Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
The pharmacodynamics of SPEVIGO in the treatment of patients with GPP have not been fully characterized.

Pharmacokinetic Properties

12.3 Pharmacokinetics
A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP, and patients with other diseases. After a single intravenous dose of 900 mg of SPEVIGO, the population PK model-estimated AUC0-∞ (95% CI) and Cmax (95% CI) in a typical anti-drug antibody (ADA)- negative patient with GPP were 4750 (4510, 4970) mcg·day/mL and 238 (218, 256) mcg/mL, respectively.

Spesolimab AUC increased dose-proportionally from 0.3 to 20 mg/kg, and CL and terminal half-life were independent of dose.

Distribution
Based on the population pharmacokinetic analysis, the typical total volume of distribution at steady state was 6.4 L.

Elimination
Metabolism
The metabolic pathway of spesolimab has not been characterized. As a humanized IgG1 monoclonal antibody, spesolimab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner Spevigo IV                                                              Prescribing Information Spesolimab 450mg                                                                     April 2024 similar to endogenous IgG.

Excretion
In the linear dose range (0.3 to 20 mg/kg), based on the population PK model, spesolimab clearance (95% CI) in a typical GPP patient without ADA, weighing 70 kg was 0.184 (0.175, 0.194) L/day. The terminal half- life was 25.5 (24.4, 26.3) days.

Specific Populations
Age, Gender, and Race
Based on population pharmacokinetic analyses, age, gender, and race did not have an effect on the pharmacokinetics of spesolimab.

Hepatic and Renal Impairment
As a monoclonal antibody, spesolimab is not expected to undergo hepatic or renal elimination. No formal study of the effect of hepatic or renal impairment on the pharmacokinetics of spesolimab was conducted.

Body Weight
Spesolimab concentrations were lower in subjects with higher body weight. The clinical impact of body weight on spesolimab plasma concentrations is unknown.

Drug Interaction Studies
No formal drug interactions studies have been conducted with spesolimab.

12.4 Immunogenicity
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of spesolimab or of other spesolimab products.

In subjects with GPP treated with SPEVIGO in Effisayil-1, ADAs formed with a median onset of 2.3 weeks.
Following administration of 900 mg intravenous SPEVIGO, (12/50) 24% of subjects had a maximum ADA titer greater than 4000 and were neutralizing antibody-positive by the end of the trial (Weeks 12 to 17). Females appeared to have higher immunogenicity response; the percentage of subjects with ADA titer greater than 4000 was 30% in females, and 12% in males, respectively.

Anti-Drug Antibody Effects on Pharmacokinetics
In subjects with ADA titers below 4000, there was no apparent impact on spesolimab pharmacokinetics. In most subjects with ADA titer values greater than 4000, plasma spesolimab concentrations were significantly reduced after reaching this ADA titer.
There are limited data on the impact of ADAs on safety and efficacy upon retreatment as the majority of subjects did not experience a subsequent, new flare in an open-label extension trial.