Canacinumab Other names: Canakinumab

Mechanism of action

Canakinumab is a human monoclonal anti-human interleukin-1 beta (IL-1 beta) antibody of the IgG1/κ isotype. Canakinumab binds with high affinity specifically to human IL-1 beta and neutralises the biological activity of human IL-1 beta by blocking its interaction with IL-1 receptors, thereby preventing IL-1 beta-induced gene activation and the production of inflammatory mediators.

Pharmacodynamic properties

Pharmacodynamic effects

CAPS, TRAPS, HIDS/MKD and FMF

In clinical studies, CAPS, TRAPS, HIDS/MKD and FMF patients who have uncontrolled over-production of IL-1 beta show a rapid and sustained response to therapy with canakinumab, i.e. laboratory parameters such as high C-reactive protein (CRP) and serum amyloid A (SAA), high neutrophil and platelet counts, and leukocytosis rapidly returned to normal.

Still’s disease (SJIA and AOSD)

Adult-onset Still’s disease and systemic juvenile idiopathic arthritis are severe autoinflammatory diseases, driven by innate immunity by means of pro-inflammatory cytokines, a key one being IL-1-beta.

Common features of SJIA and AOSD include fever, rash, hepatosplenomegaly, lymphadenopathy, polyserositis and arthritis. Treatment with canakinumab resulted in a rapid and sustained improvement of both the articular and the systemic features of SJIA with significant reduction of the number of inflamed joints, prompt resolution of fever and reduction of acute phase reactants in the majority of patients.

Gouty arthritis

A gouty arthritis attack is caused by urate (monosodium urate monohydrate) crystals in the joint and surrounding tissue, which trigger resident macrophages to produce IL-1 beta via the “NALP3 inflammasome” complex. Activation of macrophages and concomitant over-production of IL-1 beta results in an acute painful inflammatory response. Other activators of the innate immune system, such as endogenous agonists of toll-like receptors, may contribute to the transcriptional activation of the IL- 1 beta gene, initiating a gouty arthritis attack. Following canakinumab treatment, the inflammatory markers CRP or SAA and signs of acute inflammation (e.g. pain, swelling, redness) in the affected joint subside rapidly.

Pharmacokinetic properties

CAPS

Absorption

The peak serum canakinumab concentration (Cmax) occurred approximately 7 days following single subcutaneous administration of 150 mg in adult CAPS patients. The mean terminal half-life was 26 days. Mean values for Cmax and AUC inf after a single subcutaneous dose of 150 mg in a typical adult CAPS patient (70 kg) were 15.9 μg/ml and 708 μg*d/ml. The absolute bioavailability of subcutaneously administered canakinumab was estimated to be 66%. Exposure parameters (such as AUC and Cmax) increased in proportion to dose over the dose range of 0.30 to 10.0 mg/kg given as intravenous infusion or from 150 to 600 mg as subcutaneous injection. Predicted steady-state exposure values (Cmin,ss, Cmax,ss, AUC,ss,8w) after 150 mg subcutaneous administration (or 2 mg/kg, respectively) every 8 weeks were slightly higher in the weight category 40-70 kg (6.6 μg/ml, 24.3 μg/ml, 767 μg*d/ml) compared to the weight categories <40 kg (4.0 μg/ml, 19.9 μg/ml, 566 μg*d/ml) and >70 kg (4.6 μg/ml, 17.8 μg/ml, 545 μg*d/ml). The expected accumulation ratio was 1.3-fold following 6 months of subcutaneous administration of 150 mg canakinumab every 8 weeks.

Distribution

Canakinumab binds to serum IL-1 beta. The distribution volume (Vss) of canakinumab varied according to body weight. It was estimated to be 6.2 litres in a CAPS patient of body weight 70 kg.

Elimination

The apparent clearance (CL/F) of canakinumab increases with body weight. It was estimated to be 0.17 l/d in a CAPS patient of body weight 70 kg and 0.11 l/d in a SJIA patient of body weight 33 kg. After accounting for body weight differences, no clinically significant differences in the pharmacokinetic properties of canakinumab were observed between CAPS and SJIA patients.

There was no indication of accelerated clearance or time-dependent change in the pharmacokinetic properties of canakinumab following repeated administration. No gender or age-related pharmacokinetic differences were observed after correction for body weight.

TRAPS, HIDS/MKD and FMF

Bioavailability in TRAPS, HIDS/MKD and FMF patients has not been determined independently. Apparent clearance (CL/F) in the TRAPS, HIDS/MKD and FMF population at body weight of 55 kg (0.14 l/d) was comparable to CAPS population at body weight of 70 kg (0.17 l/d). The apparent volume of distribution (V/F) was 4.96 l at body weight of 55 kg.

After repeated subcutaneous administration of 150 mg every 4 weeks, canakinumab minimal concentration at week 16 (Cmin) was estimated to be 15.4 ± 6.6 μg/ml. The estimated steady state AUCtau was 636.7 ± 260.2 μg*d/ml.

Still’s disease (SJIA and AOSD)

Bioavailability in SJIA patients has not been determined independently. Apparent clearance per kg body weight (CL/F per kg) was comparable between the SJIA and CAPS population (0.004 l/d per kg). The apparent volume of distribution per kg (V/F per kg) was 0.14 l/kg. Sparse pharmacokinetics (PK) data in AOSD patients suggest similar PK of canakinumab as compared to SJIA and other patient populations.

After repeated administration of 4 mg/kg every 4 weeks the accumulation ratio of canakinumab was 1.6 fold in SJIA patients. Steady state was reached after 110 days. The overall predicted mean (±SD) for Cmin,ss, Cmax,ss and AUC,ss4w were 14.7±8.8 μg/ml, 36.5 ± 14.9 μg/ml and 696.1 ± 326.5 μg*d/ml, respectively.

The AUCss4w in each age group was 692, 615, 707 and 742 μg*d/ml for 2-3, 4-5, 6-11, and 12-19 years old, respectively. When stratified by weight, a lower (30-40%) median of exposure for Cmin,ss (11.4 vs 19 μg/ml) and AUC ss (594 vs 880 μg*d/ml) for the lower bodyweight category (≤40 kg) vs the higher bodyweight category (>40 kg) was observed.

Based on the population pharmacokinetic modelling analysis, the pharmacokinetics of canakinumab in young adult SJIA patients aged 16 to 20 years were similar to those in patients less than 16 years of age. Predicted canakinumab steady state exposures at a dose level of 4 mg/kg (maximum 300 mg) in patients over the age of 20 years were comparable to those in SJIA patients younger than 20 years of age.

Gouty arthritis population

Bioavailability in gouty arthritis patients has not been determined independently. Apparent clearance per kg body weight (CL/F per kg) was comparable between the gouty arthritis and CAPS population (0.004 l/d/kg). Mean exposure in a typical gouty arthritis patient (93 kg) after a single subcutaneous 150 mg dose (Cmax: 10.8 μg/ml and AUCinf: 495 μg*d/ml) was lower than in a typical 70 kg CAPS patient (15.9 μg/ml and 708 μg*d/ml). This is consistent with the observed increase in CL/F with body weight.

The expected accumulation ratio was 1.1-fold following subcutaneous administration of 150 mg canakinumab every 12 weeks.

Paediatric population

Peak concentrations of canakinumab occurred between 2 to 7 days (Tmax) following single subcutaneous administration of canakinumab 150 mg or 2 mg/kg in paediatric patients 4 years of age and older. The terminal half-life ranged from 22.9 to 25.7 days, similar to the pharmacokinetic properties observed in adults. Based on the population pharmacokinetic modelling analysis, the pharmacokinetics of canakinumab in children aged 2 to <4 years were similar to those in patients 4 years of age and older. Subcutaneous absorption rate was estimated to decrease with age and appeared to be fastest in the youngest patients. Accordingly, T max was shorter (3.6 days) in younger SJIA patients (2-3 years) compared to older SJIA patients (12-19 years; Tmax 6 days). Bioavailability (AUCss) was not affected.

An additional pharmacokinetics analysis showed that the pharmacokinetics of canakinumab in 6 paediatric CAPS patients under the age of 2 years were similar to the pharmacokinetics in paediatric patients 2-4 years of age. Based on the population pharmacokinetic modelling analysis, the expected exposures after a dose of 2 mg/kg were comparable across the CAPS paediatric age groups, but were approximately 40% lower in paediatric patients of very low body weight (e.g. 10 kg) than in adult patients (150 mg dose). This is consistent with the observations of higher exposure in higher body weight groups in CAPS patients.

In TRAPS, HIDS/MKD and FMF, exposure parameters (trough concentrations) were comparable across age groups from 2 to <20 years old following subcutaneous administration of canakinumab 2 mg/kg every 4 weeks.

Pharmacokinetic properties are similar in CAPS, TRAPS, HIDS/MKD, FMF and SJIA paediatric populations.

Elderly population

No change in pharmacokinetic parameters based on clearance or volume of distribution were observed between elderly patients and adult patients <65 years of age.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of cross-reactivity, repeated dose toxicity, immunotoxicity, toxicity to reproduce and development.

Formal carcinogenicity studies have not been conducted with canakinumab.

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