antification limit (0.05 mcg/ml) 63 days after discontinuation of steady-state dosing of brodalumab 210 mg administered every 2 weeks in 95% of the patients. However, brodalumab concentrations below LLOQ (Lower Limit of Quantification) were associated with IL-17 receptor occupancy up to 81%.
Based on population pharmacokinetic modelling the estimated half-life of brodalumab was 10.9 days at steady-state after every other week subcutaneous dose of 210 mg.
Impact of weight on pharmacokinetics
Population pharmacokinetic modelling indicated that exposure decreased as body weight increased. No dose adjustment is recommended.
Elderly patients
Population pharmacokinetic modelling indicated that age did not have an effect on brodalumab pharmacokinetics, which was co-based on 259 (6%) patients being 65-74 years old and on 14 (0.3%) patients being ≥75 years old, within a total PK population of 4271 plaque psoriasis patients.
Renal or hepatic impairment
No pharmacokinetic data are available in patients with impaired renal or hepatic function. Renal elimination of intact brodalumab, an IgG monoclonal antibody, is expected to be low and of minor consequence. Brodalumab is expected to be mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance.
Other populations
The pharmacokinetics of brodalumab was similar between Japanese and non-Japanese patients with psoriasis.
Population pharmacokinetic analysis indicated that gender did not have an effect on brodalumab pharmacokinetics.
Pharmacokinetic/pharmacodynamic relationship(s)
A population pharmacokinetic/pharmacodynamic model, developed using all available data indicated that at a dose of 210 mg every 2 weeks, 90% of all patients would be predicted to maintain a trough concentration greater than the estimated IC90 value of 1.51 mcg/ml. Based on an exploratory descriptive analysis, no relationship was observed between exposure and incidence of serious infections and infestations, candida infections, viral infections, and suicidal ideation and behaviour events. Exposure-response analysis indicates that higher brodalumab concentrations are related to better PASI and sPGA response.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints and assessment of fertility-related endpoints), and toxicity to reproduction and development.
Carcinogenicity studies with brodalumab have not been conducted. However, there were no proliferative changes in cynomolgus monkeys administered weekly subcutaneous doses of brodalumab at 90 mg/kg for 6 months (AUC exposure 47-fold higher than in human patients receiving Kyntheum 210 mg every 2 weeks). The mutagenic potential of brodalumab was not eva luated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
In cynomolgus monkeys there were no effects on male and female reproductive organs and on sperm count, motility and morphology following administration of brodalumab at dose levels up to 90 mg/kg once weekly for 6 months, (AUC exposure up to 47-fold higher than in human patients receiving Kyntheum 210 mg every 2 weeks).
In cynomolgus monkeys, no effects on embryo-foetal or postnatal (up to 6 months of age) development were observed when brodalumab was dosed subcutaneously throughout pregnancy at exposure levels up to 27-fold higher than those ac |
