Bimekizumab is a humanised IgG1/κ monoclonal antibody that selectively binds with high affinity to IL-17A, IL-17F and IL-17AF cytokines, blocking their interaction with the IL-17RA/IL-17RC receptor complex. Elevated concentrations of IL-17A and IL-17F have been implicated in the pathogenesis of several immune-mediated inflammatory diseases including plaque psoriasis, psoriatic arthritis, axial spondyloarthritis and hidradenitis suppurativa. IL-17A and IL-17F cooperate and/or synergize with other inflammatory cytokines to induce inflammation. IL17-F is produced in significant amount by innate immune cells. This production can be independent of IL-23. Bimekizumab inhibits the proinflammatory cytokines, resulting in the normalization of skin inflammation and substantial decrease of local and systemic inflammation, and as a consequence improvement in clinical signs and symptoms associated with psoriasis, psoriatic arthritis, axial spondyloarthritis and hidradenitis suppurativa. From in vitro models, bimekizumab was shown to inhibit psoriasis-related gene expression, cytokine production, the migration of inflammatory cells and pathological osteogenesis to a greater extent than inhibition of IL-17A alone.
The pharmacokinetic (PK) properties of bimekizumab were similar in patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis (nr-axSpA and AS).
Based on population PK analyses and using a reference bodyweight of 90 kg, the bimekizumab apparent clearance and volume of distribution, respectively, in patients with hidradenitis suppurativa were estimated to be approximately 31 and 18% higher than for the aforementioned indications, with an estimated half-life in HS of 20 days. Consequently, the median steady state trough concentration at a dose of 320 mg every 4 weeks was approximately 40% lower in HS compared to other indications.
Based on population pharmacokinetic analysis, following a single subcutaneous dose of 320 mg in plaque psoriasis patients, bimekizumab reached a median (2.5th and 97.5th percentile) peak plasma concentration of 25 (12-50) μg/mL, between 3 and 4 days post dose.
Population pharmacokinetic analysis showed that bimekizumab was absorbed with an average absolute bioavailability of 70.1% in healthy volunteers.
Based on simulated data, the median (2.5th and 97.5th percentile) peak and trough concentration at steady-state following subcutaneous administration of 320 mg every 4 weeks are 43 (20-91) µg/mL and 20 (7-50) µg/mL respectively and steady-state is reached after approximately 16 weeks with every 4 weeks dosing regimen. Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 1.74-fold increase in peak plasma concentrations and area under the curve (AUC) following repeated four weekly dosing.
After switching from the 320 mg every 4 weeks dosing regimen to 320 mg every 8 weeks dosing regimen at week 16, steady-state is achieved approximately 16 weeks after the switch. Median (2.5th and 97.5th percentile) peak and trough plasma concentrations are 30 (14-60) μg/mL and 5 (1-16) μg/mL respectively.
Based on population pharmacokinetic analyses, the median (coefficient of variation ) volume of distribution (V/F) at steady state was 11.2 (30.5) L in plaque psoriasis patients.
Bimekizumab is a monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous immunoglobulins.
Based on population pharmacokinetic analyses, the median (coefficient of variation ) apparent clearance (CL/F) of bimekizumab was 0.337 L/day (32.7) and the mean terminal elimination halflife of bimekizumab was 23 days in clinical studies in patients with plaque psoriasis.
Bimekizumab exhibited dose-proportional pharmacokinetics in patients with plaque psoriasis over a dose range from 64 mg to 480 mg following multiple subcutaneous administrations, with apparent clearance (CL/F) being independent of dose.
A population pharmacokinetic/pharmacodynamic model was developed using all available data in moderate to severe plaque psoriasis patients. The analysis showed that higher bimekizumab concentrations are related to better Psoriasis Area and Severity Index (PASI) and Investigators Global Assessment (IGA) response. A dose of 320 mg every 4 weeks was shown to be an appropriate dose for the initial treatment period and 320 mg every 8 weeks thereafter is appropriate for the maintenance period for the majority of moderate to severe plaque psoriasis patients (see Special Populations, Body weight).
Population pharmacokinetic modelling indicated that exposure decreased as body weight increased. The average plasma concentration in adult patients weighing ≥120 kg following a 320 mg subcutaneous injection was predicted to be at least 30% lower than in adult patients weighing 90 kg. Dose adjustment may be appropriate in some patients.
Based on population pharmacokinetic analysis with a limited number of elderly patients (n=355 for age ≥65 years and n= 47 for age ≥75 years), apparent clearance (CL/F) in elderly patients and patients less than 65 years of age was similar. No dose adjustment is required.
No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of bimekizumab. The renal elimination of intact bimekizumab, an IgG monoclonal antibody, is expected to be low and of minor importance. Similarly, IgGs are mainly eliminated via intracellular catabolism and hepatic impairment is not expected to influence clearance of bimekizumab. Based on population pharmacokinetic analyses, hepatic function markers (ALT/bilirubin) did not have any impact on bimekizumab clearance in patients with plaque psoriasis.
No clinically meaningful differences in bimekizumab exposure were observed in Japanese or Chinese subjects compared to Caucasian subjects in a clinical pharmacokinetic study. No dose adjustment is required.
Population pharmacokinetic modelling indicated females may have 10% faster apparent clearance (CL/F) compared to males and it is not clinically meaningful. No dose adjustment is required.
Non-clinical data revealed no special hazard for humans based on tissue cross-reactivity testing, repeat-dose toxicity studies (including safety pharmacology endpoints and assessment of fertility-related endpoints) and evaluation of pre- and postnatal development in the cynomolgus monkey.
In cynomolgus monkeys, bimekizumab-related effects were limited to mucocutaneous changes consistent with pharmacologic modulation of commensal microflora.
No mutagenicity or carcinogenicity studies were conducted with bimekizumab. However monoclonal antibodies are not expected to damage DNA or chromosomes. In a 26-week chronic toxicology study in cynomolgus monkeys there were no pre-neoplastic or neoplastic lesions observed at a dose resulting in 109 times the human exposure at 320 mg every 4 weeks.
In a peri- and postnatal development study in the cynomolgus monkey, bimekizumab showed no effects on gestation, parturition, infant survival, foetal and postnatal development when administered throughout organogenesis until parturition at a dose resulting in 27 times the human exposure at 320 mg every 4 weeks based on AUC. At birth, serum bimekizumab concentrations in infant monkeys were comparable to those of mothers.
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