Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics
Brigatinib exposure-response relationships and the time course of the pharmacodynamic response are unknown.

Cardiac Electrophysiology
The QT interval prolongation potential of ALUNBRIG was assessed in 123 patients following once daily ALUNBRIG doses of 30 mg (0.16 times the recommended dose of 180 mg ) to 240 mg (1.3 times the recommended dose of 180 mg ). ALUNBRIG did not prolong the QT interval to a clinically relevant extent.

Pharmacokinetic Properties

11.3 Pharmacokinetics
The geometric mean (CV%) steady-state maximum concentration (Cmax) of brigatinib at ALUNBRIG doses of 90 mg and 180 mg once daily was 552 (49%) ng/mL and 1452 (60%) ng/mL, respectively, and the corresponding area under the concentration-time curve (AUC0-Tau) was 8165 (45%) ng·h/mL and 20276 
(62%) ng·h/mL. After a single dose and multiple dosing of ALUNBRIG, systemic exposure of brigatinib was dose proportional over the dose range of 60 mg (0.3 times the recommended dose of 180 mg ) to 240 mg (1.3 times the recommended dose of 180 mg ) once daily. The mean accumulation ratio after repeat dosing was 1.9 to 2.4.
Absorption
Following administration of single oral doses of ALUNBRIG of 30 mg to 240 mg, the median time to peak concentration (Tmax) ranged from 1 to 4 hours.
Effect of Food
Brigatinib Cmax was reduced by 13% with no effect on AUC in healthy subjects administered ALUNBRIG after a high fat meal (approximately 920 calories, 58 grams carbohydrate, 59 grams fat and 40 grams protein) compared to the Cmax and AUC after overnight fasting.
Distribution
Brigatinib is 91% bound to human plasma proteins and the binding is not concentration-dependent . The blood-to-plasma concentration ratio is 0.69. Following oral administration of ALUNBRIG 180 mg once daily, the mean apparent volume of distribution (Vz/F) of brigatinib at steady-state was 307 L.
Elimination
Following oral administration of ALUNBRIG 180 mg once daily, the mean apparent oral clearance (CL/F) of brigatinib at steady-state is 8.9 L/h and the mean plasma elimination half-life is 25 hours.
Metabolism
Brigatinib is primarily metabolized by CYP2C8 and CYP3A4 in vitro. Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, N-demethylation and cysteine conjugation were the two major metabolic pathways. Unchanged brigatinib (92%) was the major circulating radioactive component.
Excretion
Following oral administration of a single 180 mg dose of radiolabeled brigatinib to healthy subjects, 65% of the administered dose was recovered in feces and 25% of the administered dose was recovered in urine. Unchanged brigatinib represented 41% and 86% of the total radioactivity in feces and urine, respectively.


Specific Populations
Age, race, sex, body weight, and albumin concentration have no clinically meaningful effect on the pharmacokinetics of brigatinib.
Patients with Hepatic Impairment

Following a single dose of ALUNBRIG 90 mg, unbound brigatinib systemic exposure (AUC0-INF) was 37% higher in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function. Unbound brigatinib systemic exposure (AUC0-INF) was similar between subjects with mild (Child- Pugh A) to moderate (Child-Pugh B) hepatic impairment and subjects with normal hepatic function [see Dosage and Administration (3.6)].
Patients with Renal Impairment

Following a single dose of ALUNBRIG 90 mg, unbound brigatinib systemic exposure (AUC0-INF) was 86% higher in subjects with severe renal impairment [creatinine clearance (CLcr) 15 to 29 mL/min] compared to subjects with normal renal function.
Based on a population pharmacokinetic analysis, brigatinib exposures were similar among 125 subjects with mild renal impairment (CLcr 60 to 89 mL/min), 34 subjects with moderate renal impairment (CLcr 30 to 59 mL/min) and 270 subjects with normal renal function (CLcr ≥90 mL/min) [see Dosage and Administration (3.7)].


Drug Interaction Studies
Clinical Studies
Effect of Strong and Moderate CYP3A Inhibitors on Brigatinib:
Co-administration of 200 mg twice daily doses of itraconazole (a strong CYP3A inhibitor) with a single 90 mg dose of ALUNBRIG increased brigatinib Cmax by 21% and AUC0-INF by 101%, relative to a 90 mg dose of ALUNBRIG administered alone [see Dosage and Administration (3) , Drug Interactions (8.1)].
A moderate CYP3A inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.

Effect of Strong CYP2C8 Inhibitors in Brigatinib:
Co-administration of 600 mg twice daily doses of gemfibrozil (a strong CYP2C8 inhibitor) with a single 90 mg dose of ALUNBRIG decreased brigatinib Cmax by 41% and AUC0-INF by 12%, relative to a 90 mg dose of ALUNBRIG administered alone. The effect of gemfibrozil on the pharmacokinetics of brigatinib is not clinically meaningful and the underlying mechanism for the decreased exposure of brigatinib is unknown.

Effect of Strong and Moderate CYP3A Inducers on Brigatinib:
Co-administration of 600 mg daily doses of rifampin (a strong CYP3A inducer) with a single 180 mg dose of ALUNBRIG decreased brigatinib Cmax by 60% and AUC0-INF by 80%, relative to a 180 mg dose of ALUNBRIG administered alone [see Dosage and Administration (3.5), Drug Interactions (8.1)].A moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.

Effect of Brigatinib on CYP3A Substrates:
Coadministration of 180 mg daily doses of ALUNBRIG with a single 3 mg oral dose of midazolam (a sensitive CYP3A substrate) decreased midazolam Cmax by 16% and AUC0-INF by 26%, relative to a 3 mg oral dose of midazolam administered alone. Brigatinib is considered a weak inducer of CYP3A 
In Vitro Studies
Effect of Brigatinib on CYP Enzymes:
Brigatinib, at clinically relevant plasma concentrations, induced CYP3A via activation of the pregnane X receptor (PXR). Brigatinib may also induce CYP2C enzymes via the same mechanism at clinically relevant concentrations.
Brigatinib did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5 at clinically relevant concentrations.

Effect of P-glycoprotein and BCRP Inhibitors on Brigatinib:
Brigatinib is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Given that brigatinib exhibits high solubility and high permeability in vitro, P-gp and BCRP inhibitors are unlikely to increase plasma concentrations of brigatinib.

Effect of Other Transporters on Brigatinib:
Brigatinib is not a substrate of organic anion transporting polypeptide (OATP1B1, OATP1B3), organic anion transporter (OAT1, OAT3), organic cation transporter (OCT1, OCT2), multidrug and toxin extrusion protein (MATE1, MATE2K), or bile salt export pump (BSEP).

Effect of Brigatinib on Transporters:
Brigatinib is an inhibitor of P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Therefore, brigatinib may have the potential to increase concentrations of coadministered substrates of these transporters. Brigatinib at clinically relevant concentrations did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or BSEP.