Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
In patients with SLE, following the administration of anifrolumab at 300 mg dose, via intravenous infusion every 4 weeks for 52 weeks, neutralization (≥80%) of a type I IFN gene signature was observed from Week 4 to
Week 52 in blood samples of patients with elevated levels of type I IFN inducible genes and returned to baseline levels within 8 to 12 weeks following withdrawal of anifrolumab at the end of the 52-week treatment period. However, the clinical relevance of the type I IFN gene signature neutralization is unclear.

In SLE patients with positive anti-dsDNA antibodies at baseline (Trials 2 and 3), treatment with anifrolumab 300 mg led to numerical reductions in anti-dsDNA antibodies over time through Week 52.

In patients with low complement levels (C3 and C4), increases in complement levels were observed in patients receiving anifrolumab through Week 52.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The PK of anifrolumab was studied in adult patients with SLE following intravenous doses ranging from 100 to 1000 mg once every 4 weeks, and healthy volunteers following a single intravenous dose at 300 mg.
Anifrolumab exhibits non-linear PK in the dose range of 100 mg to 1000 mg with more than dose-proportional increases in the exposure as measured by AUC. Following the 300 mg every 4 weeks intravenous 


administrations of anifrolumab, steady-state was reached by Day 85. The accumulation ratio was approximately 1.36 for Cmax and 2.49 for Ctrough.
Distribution
Based on population PK analysis, the estimated volume of distribution at steady state for a typical patient with SLE (69.1 kg) is 6.23 L.
Elimination
From population PK analysis, anifrolumab exhibited non-linear PK due to IFNAR1-mediated drug clearance.

Following the administration of anifrolumab at a dose of 300 mg via intravenous infusion every 4 weeks, the estimated systemic clearance (CL) for anifrolumab was 0.193 L/day.
Based on population PK analysis of patients who received SAPHNELO for one year, serum concentrations of anifrolumab were below detection in 95% of patients approximately 16 weeks after the last dose.
Specific Populations
There was no clinically meaningful difference in systemic clearance based on age, race, ethnicity, region, gender, IFN status or body weight, that requires dose adjustment.

Age: Based on population PK analyses, age (range 18 to 69 years) did not affect anifrolumab clearance.
Limited PK data are available for elderly patients; 3% (n=20) of the patients included in the PK analysis were 65 years or older [see Use in Specific Populations (11.5)].

Renal Impairment: No specific clinical studies have been conducted to investigate the effect of renal impairment on anifrolumab. Based on population PK analyses, anifrolumab clearance was comparable in SLE patients with mild (60-89 mL/min/1.73 m2) and moderate (30-59 mL/min/1.73 m2) decrease in eGFR values and patients with normal renal function (≥90 mL/min/1.73 m2). There were no SLE patients with a severe decrease in eGFR or end stage renal disease (<30 mL/min/1.73 m2); anifrolumab is not cleared renally.

Patients with UPCR >2 mg/mg were excluded from the clinical trials. Based on population PK analyses, increased urine protein/creatinine ratio (UPCR) did not significantly affect anifrolumab clearance.

Hepatic Impairment: No specific clinical studies have been conducted to investigate the effect of hepatic impairment on anifrolumab. IgG1 monoclonal antibodies are predominantly eliminated via catabolism and are not expected to undergo hepatic metabolism; changes in hepatic function are not expected to influence anifrolumab clearance. Based on population PK analyses, baseline hepatic function biomarkers (ALT and AST ≤2.0 × ULN, and total bilirubin) had no clinically relevant effect on anifrolumab clearance.

Drug Interactions
No formal drug-drug interaction studies have been conducted.

Based on population PK analysis, concomitant use of oral corticosteroids, anti-malarials, immunosuppressants (azathioprine, methotrexate, mycophenolate mofetil, mycophenolic acid, and mizoribine), NSAIDs, ACE inhibitors, and HMG-CoA reductase inhibitors did not significantly affect the PK of anifrolumab.

12.6 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 anifrolumab.

In Trials 2, 3, and the long-term extension, treatment emergent anti-anifrolumab antibodies were detected in 9 of 350 (ADA incidence 2.6%) patients who received SAPHNELO at the recommended dosing regimen for up to 4 years.

Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of anifrolumab products is unknown.