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 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 through 40 weeks.
There was no apparent accumulation in serum mirikizumab concentration over time when given subcutaneously every 4 weeks.
Mean (coefficient variation [CV%]) 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 (22.7) µg/mL and 538 (34.4) µg*day/mL, respectively. The mean (CV%) Cmax and AUC after maintenance dosing (200 mg every 4 weeks by subcutaneous injection) were 10.1 (52.1) µg/mL and 160 (57.6) µg*day/mL, respectively.
Following subcutaneous dosing of mirikizumab, peak serum concentrations were achieved 2-3 days post dose with an estimated absolute bioavailability of 44%. Injection site location did not significantly influence absorption of mirikizumab.
The mean total volume of distribution was 4.83 L.
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, mean apparent clearance was 0.0229 L/hr and the mean elimination half-life is approximately 9.3 days in patients with ulcerative colitis. 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 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. 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.
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 30 times the human maintenance dose).
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
