Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2    Pharmacodynamics
Cardiac Electrophysiology
Twelve of 919 patients (1.3%) treated with ZYKADIA 750 mg once daily under fasted conditions with at least one post- baseline ECG assessment were found to have a QTc > 500 msec and 58 patients (6%) had an increase from baseline QTc> 60 msec. In ASCEND-4, a central tendency analysis of the QTc data at average steady-state concentrations demonstrated that the upper bound of the 2-sided 90% CI for QTc was 15.3 msec at ZYKADIA 750 mg once daily under fasted conditions. A pharmacokinetic / pharmacodynamic analysis suggested concentration-dependent QTc interval prolongation [see Warnings and Precautions (5.4)].
Ten of 925 patients (1.1%) had bradycardia defined as < 50 beats/ per minute [see Warnings and Precautions (5.6)].

Pharmacokinetic Properties

12.3    Pharmacokinetics
After a single oral administration of ZYKADIA in patients, AUC and Cmax increased dose proportionally over 50 mg to 750 mg under fasted conditions.

ZYK API FEB22 V5
Following ZYKADIA 750 mg once daily under fasted conditions, steady state was reached by 15 days with a geometric mean accumulation ratio of 6.2 after 3 weeks. Systemic exposure increased in a greater than dose proportional manner after repeat doses of 50 mg to 750 mg once daily under fasted conditions.
Absorption
After a single oral administration of ZYKADIA in patients, peak plasma levels (Cmax) of ceritinib were achieved around 4 to 6 hours.

Food Effect
A food effect study conducted in healthy subjects with a single 500 mg dose of ZYKADIA capsules showed that a high‐fat meal (containing approximately 1000 calories and 58 grams of fat) increased ceritinib AUC by 73% and Cmax by 41% and a low‐fat meal (containing approximately 330 calories and 9 grams of fat) increased ceritinib AUC by 58% and Cmax by 43% as compared with the fasted conditions.
A food effect study conducted in healthy subjects with a single 750 mg dose of ZYKADIA tablets showed that a high‐fat meal (containing approximately 1000 calories and 58 grams of fat) increased ceritinib AUC by 64% and Cmax by 58% and a low‐fat meal (containing approximately 330 calories and 9 grams of fat) increased ceritinib AUC by 39% and Cmax by 42% as compared with the fasted conditions
Dose Optimization Study: Dosing Regimen of 450 mg Daily with Food
In a dose optimization study (ASCEND-8) in patients receiving 450 mg dose of ZYKADIA capsules daily with food (approximately 100 to 500 calories and 1.5 to 15 grams of fat) or 750 mg daily under fasted conditions, there was no clinically meaningful difference in the systemic steady-state exposure of ceritinib (AUC) between the 450 mg with food arm and the 750 mg fasted arm.
Distribution
Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. The geometric mean apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg ZYKADIA dose under fasted conditions in patients. Ceritinib also has a slight preferential distribution to red blood cells, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35.
Elimination
Following a single 750 mg ZYKADIA dose under fasted conditions, the geometric mean apparent plasma terminal half-life (t1/2) of ceritinib was 41 hours in patients. Ceritinib demonstrates nonlinear PK over time.
The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h).

Metabolism: In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled dose under fasted conditions ceritinib was the main circulating component (82%) in human plasma.
Excretion: Following oral administration of a single 750 mg radiolabeled dose under fasted conditions, 92% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine.
Specific Populations
Age, sex, race, body weight, and mild-to-moderate renal impairment (CLcr 30 to < 90 mL/min estimated with Cockcroft- Gault) has no clinically important effect on the systemic exposure of ceritinib based on population pharmacokinetic analyses. Patients with severe renal impairment (CLcr < 30 mL/min) were not included in the clinical trial.
ZYK API FEB22 V5
Patients with Hepatic Impairment: Following a single 750 mg ZYKADIA dose under fasted conditions, the geometric mean systemic exposure (AUC0-INF) of ceritinib was increased by 66% and unbound ceritinib AUC0-INF was increased by 108% in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function [see Dosage and Administration (2.5)]. Total and unbound systemic exposure of ceritinib were similar in subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment compared to subjects with normal hepatic function.
Drug Interaction Studies
Effect of Strong CYP3A/P-gp Inhibitors on Ceritinib: Coadministration of a single 450 mg ZYKADIA dose under fasted conditions with ketoconazole (a strong CYP3A/P-gp inhibitor) for 14 days increased ceritinib AUC by 2.9- fold and Cmax by 22%. The steady-state AUC of ceritinib at a dose of 450 mg once daily under fasted conditions with ketoconazole for 14 days was predicted to be similar to the steady-state AUC of ceritinib at a dose of 750 mg alone under fasted conditions.
Effect of Strong CYP3A/P-gp Inducers on Ceritinib: Coadministration of a single 750 mg ZYKADIA dose under fasted conditions with rifampin (a strong CYP3A/P-gp inducer) for 14 days decreased ceritinib AUC by 70% and Cmax by 44%.
Effect of Ceritinib on CYP3A Substrates: Coadministration of a single dose of midazolam (a sensitive CYP3A substrate) following 3 weeks of ZYKADIA (750 mg daily under fasted conditions) increased the midazolam AUC by 5.4-fold and Cmax by 1.8-fold compared to midazolam administered alone [see Drug Interactions (7.2)].
Effect of Ceritinib on CYP2C9 Substrates: Coadministration of a single dose of warfarin (a CYP2C9 substrate) following 3 weeks of ZYKADIA (750 mg daily under fasted conditions) increased the S-warfarin AUC by 54% with no change in Cmax compared to warfarin administered alone [see Drug Interactions (7.2)].
Effect of Acid Reducing Agents on Ceritinib: Coadministration of a single 750 mg ZYKADIA dose under fasted conditions with a proton pump inhibitor (esomeprazole) for 6 days in healthy subjects decreased ceritinib AUC by 76% and Cmax by 79%; however, coadministration of a single 750 mg ZYKADIA dose under fasted conditions with proton pump inhibitors for 6 days in a subgroup of patients from ASCEND-1 suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC decreased by 30% and Cmax decreased by 25% and no clinically meaningful effect on ceritinib exposure was observed at steady-state.
Effect of Transporters on Ceritinib Disposition: Ceritinib is a substrate of efflux transporter P-gp, but is not a substrate of BCRP, MRP2, OCT1, OAT2, or OATP1B1 in vitro .
Effect of Ceritinib on Transporters: Based on in vitro data, ceritinib is unlikely to inhibit P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2 at clinical concentrations.