Lebrikizumab is an immunoglobulin (IgG4) monoclonal antibody that binds with high affinity to interleukin (IL)-13 and selectively inhibits IL-13 signalling through the IL-4 receptor alpha (IL-4Rα)/ IL-13 receptor alpha 1 (IL-13Rα1) heterodimer, thereby inhibiting the downstream effects of IL-13. Inhibition of IL-13 signalling is expected to be of benefit in diseases in which IL-13 is a key contributor to the disease pathogenesis. Lebrikizumab does not prevent the binding of IL-13 to the IL-13 receptor alpha 2 (IL-13Rα2 or decoy receptor), which allows the internalisation of IL-13 into the cell.
In lebrikizumab clinical studies, lebrikizumab reduced the levels of serum periostin, total immunoglobulin E (IgE), CC chemokine ligand (CCL)17 [thymus and activation-regulated chemokine (TARC)], CCL18 [pulmonary and activation-regulated chemokine (PARC)], and CCL13 [monocyte chemotactic protein-4 (MCP-4)]. The decreases in the type 2 inflammation mediators provide indirect evidence of inhibition of the IL-13 pathway by lebrikizumab.
Anti-drug antibodies (ADA) were commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
After a subcutaneous dose of 250 mg lebrikizumab, peak serum concentrations were achieved approximately 7 to 8 days post dose.
Following the 500 mg loading doses at week 0 and week 2, steady-state serum concentrations were achieved with the first 250 mg Q2W dose at week 4.
Based on a population pharmacokinetic (PK) analysis, the predicted steady-state trough concentrations (Ctrough,ss) following lebrikizumab 250 mg Q2W and Q4W subcutaneous dosing in patients with atopic dermatitis (median and 5th-95th percentile) were 87 (46-159) µg/mL and 36 (18-68) µg/mL, respectively.
The absolute bioavailability was estimated at 86% based on a population PK analysis. Injection site location did not significantly influence the absorption of lebrikizumab.
Based on a population PK analysis, the total volume of distribution at steady-state was 5.14 L.
Specific metabolism studies were not conducted because lebrikizumab is a protein. Lebrikizumab is expected to degrade to small peptides and individual amino acids via catabolic pathways in the same manner as endogenous IgG.
In the population PK analysis, clearance was 0.154 L/day and was independent of dose. The mean elimination half-life was approximately 24.5 days.
Lebrikizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure over a dose range of 37.5 to 500 mg given as a subcutaneous injection in patients with AD or in healthy volunteers.
Gender, age (range 12 to 93 years), and race did not have a significant effect on the pharmacokinetics of lebrikizumab.
Specific clinical pharmacology studies to evaluate the effects of renal or hepatic impairment on the pharmacokinetics of lebrikizumab have not been conducted. Lebrikizumab, as a monoclonal antibody, is not expected to undergo significant renal or hepatic elimination. Population PK analyses show that markers of renal or hepatic function did not affect the pharmacokinetics of lebrikizumab.
Exposure to lebrikizumab was lower in subjects with higher body weight but this had no meaningful impact on clinical efficacy.
Based on population PK analysis adolescents 12 to 17 years of age with atopic dermatitis had slightly higher lebrikizumab serum trough concentrations compared to adults, which was related to their lower body weight distribution.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development.
The mutagenic potential of lebrikizumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with lebrikizumab. Evaluation of the available evidence related to IL-13 inhibition and animal toxicology data with lebrikizumab does not suggest carcinogenic potential for lebrikizumab.
No effects on fertility parameters were observed in sexually mature monkeys after a long-term intravenous (females) or subcutaneous (males) treatment with lebrikizumab. Lebrikizumab had no effects on embryo-fetal or postnatal development.
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