d Water for Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Risankizumab-rzaa is a humanized immunoglobulin G1 (IgG1) monoclonal antibody thatselectively binds to the p19 subunit of human interleukin 23 (IL-23) cytokine and inhibits itsinteraction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved ininflammatory and immune responses.
Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines.
12.2 Pharmacodynamics
No formal pharmacodynamics studies have been conducted with risankizumab-rzaa.
12.3 Pharmacokinetics
Risankizumab-rzaa plasma concentrations increased dose-proportionally from 90 to 180 mg andfrom 18 to 300 mg (0.6 to 1.2 and 0.12 to 2.0 times the approved recommended dosage)following subcutaneous administration in subjects with plaque psoriasis and healthy volunteers,respectively. Steady-state concentrations were achieved by Week 16 following subcutaneousadministration of risankizumab-rzaa at Weeks 0, 4, and every 12 weeks thereafter. At the 150 mgdose, the estimated steady-state peak concentration (Cmax) and trough concentration (Ctrough) wereapproximately 12 mcg/mL and 2 mcg/mL, respectively.
Absorption
The absolute bioavailability of risankizumab-rzaa was estimated to be 89% followingsubcutaneous injection. Cmax was reached by 3-14 days.
Distribution
The estimated steady-state volume of distribution (inter-subject CV%) was 11.2 L (34%) insubjects with plaque psoriasis.
Elimination
The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) and terminalelimination half-life was approximately 28 days in subjects with plaque psoriasis.
Metabolism
The metabolic pathway of risankizumab-rzaa has not been characterized. As a humanized IgG1monoclonal antibody, risankizumab-rzaa is expected to be degraded into small peptides andamino acids via catabolic pathways in a manner similar to endogenous IgG.
Specific Populations
No clinically significant differences in the pharmacokinetics of risankizumab-rzaa were observedbased on age (≥18 years). No specific studies have been conducted to determine the effect ofrenal or hepatic impairment on the pharmacokinetics of risankizumab-rzaa.
Body Weight
Risankizumab-rzaa clearance and volume of distribution increase and plasma concentrationsdecrease as body weight increases; however, no dose adjustment is recommended based on bodyweight.
Drug Interaction Studies
Cytochrome P450 Substrates
No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin(CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), ormidazolam (CYP3A substrate) were observed when used concomitantly with risankizumab-rzaa150 mg administered subcutaneously at Weeks 0, 4, 8 and 12 (more frequent than the approvedrecommended dosing frequency) in subjects with plaque psoriasis.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and mutagenicity studies have not been conducted with SKYRIZI.
No effects on male fertility parameters were observed in sexually mature male cynomolgusmonkeys subcutaneously treated with 50 mg/kg risankizumab-rzaa (at 20 times the clinicalexposure at the MRHD, based on mg/kg comparison) once weekly for 26 weeks.
14 CLINICAL STUDIES
Four multicenter, randomiz |
