Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
In clinical studies with CINQAIR 3 mg/kg, reductions in blood eosinophil counts were observed following the first dose and maintained through 52 weeks of treatment with no signs of tachyphylaxis. Mean eosinophil counts were 696 cells/mcL (n=245) and 624 cells/mcL (n=244) at baseline, and were 55 cells/mcL (92% reduction, n=212) and 496 cells /mcL (21% reduction, n=212) at the Week 52 visit for the CINQAIR and placebo treatment groups, respectively. Early eosinophil reduction was apparent in a subset of patients who had blood eosinophil counts assessed at days 2-3: 220 cells/mcL and 610/mcL for CINQAIR (n=35) and placebo (n=32), respectively.

Eosinophils returned towards baseline in those CINQAIR-treated patients who completed a 90-day follow-up assessment (n=35, 480 cells/mcL), approximately 120 days after the last dose of CINQAIR.

Reductions of blood eosinophils were related to reslizumab serum levels, i.e., greater reductions of blood eosinophils were observed in subjects with higher reslizumab serum concentrations.
Treatment-emergent anti-reslizumab antibodies did not interfere with the blood eosinophil reduction effect by reslizumab.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetics (PK) of reslizumab were characterized in healthy adults (n=130), in patients with asthma (n=438), and in other patient populations (n=236). The PK characteristics of reslizumab were similar across these populations. Inter-individual variability in peak and overall exposure was approximately 20-30%.
Peak serum concentrations were typically observed at the end of the infusion. Serum reslizumab concentrations generally declined from peak in a biphasic manner. Following multiple doses, serum concentrations of reslizumab accumulated approximately 1.5 to 1.9- fold.
Systemic exposure to reslizumab appeared to be unaffected by the presence of treatment- emergent anti-reslizumab antibodies.

Distribution
Reslizumab has a volume of distribution of approximately 5 liters, suggesting minimal distribution to the extravascular tissues.

Metabolism
Similar to other monoclonal antibodies, reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids. As reslizumab binds to a soluble target, it is not expected to go through a target-mediated clearance.

Elimination
Reslizumab clearance was approximately 7 mL/hour. Reslizumab has a half-life of about 24 days.

Specific Populations
Age, Race, and Gender

Population PK analyses demonstrated that there was no significant effect of age, race, or gender on the PK of reslizumab.

Hepatic Impairment
No clinical studies were conducted to assess the effect of hepatic impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal liver function tests (total bilirubin less than or equal to the ULN and aspartate aminotransferase [AST] less than or equal to the ULN) and mildly increased liver function tests (total bilirubin above the ULN and less than or equal to 1.5-times the ULN or AST greater than ULN and total bilirubin less than or equal to the ULN).

Renal Impairment
No clinical studies have been conducted to assess the effect of renal impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal renal function (estimated glomerular filtration rate [eGFR] greater than or equal to 90 mL/min/1.73 m2), mild renal impairment (eGFR 60-89 mL/min/1.73 m2), and moderate renal impairment (eGFR 30-59 mL/min/1.73 m2).

Drug Interactions
In vitro data indicate that IL-5 and reslizumab are unlikely to affect CYP1A2, 2B6, or 3A4 enzyme activity.
No formal clinical drug interaction studies have been conducted with reslizumab.
Population PK analyses indicate that concomitant use of either leukotriene antagonists or corticosteroids does not affect the PK of reslizumab.