Crizanlizumab

Crizanlizumab-tmca is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands including P-selectin glycoprotein ligand 1.

Binding P-selectin on the surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, red blood cells, and leukocytes.

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

The pharmacokinetics of crizanlizumab-tmca were evaluated in healthy volunteers and patients with sickle cell disease. The mean crizanlizumab-tmca C_max, AUC_last, or AUC_inf 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-tmca C_max, AUC_last, or AUC_inf 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-tmca 5 mg/kg intravenous infusion in healthy volunteers.

Elimination

The mean (% CV) terminal elimination half-life (t_1/2) of crizanlizumab-tmca 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 t_1/2 of crizanlizumab-tmca was 7.6 (28.5%) days during dosing interval in patients with sickle cell disease.

Metabolism

Crizanlizumab-tmca 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-tmca is unknown.

Drug Interaction Studies

Hydroxyurea had no clinically meaningful effect on crizanlizumab-tmca pharmacokinetics in patients in clinical studies.

In the 26-week repeat-dose toxicity study, administration of crizanlizumab-tmca in cynomolgus monkeys at dose levels up to 50 mg/kg/dose once every 4 weeks resulted in inflammation of the vessels in multiple tissues in 2 out of 10 animals.