Zykadia Drug Interactions

Agents that may increase ceritinib plasma concentrations: In healthy subjects, co-administration of a single 450 mg fasted ceritinib dose with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A/P-gp inhibitor, resulted in 2.9-fold and 1.2-fold increase in ceritinib AUC_inf and C_max, respectively, compared to when ceritinib was given alone. The steady-state AUC of ceritinib at reduced doses after co-administration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib alone. If it is not possible to avoid concomitant use with strong CYP3A inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone), reduce the ceritinib dose by approximately one third, rounded to the nearest multiple of the 150 mg dosage strength. After discontinuation of a strong CYP3A inhibitor, resume the ceritinib dose that was taken prior to initiating the strong CYP3A inhibitor.
P-gp inhibitors: Based on in vitro data, ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If ceritinib is administered with medicinal products that inhibit P-gp, an increase in ceritinib concentration is likely. Caution should be exercised with concomitant use of P-gp inhibitors and ADRs carefully monitored.
Agents that may decrease ceritinib plasma concentrations: Strong CYP3A and P-gp inducers: In healthy subjects, co-administration of a single 750 mg fasted ceritinib dose with rifampicin (600 mg daily for 14 days), a strong CYP3A/P-gp inducer, resulted in 70% and 44% decreases in ceritinib AUC_inf and C_max, respectively, compared to when ceritinib was given alone. Co-administration of ceritinib with strong CYP3A/P-gp inducers decreases ceritinib plasma concentrations. Concomitant use of strong CYP3A inducers should be avoided; this includes, but is not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John's Wort (Hypericum perforatum). Caution should be exercised with concomitant use of P-gp inducers.
Agents that affect gastric pH: Ceritinib demonstrates pH-dependent solubility and becomes poorly soluble as pH increases in vitro. Acid reducing agents (e.g., proton pump inhibitors, H₂-receptor antagonists, antacids) can alter the solubility of ceritinib and reduce its bioavailability. Co-administration of a single 750 mg fasted ceritinib dose with a proton pump inhibitor (esomeprazole) 40 mg daily for 6 days in healthy, fasting subjects decreased ceritinib AUC by 76% and C_max by 79%. The drug-drug interaction study was designed to observe the impact of proton pump inhibitor in the worst scenario, but in clinical use the impact of proton pump inhibitor on ceritinib exposure appears to be less pronounced. A dedicated study to evaluate the effect of gastric acid-reducing agents on the bioavailability of ceritinib under steady state has not been conducted. Caution is advised with concomitant use of proton pump inhibitors, as exposure of ceritinib may be reduced. There is no data with concomitant use of H₂ blockers or antacids. However, the risk for a clinically relevant decrease in bioavailability of ceritinib is possibly lower with concomitant use of H₂ blockers if they are administered 10 hours before or 2 hours after the ceritinib dose, and with antacids if they are administered 2 hours before or 2 hours after the ceritinib dose.
Agents whose plasma concentration may be altered by ceritinib: CYP3A and CYP2C9 substrates: Based on in vitro data, ceritinib competitively inhibits the metabolism of a CYP3A substrate, midazolam, and a CYP2C9 substrate, diclofenac. Time-dependent inhibition of CYP3A was also observed. The steady-state C_max value of ceritinib at the dose of 450 mg daily taken with food may exceed the Ki values for CYP3A and CYP2C9, suggesting that ceritinib could inhibit the clearance of other medicinal products metabolised by these enzymes at clinically relevant concentrations. Dose reduction may be needed for co-administered medicinal products that are predominantly metabolised by CYP3A and CYP2C9. Co-administration of ceritinib with CYP3A substrates known to have narrow therapeutic indices (e.g. astemizole, cisapride, ciclosporin, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus) and CYP2C9 substrates known to have narrow therapeutic indices (e.g. phenytoin and warfarin) should be avoided.
CYP2A6 and CYP2E1 substrates: Based on in vitro data, ceritinib also inhibits CYP2A6 and CYP2E1 at clinically relevant concentrations. Therefore, ceritinib may have the potential to increase plasma concentrations of co-administered medicinal products that are predominantly metabolised by these enzymes. Caution should be exercised with concomitant use of CYP2A6 and CYP2E1 substrates and ADRs carefully monitored.
A risk for induction of other PXR regulated enzymes apart from CYP3A4 cannot be completely excluded. The effectiveness of concomitant administration of oral contraceptives may be reduced.
Agents that are substrates of transporters: Based on in vitro data, ceritinib does not inhibit apical efflux transporter MRP2, hepatic uptake transporters OATP1B1 or OATP1B3, renal organic anion uptake transporters OAT1 and OAT3, or the organic cation uptake transporters OCT1 or OCT2 at clinically relevant concentrations. Therefore, clinical drug-drug interactions as a result of ceritinib-mediated inhibition of substrates for these transporters are unlikely to occur. Based on in vitro data, ceritinib is predicted to inhibit intestinal P-gp and BCRP at clinically relevant concentrations. Therefore, ceritinib may have the potential to increase plasma concentrations of co-administered medicinal products transported by these proteins. Caution should be exercised with concomitant use of BCRP substrates (e.g. rosuvastatin, topotecan, sulfasalazine) and P-gp substrates (digoxin, dabigatran, colchicine, pravastatin) and ADRs carefully monitored.
Pharmacodynamic interactions: In clinical studies, QT prolongation was observed with ceritinib. Therefore, ceritinib should be used with caution in patients who have or may develop prolongation of the QT interval, including those patients taking anti-arrhythmic medicinal products such as class I (e.g. quinidine, procainamide, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) anti-arrhythmics or other medicinal products that may lead to QT prolongation such as astemizole, domperidone, droperidol, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, cisapride and moxifloxacin. Monitoring of the QT interval is indicated in the event of combinations of such medicinal products (see Dosage & Administration and Precautions).
Food/drink interactions: Zykadia should be taken with food. The bioavailability of ceritinib is increased in the presence of food (see Pharmacology: Pharmacokinetics under Actions).
For patients who develop a concurrent medical condition and are unable to take Zykadia with food, Zykadia can be taken on an empty stomach as the alternate continued treatment regimen, in which no food should be eaten for at least two hours before and one hour after the dose. Patients should not alternate between fasted and fed dosing. Dose must be adjusted properly, i.e for patients treated with 450 mg or 300 mg with food, the dose should be increased to 750 mg or 450 mg taken on an empty stomach, respectively (see Pharmacology: Pharmacokinetics under Actions) and for patients treated with 150 mg with food treatment should be discontinued. For subsequent dose adjustment and management recommendations for ADRs, please follow table 5 (see Dosage & Administration). The maximum allowable dose under fasted condition is 750 mg (see Pharmacology: Pharmacokinetics under Actions).
Patients should be instructed to avoid grapefruit and grapefruit juice as they may inhibit CYP3A in the gut wall and may increase the bioavailability of ceritinib.