naturally occurring cytokine that isinvolved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatorycytokines and chemokines.
12.2 Pharmacodynamics
No formal pharmacodynamics studies have been conducted with ILUMYA.
12.3 Pharmacokinetics
Tildrakizumab pharmacokinetics increases proportionally over a dose range from 50 mg to 200 mg(0.5 to 2 times the approved recommended dosage) following subcutaneous administration in subjectswith plaque psoriasis. Steady-state concentrations were achieved by Week 16 following subcutaneousadministration of tildrakizumab at Weeks 0, 4, and every 12 weeks thereafter. At the 100 mg dose atWeek 16, the mean (± SD) steady-state trough concentrations ranged from 1.22 ± 0.94 mcg/mL to 1.47 ±1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%).
Data
Animal Data
In an embryofetal developmental study, subcutaneous doses up to 300 mg/kg tildrakizumab wereadministered to pregnant cynomolgus monkeys once every two weeks during organogenesis to gestationday 118 (22 days from parturition). No maternal or embryofetal toxicities were observed at doses up to300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed theplacenta in monkeys.
In a pre- and postnatal developmental study, subcutaneous doses up to 100 mg/kg tildrakizumabwere administered to pregnant cynomolgus monkeys once every two weeks from gestation day 50 toparturition. Neonatal deaths occurred in the offspring of one control monkey, two monkeys at 10 mg/kgdose (6 times the MRHD based on AUC comparison), and four monkeys at 100 mg/kg dose (59 times theMRHD based on AUC comparison). The clinical significance of these nonclinical findings is unknown. No
tildrakizumab-related adverse effects were noted in the remaining infants from birth through 6 months ofage.
Absorption
The absolute bioavailability of tildrakizumab was estimated to be 73-80% following subcutaneousinjection. The peak concentration (Cmax) was reached by approximately 6 days.
Distribution
The geometric mean (CV%) volume of distribution is 10.8 L (24%).
Elimination
The geometric mean (CV%) systemic clearance was 0.32 L/day (38%) and the half-life was
approximately 23 days (23%).
Metabolism
The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/kmonoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids viacatabolic pathways in a manner similar to endogenous IgG.
Specific Populations
No clinically significant differences in the pharmacokinetics of tildrakizumab were observed basedon age (≥18 years). No specific studies have been conducted to determine the effect of renal or hepaticimpairment on the pharmacokinetics of tildrakizumab.
Body Weight
Tildrakizumab concentrations were lower in subjects with higher body weight.
Drug Interaction Studies
Cytochrome P450 Substrates
The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantlywith tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously atWeeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine(CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam(CYP3A4 substrate) were observed.
13 NONCLINICAL TO |
