Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2   Pharmacodynamics
Fedratinib inhibited cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis.
The inhibition of STAT3 phosphorylation was maximal approximately 2 hours after the first dose, with values returning to near baseline at 24 hours. After daily administration of fedratinib, levels of inhibition at steady state PK were similar to the maximal inhibition reached after the first dose of 300 (0.75 times the recommended dose), 400 or 500 mg (1.25 times the recommended dose) of fedratinib.
Cardiac Electrophysiology
The potential for QTc prolongation with fedratinib was evaluated in 31 patients with solid tumors. No large mean increase in the QTc interval (>20 ms) was detected with daily dosing of fedratinib 500 mg (1.25 times the recommended dose) for 14 days.

Pharmacokinetic Properties

12.3   Pharmacokinetics
INREBIC at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose) results in a dose proportional increase in geometric mean fedratinib peak concentrations (C max) and the area under the plasma concentration time curve over the dosing interval (AUCtau). The mean steady state levels are achieved within 15 days of daily dosing. The mean accumulation ratio ranged between 3- to 4-fold.
At the dose of 400 mg once daily, the geometric mean (coefficient of variation, %CV) fedratinib C max is 1804 ng/mL (49%) and AUCtau is 26870 ng.hr/mL (43%) in patients with myelofibrosis.
Absorption
Following 400 mg once daily, fedratinib median time to peak concentrations (T max) at steady-state is 3 hours (range: 2 to 4 hours).
Effect of Food
A low-fat, low-calorie (total 162 calories: 6% from fat, 78% from carbohydrate and 16% from protein) or a high-fat, high-calorie (total 815 calories: 52% from fat, 33% from carbohydrate and 15% from protein) meal increased area under the curve over time to infinity (AUC inf) up to 24% and Cmax up to 14% of a single 500 mg dose (1.25 times the recommended dose) of fedratinib.
Distribution


The apparent volume of distribution of fedratinib at steady-state is 1770 L in patients with myelofibrosis at 400 mg once daily dose. Fedratinib is 92% or greater bound to human plasma proteins.
Elimination
Fedratinib pharmacokinetics is characterized by a biphasic disposition with an effective half-life of 41 hours, a terminal half-life of approximately 114 hours, and apparent clearance (CL/F) (%CV) of 13 L/hr (51%) in patients with myelofibrosis.
Metabolism
Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3). Fedratinib accounts for approximately 80% of total circulating drug in plasma after oral administration.

Excretion
Following a single oral dose of radiolabeled fedratinib, 77% (23% unchanged) of the administered dose was excreted in feces and 5% (3% unchanged) was eliminated in urine.

Specific Populations
Age (20 years to 95 years), race (White, Asians), sex, body weight (40 kg to 135 kg), mild [total bilirubin ≤upper limit of normal (ULN) and AST >ULN or total bilirubin 1 to 1.5 times ULN and any AST] or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment, and mild (CLcr 60 mL/min to 89 mL/min by C-G) renal impairment did not have clinically meaningful effects on the pharmacokinetics of fedratinib.
The effect of severe (total bilirubin >3 times ULN and any AST) hepatic impairment on fedratinib pharmacokinetics is unknown.
Patients with Renal Impairment
Following a single 300 mg dose (0.75 times the recommended dose) of INREBIC, the AUC inf of fedratinib increased by 1.5-fold in subjects with moderate (CLcr 30 mL/min to 59 mL/min by C-G) renal impairment and 1.9-fold in subjects with severe (CLcr 15 mL/min to 29 mL/min by C-G) renal impairment, compared to that in subjects with normal renal function (CLcr ≥90 mL/min by C-G).

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches
Effect of Strong and Moderate CYP3A4 Inhibitors
Coadministration of ketoconazole (strong CYP3A4 inhibitor: 200 mg twice daily) with a single dose of INREBIC (300 mg; 0.75 times the recommended dose) increased fedratinib AUC inf by 3-fold.

Coadministration of ketoconazole (400 mg once daily) with INREBIC 400 mg once daily is predicted to increase fedratinib AUC at steady state by 2-fold.

Coadministration of moderate CYP3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), with INREBIC 400 mg once daily is predicted to increase fedratinib AUC at steady state by 1.2-, and 1.1-fold, respectively.

Effect of Dual CYP3A4 and CYP2C19 Inhibitor
Coadministration of fluconazole (dual CYP3A4 and CYP2C19 inhibitor; 200 mg once daily) with a single dose of fedratinib (100 mg; 0.25 times the recommended dose) increased AUC inf by 1.7-fold.

Coadministration of fluconazole (200 mg once daily) with INREBIC 400 mg once daily is predicted to increase fedratinib AUC at steady state by approximately 1.5-fold.

Effect of Strong and Moderate CYP3A4 Inducers
Coadministration of rifampin (strong CYP3A4 inducer: 600 mg once daily) or efavirenz (moderate CYP3A4 inducer: 600 mg once daily) with a single dose of fedratinib (500 mg; 1.25 times the recommended dose) decreased AUCinf of fedratinib by approximately 81% or 47%, respectively.

Effect of Gastric Acid Reducing Agents
Coadministration of pantoprazole (proton pump inhibitor: 40 mg once daily) with a single dose of INREBIC (500 mg; 1.25 times the recommended dose) increased fedratinib AUC inf by 1.2-fold.

Effect of Fedratinib on Drugs that are CYP3A, CYP2C19, or CYP2D6 Substrates Coadministration of a single dose of midazolam (CYP3A substrate: 2 mg), omeprazole (CYP2C19 substrate: 20 mg), and metoprolol (CYP2D6 substrate: 100 mg) with fedratinib increased midazolam, omeprazole, or metoprolol AUCinf by 4-, 3-, and 2-fold, respectively.
In Vitro and Clinical Transporter Studies
Fedratinib as a Substrate for Transporters:
Fedratinib is a substrate of P-glycoprotein (P-gp) but not breast cancer resistance protein (BCRP), BSEP, multidrug resistance protein (MRP2), and organic anion transporting polypeptide (OATP)1B1 and OATP1B3 in vitro.
Effect of Fedratinib on Transporter Substrates

Fedratinib inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, and MATE2-K, but not BSEP, MRP2, and organic anion transporter (OAT)1 and OAT3 in vitro.

Coadministration of a single dose of fedratinib (600 mg; 1.5 times the recommended dose) with a single dose of digoxin (P-gp substrate: 0.25 mg), rosuvastatin (OATP1B1/1B3 and BCRP substrate: 10 mg), and metformin (OCT2 and MATE1/2-K substrate: 1000 mg) had no clinically meaningful effect on the AUC inf of digoxin, rosuvastatin, and metformin. Renal clearance of metformin was decreased by 36% in the presence of fedratinib.
Contrary to unchanged PK, the glucose lowering PD effect of metformin in the presence of fedratinib appears reduced, with baseline adjusted glucose AUC being approximately 50% higher in response to an oral glucose challenge.