availability 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- 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.
Distribution
Tildrakizumab has limited extravascular distribution with volume of distribution (Vd) values ranging from 76.9 to 106 mL/kg.
Biotransformation
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.
Elimination
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.
Linearity/non-linearity
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.
Body weight
Population pharmacokinetic modelling indicated that exposure decreased as body weight increased. The geometric mean exposure (AUC0- 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 (see section 4.2).
Pharmacokinetics in special populations
Elderly
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).
Renal and Hepatic impairment
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.
Drug interactions
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 (see section 4.5).
5.3 Preclinical safety data
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 t |
