Tildrakizumab is a humanized IgG1/k monoclonal antibody that specifically binds to the p19 protein subunit of the interleukin-23 (IL-23) cytokine without binding to IL-12 and inhibits its interaction with the IL-23 receptor.
IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.
The subcutaneous formulation of tildrakizumab showed an absolute bioavailability ranging from 73% (90% CI: 46%-115%, 200 mg SC vs. 3 mg/kg IV) to 80% (90% CI: 62%-103%, 50 mg SC vs. 0.5 mg/kg IV) in healthy subjects, as a result of cross study single dose comparison. Maximum concentration was reached at 6.2 days after injection. Population PK analysis indicated a 31% higher bioavailability in healthy subjects compared to patients.
At steady state, following administration of 100 mg of tildrakizumab in subjects with moderate to severe plaque psoriasis geometric means (% CV) of AUC0-τ and Cmax values were respectively 305 μg·day/mL (41%) and 8.1 μg/mL (34%), whereas they were 612 μg·day/mL (40%) and 16.3 μg/mL (33%) following administration of 200 mg.
Tildrakizumab has limited extravascular distribution with volume of distribution (Vd) values ranging from 76.9 to 106 mL/kg.
Tildrakizumab is catabolized into component amino acids by general protein degradation processes. Small-molecule metabolic pathways (e.g., CYP450 enzymes, glucuronosyltransferases) do not contribute to its clearance.
Clearance values range from 2.04 to 2.52 mL/day/kg and the half-life was 23.4 days (23% CV) in subjects with plaque psoriasis.
Tildrakizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 50 mg to 400 mg following subcutaneous administration, with clearance being independent of dose.
Steady-state is achieved by 16 weeks with the clinical regimen of 0, 4, and every 12 weeks thereafter, with 1.1-fold accumulation in exposure between week-1 and week-12 independent of dose.
Population pharmacokinetic modelling indicated that exposure decreased as body weight increased. The geometric mean exposure (AUC0-τ at steady state) in adult patients weighing >90 kg following a 100 mg or 200 mg SC dose was predicted to be about 30% lower than in an adult patient weighing ≤90 kg.
Population pharmacokinetic analysis indicated that age did not have a clinically significant influence on the clearance of tildrakizumab in adult subjects with plaque psoriasis. Following administration of 100 mg or 200 mg of tildrakizumab, subjects who are 65 years or older (n=81 and n=82, respectively) had a similar tildrakizumab clearance as compared to subjects less than 65 years old (n=884).
No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of tildrakizumab was conducted. Tildrakizumab is catabolized into component amino acids by general protein degradation processes and is not eliminated by renal or hepatic pathways.
Results from a drug-drug interaction study conducted in plaque psoriasis subjects suggest that tildrakizumab had no clinically relevant effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Therefore, tildrakizumab does not impact the pharmacokinetics of concomitant medicines metabolized by CYP enzyme.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, and repeated dose toxicity.
Animal carcinogenicity studies have not been conducted with tildrakizumab. Studies in mouse tumor models showed that selective inhibition of IL-23p19 does not increase carcinogenic risk.
In cynomolgus monkeys, there was negligible secretion of the product into breast milk. One month after birth, the milk/serum ratio was ≤0.002. Tildrakizumab was shown to distribute across the placental barrier. After repeated dosing to pregnant cynomolgus monkeys, serum concentrations were quantifiable in the fetus, but the reproduction toxicity studies did not reveal any untoward effects.
No effects on fertility parameters such as reproductive organs, menstrual cycle length, and/or hormones were observed in male and female cynomolgus monkeys that were administered tildrakizumab at doses resulting in >100 times the human exposure at the recommended clinical dose based on AUC.
In a pre- and postnatal development toxicity study in monkeys, no related increase in pregnancy loss was observed at exposures up to 85 times the human exposure at the recommended dose. No harmful effects were noted in neonates at maternal exposures up to 9 times the human exposure at the recommended dose. Two neonatal deaths from monkeys administered tildrakizumab at maternal exposure of 85 times the human exposure at the recommended dose were attributed to possible viral infection and considered of uncertain relationship to the treatment. The clinical significance of these findings is unknown.
© 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.
