Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

13.2     Pharmacodynamics
ADAKVEO resulted in a dose-dependent P-selectin inhibition (measured ex vivo) in patients with sickle cell disease and healthy volunteers.

Pharmacokinetic Properties

13.3     Pharmacokinetics
The pharmacokinetics of crizanlizumab were evaluated in healthy volunteers and patients with sickle cell disease. The mean crizanlizumab Cmax, AUClast, or AUCinf increased disproportionally over the dose range of 0.2 to 8 mg/kg (0.04 to 1.6 times the approved recommended dosage) in healthy volunteers. In healthy volunteers administered the 5 mg/kg dose, the mean [coefficient of variation (CV%)] crizanlizumab Cmax, AUClast, or AUCinf were 0.16 (15.3%) mg/mL, 33.6 (12.6%) mg*hr/mL and 34.6 (13.1%) mg*hr/mL, respectively.
Distribution
The mean (% CV) volume of distribution was 4.26 (25.1%) L after a single crizanlizumab 5 mg/kg intravenous infusion in healthy volunteers.
Elimination
The mean (% CV) terminal elimination half-life (t1/2) of crizanlizumab was 10.6 (20.5%) days and the mean clearance was 11.7 (16.2%) mL/hr at 5 mg/kg doses in healthy volunteers. The mean (% CV) elimination t1/2 of crizanlizumab was 11.4 (31.5%) days during dosing interval in patients with sickle cell disease.
Metabolism
Crizanlizumab is expected to be metabolized into small peptides by catabolic pathways. Specific Populations
The effect of renal or hepatic impairment on the pharmacokinetics of crizanlizumab is unknown.
Drug Interaction Studies
Hydroxyurea had no clinically meaningful effect on crizanlizumab pharmacokinetics in patients in clinical studies.
13.4   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 ADAKVEO or of other crizanlizumab products.
The immunogenicity of ADAKVEO was evaluated using a validated bridging immunoassay for the detection of binding anti-crizanlizumab antibodies. In a single arm, open label multiple dose study, 0 of the 45 patients with sickle cell disease treated with ADAKVEO 5 mg/kg tested positive for treatment-induced anti-crizanlizumab antibodies.
In a single-dose study of healthy subjects, 1 of the 61 (1.6%) evaluable subjects tested positive for a treatment-induced anti- crizanlizumab antibodies. No treatment induced anti-crizanlizumab antibodies were detected (0 of 84 patients) in a Phase 3 study at 5 mg/kg over the 52 week time period (samples collected at baseline, Weeks 3, 15, 19, 27, and 51).
Therefore, no significant effect on pharmacokinetics or pharmacodynamics has been observed or is expected.