lightly yellow solution. ILUMYA is supplied in a single-dose prefilled syringe witha glass barrel and 29-gauge fixed, 1/2-inch needle.
The syringe is fitted with a passive needle guard and a needle cover.
Each 1 mL single-dose prefilled syringe contains 100 mg of tildrakizumab-asmn formulated in: Lhistidine(0.495 mg), L-histidine hydrochloride monohydrate (1.42 mg), polysorbate 80 (0.5 mg), sucrose(70.0 mg), and Water for Injection, USP with a pH of 5.7-6.3.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunitof IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a 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 m(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%).
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 wasapproximately 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 TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to eva luate the carcinogenic or mutagenic potential ofILUMYA.
No effects on fertility parameters were observed in male or female cynomolgus monkeys that wereadministered tildrakizumab at subcutaneous or intravenous doses up to 140 mg/kg once ev |
