Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2         Pharmacodynamics
Cardiac Electrophysiology
The effect of NERLYNX on the QTc interval was evaluated in a randomized, placebo and positive-controlled, double-blind, single-dose, crossover study in 60 healthy subjects. At 140%the therapeutic exposures of NERLYNX, there was no clinically relevant effect on the QTc interval.

Pharmacokinetic Properties

12.3         Pharmacokinetics
Neratinib exhibits a non-linear PK profile with less than dose proportional increase of AUC with the increasing daily dose over the range of 40 to 400 mg.
Absorption
The neratinib and major active metabolites M3, M6 and M7 peak concentrations are reached in the range of 2 to 8 hours after oral administration.
Effect of Food
The food-effect assessment was conducted in healthy volunteers who received NERLYNX 240 mg under fasting conditions and with high-fat food (approximately 55% fat, 31% carbohydrate, and 14% protein) or standard breakfast (approximately 50% carbohydrate, 35% fat, and 15% protein). A high-fat meal increased neratinib Cmax and AUCinf by 70%(90% CI: 1.1- 2.7) and 120%(90% CI: 1.4- 3.5), respectively. A standard breakfast increased the Cmax and AUCinf by 20%(90% CI: 0.97- 1.42) and 10% (90% CI: 1.02- 1.24), respectively. [See Dosage and Administration (3.2)]
Distribution
In patients, following multiple doses of NERLYNX, the mean (%CV) apparent volume of distribution at steady-state (Vss/F) was 6433 (19%) L. In vitro protein binding of neratinib in human plasma was greater than 99% and independent of concentration. Neratinib bound predominantly to human serum albumin and human alpha-1 acid glycoprotein.
Elimination
Following 7 days of daily 240 mg oral doses of NERLYNX in healthy subjects, the mean (%CV) plasma half- life of neratinib, M3, M6, and M7 was 14.6 (38%), 21.6 (77%), 13.8 (50%) and 10.4 (33%) hours, respectively.
The mean elimination half-life of neratinib ranged from 7 to 17 hours following a single oral dose in patients.
Following multiple doses of NERLYNX at once-daily 240 mg in cancer patients, the mean (%CV) CL/F after first dose and at steady state (day 21) were 216 (34%) and 281 (40%) L/hour, respectively.
Metabolism
Neratinib is metabolized primarily in the liver by CYP3A4 and to a lesser extent by flavin-containing monooxygenase (FMO).
After oral administration of NERLYNX, neratinib represents the most prominent component in plasma. At steady state after 240 mg daily oral doses of NERLYNX in a healthy subject study (n=25), the systemic exposures (AUC) of the active metabolites M3, M6, M7 and M11were 15%, 33%, 22% and 4% of the systemic neratinib exposure (AUC) respectively.
Excretion
After oral administration of 200 mg (0.83 times of approved recommended dosage) radiolabeled neratinib oral formulation, fecal excretion accounted for approximately 97. % and urinary excretion accounted for 1.1% of the total dose. Sixty-one percent of the excreted radioactivity was recovered within 96 hours and 98% was recovered after 10 days.
Specific Populations
Age, gender, race, and renal function do not have a clinically significant effect on neratinib pharmacokinetics.
Patients With Hepatic Impairment
Neratinib is mainly metabolized in the liver. Single doses of 120 mg NERLYNX were evaluated in non-cancer patients with chronic hepatic impairment (n=6 each in Child Pugh Class A, B, and C) and in healthy subjects (n=9) with normal hepatic function. Neratinib exposures in the patients with Child Pugh Class A (mild impairment) and Child Pugh Class B (moderate impairment) were similar to that in normal healthy volunteers.
Patients with severe hepatic impairment (Child Pugh Class C) had neratinib Cmax and AUC increased by 173% and 181%, respectively, as compared to the normal hepatic function controls. [see Dosage and Administration (3.3) and Use in Specific Populations (8.6)].
Drug Interaction Studies
Gastric Acid Reducing Agents: NERLYNX solubility decreases with increasing GI tract pH values. Drugs that alter the pH values of the GI tract may alter the solubility of neratinib and hence its absorption and systemic exposure. When multiple doses of lansoprazole (30 mg daily), a proton pump inhibitor, were co-administered with a single 240 mg oral dose of NERLYNX, the neratinib Cmax and AUC decreased by 71% and 65%, respectively. When a single oral dose of 240 mg NERLYNX was administered 2 hours following a daily dose of 300 mg ranitidine, an H2 receptor antagonist, the neratinib Cmax and AUC were reduced by 57% and 48%, respectively. When a single oral dose of 240 mg NERLYNX was administered 2 hours prior to 150 mg ranitidine twice daily (administered in the morning and evening, approximately 12 hours apart), the neratinib Cmax and AUC were reduced by 44% and 32%, respectively. [See Dosage and Administration (3.3) and Drug Interactions (7.1)].
Strong CYP3A4 Inhibitors: Concomitant use of ketoconazole (400 mg once-daily for 5 days), a strong inhibitor of CYP3A4 and an inhibitor of P-gp, with a single oral 240 mg NERLYNX dose in healthy subjects (n=24) increased neratinib Cmax by 221% and AUC by 381% [see Drug Interactions (7.1)].
Moderate CYP3A4 and P-gp dual Inhibitors: Simulations using physiologically based pharmacokinetic (PBPK) models suggested that a moderate CYP3A4 and P-gp dual inhibitor (verapamil) may increase the Cmax and AUC of neratinib by 203% and 299%, respectively [see Drug Interactions (7.1)].
Moderate CYP3A4 inhibitors: Simulations using PBPK models suggested that a moderate CYP3A4 inhibitor (fluconazole) may increase the Cmax and AUC of neratinib by 30% and 68%, respectively.


Strong and Moderate CYP3A4 Inducers: Concomitant use of rifampin, a strong inducer of CYP3A4, with a single oral 240 mg NERLYNX dose in healthy subjects (n=24) reduced neratinib Cmax by 76% and AUC by 87%. The AUC of active metabolites M6 and M7 were also reduced by 37-49% when compared to NERLYNX administered alone. Simulations using PBPK models suggested that a moderate CYP3A4 inducer (efavirenz) may decrease the Cmax and AUC of neratinib by 36% and 52%, respectively [see Drug Interactions (7.1)].


Effect of NERLYNX on P-gp Transporters: Concomitant use of digoxin (a single 0.5 mg oral dose), a P-gp substrate, with multiple oral doses of NERLYNX 240 mg in healthy subjects (n=18) increased the mean digoxin Cmax by 54% and AUC by 32% [see Drug Interactions (7.2)].