Mirikizumab is a humanised IgG4 monoclonal, anti-interleukin-23 (anti-IL-23) antibody that selectively binds to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor.
IL-23, a regulatory cytokine, affects the differentiation, expansion, and survival of T cell subsets, (e.g., Th17 cells and Tc17 cells) and innate immune cell subsets, which represent sources of effector cytokines, including IL-17A, IL-17F and IL-22 that drive inflammatory disease. In humans, selective blockade of IL-23 was shown to normalise production of these cytokines.
Inflammatory biomarkers were measured in the phase 3 ulcerative colitis and Crohn’s disease studies. Mirikizumab administered intravenously every 4 weeks during induction dosing significantly reduced levels of fecal calprotectin and C-reactive protein from baseline to week 12. Also, mirikizumab administered subcutaneously every 4 weeks during maintenance dosing sustained significantly reduced levels of fecal calprotectin and C-reactive protein up to 52 weeks.
There was no apparent accumulation in serum mirikizumab concentration over time when given subcutaneously every 4 weeks.
Mean (coefficient of variation in ) Cmax and area under the curve (AUC) after induction dosing (300 mg every 4 weeks administered by intravenous infusion) in patients with ulcerative colitis were 99.7 μg/mL (22.7) and 538 μg*day/mL (34.4%), respectively. The mean (CV % ) Cmax and AUC after maintenance dosing (200 mg every 4 weeks by subcutaneous injection) were 10.1 μg/mL (52.1%) and 160 μg*day/mL (57.6%), respectively.
Mean (coefficient of variation in ) Cmax and area under the curve (AUC) after induction dosing (900 mg every 4 weeks administered by intravenous infusion) in patients with Crohn’s disease were 332 μg/mL (20.6) and 1820 μg*day/mL (38.1%), respectively. The mean (CV % ) Cmax and AUC after maintenance dosing (300 mg every 4 weeks by subcutaneous injection) were 13.6 μg/mL (48.1%) and 220 μg*day/mL (55.9%), respectively.
Following subcutaneous dosing of mirikizumab for ulcerative colitis, median (range) Tmax was 5 (3.08-6.75) days post dose and geometric mean (CV%) absolute bioavailability was 44% (34%). Following subcutaneous dosing of mirikizumab for Crohn’s disease, median (range) Tmax was 5 (3 to 6.83) days post dose and geometric mean (CV % ) absolute bioavailability was 36.3% (31%).
Injection site location did not significantly influence absorption of mirikizumab.
The geometric mean total volume of distribution was 4.83 L (21%) in patients with ulcerative colitis and 4.40 L (14%) in patients with Crohn’s disease.
Mirikizumab is a humanised IgG4 monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgGs.
In the population PK analysis, geometric mean (CV % ) clearance was 0.0229 L/hr (34%) and the geometric mean half-life is approximately 9.3 days (40%) in patients with ulcerative colitis. The geometric mean (CV % ) clearance was 0.0202 L/hr (38%) and the geometric mean (CV % ) half-life is also approximately 9.3 days (26%) in patients with Crohn’s disease. Clearance is independent of dose.
Mirikizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure over a dose range of 5 to 2 400 mg given as an intravenous infusion or over a dose range of 120 to 400 mg given as a subcutaneous injection in patients with ulcerative colitis or Crohn’s disease or in healthy volunteers.
Population pharmacokinetic analysis showed that age, sex, weight, or race/ethnicity did not have a clinically meaningful effect on the pharmacokinetics of mirikizumab. Among the 1 362 subjects with ulcerative colitis exposed to mirikizumab in Phase 2 and Phase 3 studies, 99 (7.3%) patients were 65 years or older and 11 (0.8%) patients were 75 years or older.
Specific clinical pharmacology studies to evaluate the effects of renal impairment and hepatic impairment on the pharmacokinetics of mirikizumab have not been conducted.
In patients with ulcerative colitis, population pharmacokinetic analysis showed that creatinine clearance (range of 36.2 to 291 mL/min) or total bilirubin (range of 1.5 to 29 μmol/L) did not affect mirikizumab pharmacokinetics.
In patients with Crohn’s disease, population pharmacokinetic analysis showed that creatinine clearance (range of 26.5 to 269 mL/min) or total bilirubin (range of 1.5 to 36 μmol/L) did not affect mirikizumab pharmacokinetics.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development.
Non-clinical studies have not been conducted to evaluate the carcinogenic or mutagenic potential of mirikizumab.
No reproductive organ weight or histopathology effects were observed in sexually mature cynomolgus monkeys that received mirikizumab once weekly for 26 weeks, at a dose of 100 mg/kg (at least 20 times the human maintenance dose).
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