Chemical formula: C₆₅₈₄H₁₀₁₃₄N₁₇₅₄O₂₀₄₂S₄₄
Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.
IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis, hidradenitis suppurativa, psoriatic arthritis and axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis) and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients and in synovial tissue of psoriatic arthritis patients. IL-17A is also upregulated in hidradenitis suppurativa lesions and increased IL-17A serum levels have been observed in affected patients. The frequency of IL-17-producing cells was also significantly higher in the subchondral bone marrow of facet joints from patients with ankylosing spondylitis. Increased numbers of IL-17A producing lymphocytes have also been found in patients with non-radiographic axial spondyloarthritis. Inhibition of IL-17A was shown to be effective in the treatment of ankylosing spondylitis, thus establishing the key role of this cytokine in axial spondyloarthritis.
Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab- bound IL-17A, indicating that secukinumab selectively captures free IL-17A, which plays a key role in the pathogenesis of plaque psoriasis.
In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil-associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment.
Secukinumab has been shown to lower (within 1 to 2 weeks of treatment) levels of C-reactive protein, which is a marker of inflammation.
Most pharmacokinetics properties observed in patients with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis were similar.
Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 μg/ml between 2 and 14 days post dose.
Based on population pharmacokinetic analysis, following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7±4.8 μg/ml or 27.3±9.5 μg/ml, respectively, between 5 and 6 days post dose.
After initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis.
On the basis of simulated data, peak concentrations at steady-state (Cmax,ss) following subcutaneous administration of 150 mg or 300 mg were 27.6 μg/ml and 55.2 μg/ml, respectively. Population pharmacokinetic analysis suggests that steady-state is reached after 20 weeks with monthly dosing regimens.
Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 2-fold increase in peak serum concentrations and area under the curve (AUC) following repeated monthly dosing during maintenance.
Population pharmacokinetic analysis showed that secukinumab was absorbed with an average absolute bioavailability of 73% in patients with plaque psoriasis. Across studies, absolute bioavailabilities in the range between 60 and 77% were calculated.
The bioavailability of secukinumab in PsA patients was 85% on the basis of the population pharmacokinetic model.
Following a single subcutaneous injection of 300 mg solution for injection in pre-filled syringe in plaque psoriasis patients, secukinumab systemic exposure was similar to what was observed previously with two injections of 150 mg.
Following subcutaneous administration of 300 mg at weeks 0, 1, 2, 3 and 4 followed by 300 mg every 2 weeks, the mean ± SD steady-state secukinumab trough concentration at week 16 was approximately 55.1±26.7 μg/ml and 58.1±30.1 μg/ml in HS study 1 and HS study 2, respectively.
The mean volume of distribution during the terminal phase (Vz) following single intravenous administration ranged from 7.10 to 8.60 litres in plaque psoriasis patients, suggesting that secukinumab undergoes limited distribution to peripheral compartments.
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or receptor mediated endocytosis.
Mean systemic clearance (CL) following a single intravenous administration to patients with plaque psoriasis ranged from 0.13 to 0.36 l/day. In a population pharmacokinetic analysis, the mean systemic clearance (CL) was 0.19 l/day in plaque psoriasis patients. The CL was not impacted by gender. Clearance was dose- and time-independent.
The mean elimination half-life, as estimated from population pharmacokinetic analysis, was 27 days in plaque psoriasis patients, ranging from 18 to 46 days across psoriasis studies with intravenous administration.
In a population pharmacokinetic analysis, the mean systemic CL following subcutaneous administration of 300 mg at weeks 0, 1, 2, 3, and 4 followed by 300 mg every 2 weeks to patients with hidradenitis suppurativa was 0.26 l/day.
The mean elimination half-life, as estimated from population pharmacokinetic analysis, was 23 days in hidradenitis suppurativa patients.
The single and multiple dose pharmacokinetics of secukinumab in plaque psoriasis patients were determined in several studies with intravenous doses ranging from 1x 0.3 mg/kg to 3x 10 mg/kg and with subcutaneous doses ranging from 1x 25 mg to multiple doses of 300 mg. Exposure was dose proportional across all dosing regimens.
Based on population pharmacokinetic analysis with a limited number of elderly patients (n=71 for age ≥65 years and n=7 for age ≥75 years), clearance in elderly patients and patients less than 65 years of age was similar.
No pharmacokinetic data are available in patients with renal or hepatic impairment. The renal elimination of intact secukinumab, an IgG monoclonal antibody, is expected to be low and of minor importance. IgGs are mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance of secukinumab.
Secukinumab clearance and volume of distribution increase as body weight increases.
Plaque psoriasis:
In a pool of the two paediatric studies, patients with moderate to severe plaque psoriasis (6 to less than 18 years of age) were administered secukinumab at the recommended paediatric dosing regimen. At week 24, patients weighing ≥25 and <50 kg had a mean ± SD steady-state trough concentration of 19.8 ± 6.96 μg/ml (n=24) after 75 mg of secukinumab and patients weighing ≥50 kg had mean ±SD trough concentration of 27.3 ± 10.1 μg/ml (n=36) after 150 mg of secukinumab. The mean ± SD steady-state trough concentration in patients weighing <25 kg (n=8) was 32.6 ± 10.8 μg/ml at week 24 after 75 mg dose.
Juvenile idiopathic arthritis:
In a paediatric study, ERA and JPsA patients (2 to less than 18 years of age) were administered secukinumab at the recommended paediatric dosing regimen. At week 24, patients weighing <50 kg, and weighing ≥50 kg had a mean ± SD steady-state trough concentration of 25.2±5.45 μg/ml (n=10) and 27.9±9.57 μg/ml (n=19), respectively.
Non-clinical data revealed no special hazard for humans (adult or paediatric) based on conventional studies of safety pharmacology, repeated dose and reproductive toxicity, or tissue cross-reactivity.
Animal studies have not been conducted to evaluate the carcinogenic potential of secukinumab.
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