, as made for efalizumab [48,49] (an anti-CD11a mAb which was removed from the market in 2009) and ofatumumab [50] (anti-CD20).…”

Hyperphosphatemic Familial Tumoral Calcinosis With Galnt3 Mutation: Transient Response to Anti‐Interleukin‐1 Treatments

“…This suggestion is based on comparison to the clinical effect of anti‐IL‐1 treatments in auto‐inflammatory syndromes observed in our clinical practice; actually, our case remains descriptive, and we did not perform cytokine analyses. To explain the result, the patient could have developed immunization against the drug; we did not measure these antidrug antibodies, but antibodies against anakinra or canakinumab have not been reported to lower efficiency or tolerance of these treatments . We cannot exclude that anti‐IL‐1 therapy could be more effective if initiated earlier in the disease course, before a long‐lasting history of diffuse, recurrent tumoral calcinosis.…”

“…To explain the result, the patient could have developed immunization against the drug; we did not measure these antidrug antibodies, but antibodies against anakinra or canakinumab have not been reported to lower efficiency or tolerance of these treatments. (15)(16)(17)(18)(19)(20)(21)(22)(23) We cannot exclude that anti-IL-1 therapy could be more effective if initiated earlier in the disease course, before a long-lasting history of diffuse, recurrent tumoral calcinosis.…”

Dosage Considerations for Canakinumab in Children With Periodic Fever Syndromes

“…The population PK-binding model was used to describe the concentration-time profiles of canakinumab in healthy volunteers and patients with variable disease status. The model-estimated clearance values for subjects with a body weight of 70 kg and a serum albumin concentration of 43 g/L were 0.14, 0.17, 0.20, 0.17, 0.19, 0.17, 0.20, and 0.18 L/day in healthy white subjects, healthy Japanese subjects, patients with rheumatoid arthritis, patients with mild asthma, patients with psoriasis, patients with CAPS, 21 patients with systemic juvenile systemic arthritis (SJIA), 22 and patients with gouty arthritis, 23 respectively, demonstrating that the PK characteristics of canakinumab are generally comparable regardless of disease status.…”