Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

14.2    Pharmacodynamics
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized.
Cardiac Electrophysiology
At a dose 1.5 times the maximum recommended dose, KOSELUGO does not prolong the QT/QTc interval to any clinically relevant extent.

Pharmacokinetic Properties

14.3    Pharmacokinetics
At the recommended dosage of 25 mg/m2 twice daily in pediatric patients (2 to ≤ 18 years old), the mean maximum plasma concentration (Cmax) (coefficient of variation [CV%]) following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively. The mean area under the plasma drug concentration curve (AUC0-12h) following the first dose was 2009 (35%) ng•h/mL and the AUC0-6h at steady state was 1958 (41%) ng•h/mL. Selumetinib AUC and Cmax increases proportionally over a dose range from 20 mg/m2 to 30 mg/m2 (0.8 to 1.2 times the recommended dose). The accumulation was 1.1- fold following administration of KOSELUGO 25 mg/m2 twice daily.
Absorption
The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (Tmax) at steady-state in pediatric patients was 1 to 1.5 hours.
Effect of Food
Selumetinib Cmax and AUC decreased by 24% and 8%, respectively, following a low-fat meal (400 calories, 25% fat) in adolescent patients with NF1 and inoperable PN administered multiple doses of 25 mg/m2 twice daily and-. Tmax was delayed byapproximately 0.6 hours.


A population PK analysis including children and adolescent patients with NF1 and inoperable PN, adult patients with cancers, and healthy adults showed that a low or high-fat meal had no clinically relevant effect on the AUC of selumetinib.


Distribution
The mean apparent volume of distribution at steady state (Vss) of selumetinib across a dose range of 20 mg/m2 to 30 mg/m2 (0.8 to 1.2 times the recommended dosage) ranged from 78 L to 171 L in pediatric patients.
The plasma protein binding was 98.4% in humans in vitro. Selumetinib binds to serum albumin (96%) and α-1 acid glycoprotein (< 35%).
Elimination
In pediatric patients, selumetinib had an apparent oral clearance (CL/F) of 8.8 L/hr and a mean elimination half-life of approximately 6.2 hours following a dose of 25 mg/m2.
Metabolism
Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib could be attributed to CYP metabolism and about 29% attributed to direct glucuronidation by UGT enzymes in vitro. The active metabolite, N-desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and metabolized through the same routes as selumetinib.
N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately 3 to 5 times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.
Excretion
After a single oral dose of radiolabeled selumetinib 75 mg (1.5 times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (< 1% as parent).
Specific Populations
Racial or Ethnic Groups
No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on race (White, Asian, Black).
Patients with Renal Impairment
Following administration of a single dose of 50 mg, selumetinib exposures were similar in subjects with End Stage Renal Disease (CLcr < 15 mL/min) who required dialysis compared to subjects with normal renal function (CLcr ≥ 90 mL/min).
Patients with Hepatic Impairment
Following administration of a single-dose of selumetinib, dose normalized total AUC0-INF decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 59% in subjects with moderate hepatic impairment (Child-Pugh B) and by 57% in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function. Selumetinib unbound AUC0-INF decreased by 31% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 41% in subjects with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of Strong or Moderate CYP3A4 Inhibitors: Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased selumetinib AUC by 49% and Cmax by 19%. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and Cmax by 23%.
Effect of Fluconazole: Concomitant use of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased selumetinib AUC by 53% and Cmax by 26%.
Effect of Strong or Moderate CYP3A4 Inducers: Concomitant use of rifampicin (strong CYP3A4 inducer) decreased selumetinib AUC by 51% and Cmax by 26%. Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and Cmax by 22%.



In Vitro Studies
CYP Enzymes: Selumetinib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1. Selumetinib does not induce CYP3A4, CYP1A2, or CYP2B6.
Transporter Systems: Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters.
Selumetinib is a substrate of BCRP and P-gp transporters.