duct. Co-administration of a single dose of midazolam (a sensitive CYP3A substrate) following 3 weeks of ceritinib dosing in patients (750 mg daily fasted) increased the midazolam AUCinf (90% CI) by 5.4-fold (4.6, 6.3) compared to midazolam alone. Co-administration of ceritinib with substrates primarily metabolised by CYP3A or CYP3A substrates known to have narrow therapeutic indices (e.g. alfuzosin, amiodarone, cisapride, ciclosporin, dihydroergotamine, ergotamine, fentanyl, pimozide, quetiapine, quinidine, lovastatin, simvastatin, sildenafil, midazolam, triazolam, tacrolimus, alfentanil and sirolimus) should be avoided and alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible. If unavoidable, dose reduction for co-administered medicinal products that are CYP3A substrates with narrow therapeutic indices should be considered.
Ceritinib has been classified in vivo as a weak CYP2C9 inhibitor. Co-administration of a single dose of warfarin (a CYP2C9 substrate) following 3 weeks of ceritinib dosing in patients (750 mg daily fasted) increased the S-warfarin AUCinf (90% CI) by 54% (36%, 75%) compared to warfarin alone. Co-administration of ceritinib with substrates primarily metabolised by CYP2C9 or CYP2C9 substrates known to have narrow therapeutic indices (e.g. phenytoin and warfarin) should be avoided. If unavoidable, dose reduction for co-administered medicinal products that are CYP2C9 substrates with narrow therapeutic indices should be considered. Increasing the frequency of international normalised ratio (INR) monitoring may be considered if co-administration with warfarin is unavoidable.
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, includ |
