Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics
Cardiac Electrophysiology
NINLARO did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients.

Pharmacokinetic Properties

11.3 Pharmacokinetics
Absorption
After oral administration, the median time to achieve peak ixazomib plasma concentrations was one hour. The mean absolute oral bioavailability was 58%, based on population PK analysis. Ixazomib AUC increases in a dose proportional manner over a dose range of 0.2 to 10.6 mg.
A food effect study conducted in patients with a single 4 mg dose of ixazomib showed that a high-fat meal decreased ixazomib AUC by 28% and Cmax by 69% [see Dosage and Administration (2.1)].
Distribution
Ixazomib is 99% bound to plasma proteins and distributes into red blood cells with a blood-to-plasma ratio of 10. The steady-state volume of distribution is 543 L.
Elimination
Based on a population PK analysis, systemic clearance was approximately 1.9 L/hr with inter- individual variability of 44%. The terminal half-life (t1/2) of ixazomib was 9.5 days. Following weekly oral dosing, the accumulation ratio was determined to be 2-fold.
Metabolism
After oral administration of a radiolabeled dose, ixazomib represented 70% of total drug-related material in plasma. Metabolism by multiple CYP enzymes and non-CYP proteins is expected to be the major clearance mechanism for ixazomib. At clinically relevant ixazomib concentrations, in vitro studies using human cDNA- expressed cytochrome P450 isozymes showed that no specific CYP isozyme predominantly contributes to ixazomib metabolism. At higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms with estimated relative contributions of 3A4 (42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (< 1%).

Excretion
After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for < 3.5% of the administered dose recovered in urine.
Specific Populations
There was no clinically meaningful effect of age (range 23-91 years), sex, body surface area (range 1.2-2.7 m2), or race on the clearance of ixazomib based on population PK analysis.

Patients with Hepatic Impairment
The PK of ixazomib was similar in patients with normal hepatic function and in patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1-1.5 x ULN and any AST) based on population PK analysis.
The PK of ixazomib was characterized in patients with normal hepatic function at 4 mg (N=12), moderate hepatic impairment at 2.3 mg (total bilirubin > 1.5-3 x ULN, N=13) or severe hepatic impairment at 1.5 mg (total bilirubin > 3 x ULN, N=18). Dose-normalized mean AUC was 20% higher in patients with moderate or severe hepatic impairment as compared to patients with normal hepatic function [see Dosage and Administration (2.3)].

Patients with Renal Impairment
The PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min) based on population PK analysis.
The PK of ixazomib was characterized at a dose of 3 mg in patients with normal renal function (creatinine clearance ≥ 90 mL/min, N=18), severe renal impairment (creatinine clearance < 30 mL/min, N=14), or ESRD requiring dialysis (N=6). Mean AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function. Pre- and post- dialyzer concentrations of ixazomib measured during the hemodialysis session were similar, suggesting that ixazomib is not dialyzable [see Dosage and Administration (2.4)].

Drug Interaction Studies
Effect of Other Drugs on NINLARO
Strong CYP3A Inducers
Co-administration of NINLARO with rifampin decreased ixazomib Cmax by 54% and AUC by 74% [see Drug Interactions (7.1)].

Strong CYP3A Inhibitors
Co-administration of NINLARO with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib.


Strong CYP1A2 Inhibitors
Co-administration of NINLARO with strong CYP1A2 inhibitors did not result in a clinically meaningful change in the systemic exposure of ixazomib based on a population PK analysis.
Effect of NINLARO on Other Drugs
Ixazomib is neither a reversible nor a time-dependent inhibitor of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Ixazomib did not induce CYP1A2, CYP2B6, and CYP3A4/5 activity or corresponding immunoreactive protein levels. NINLARO is not expected to produce drug-drug interactions via CYP inhibition or induction.


Transporter-Based Interactions
Ixazomib is a low affinity substrate of P-gp. Ixazomib is not a substrate of BCRP, MRP2 or hepatic OATPs.
Ixazomib is not an inhibitor of P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2-K. NINLARO is not expected to cause transporter-mediated drug-drug interactions.