NINLARO® CLINICAL PHARMACOLOGY CARD
NINLARO® (ixazomib) Capsule for Patients with Multiple Myeloma
A reversible proteasome inhibitor, preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome.
|Pharmacodynamics (PD)||Did not prolong the QTc interval at clinically relevant exposures|
|Pharmacokinetics (PK)||Approximately 58% absolute bioavailability (median Tmax of 1 hour) in patients.
A 28% and 69% decreased in ixazomib AUC and Cmax, respectively, following the administration of NINLARO with a high-fat meal
AUC increased in a dose proportional manner over a dose range of 0.2 to 10.6 mg (i.e., 0.05 to 2.65 times the approved recommended dosage)
Accumulation approximately 2-fold
Systemic clearance was approximately 1.9 L/h and terminal half-life (t1/2) was 9.5 days
Extensive metabolism with both non-CYP and CYP enzymes contributing to ixazomib metabolism. At higher than clinical concentrations (in vitro), CYP3A4 is predominant (42%)
Plasma protein binding was approximately 99%.
Approximately 62% of the administered radioactivity was excreted in the urine (< 3.5% as unchanged drug) and 22% in the feces
|PK-PD Analysis||Did not prolong the QTc interval at clinically relevant exposures based on pharmacokinetic-pharmacodynamic analysis of data from 245 patients|
|Population PK||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|
|Special Populations||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)
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). Mean AUC was 39% higher in patients with severe renal impairment or ESRD requiring dialysis as compared to patients with normal renal function.
|Drug Interactions||Co-administration of ixazomib with rifampin decreased ixazomib Cmax by 54% and AUC by 74%
Co-administration of ixazomib with clarithromycin did not result in a clinically meaningful change in the systemic exposure of ixazomib
Ixazomib is a low affinity substrate of P-gp, but is not expected to cause transporter-mediated drug-drug interactions.
Source : http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf