Alkixen 250mg (Crizotinib)

Description:

Following oral single-dose administration, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady state systemic exposure (C.min and AUC) appeared to increase in a greater than dose proportional manner over the dose range of 200-300 mg twice daily. The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following the administration of a single 250 mg oral dose. A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%.

Distribution:

The geometric mean volume of distribution (Vss) of crizotinib was 1772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma. Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotcin (P-gp). The blood-to-plasma concentration ratio is approximately 1.

Elimination:

Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients. Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/hr) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/hr), which was likely due to auto inhibition of CYP3A by crizotinib after multiple dosing.

Metabolism:

In vitro studies demonstrated that crizotinib is predominantly metabolized by CYP3A4/5. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O dealkylation, with subsequent Phase 2 conjugation of O-dcalkylatcd metabolites.