UGT1A1 and UGT1A9 Substrates
Caution is recommended when administering NEXAVAR with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). Sorafenib inhibits glucuronidation by the UGT1A1 (Ki value: 1 µM) and UGT1A9 pathways (Ki value: 2 µM). Systemic exposure to substrates of UGT1A1 and UGT1A9 may increase when co-administered with NEXAVAR [see Warnings and Precautions ].
In clinical studies, when NEXAVAR was administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown.
Concomitant use of docetaxel (75 or 100 mg/m2 administered every 21 days) with NEXAVAR (200 or 400 mg twice daily), administered with a 3-day break in dosing around administration of docetaxel, resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax. Caution is recommended when NEXAVAR is co-administered with docetaxel [see Warnings and Precautions].
Concomitant treatment with NEXAVAR resulted in a 21% increase in the AUC of doxorubicin. Caution is recommended when administering doxorubicin with NEXAVAR. The clinical significance of these findings is unknown [see Warnings and Precautions ].
Both increases (21%-47%) and decreases (10%) in the AUC of fluorouracil were observed with concomitant treatment with NEXAVAR. Caution is recommended when NEXAVAR is co-administered with fluorouracil/leucovorin.
CYP2B6 and CYP2C8 Substrates
Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 µM, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered with NEXAVAR. Caution is recommended when administering substrates of CYP2B6 and CYP2C8 with NEXAVAR.
Continuous concomitant administration of NEXAVAR and rifampicin resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity (e.g. Hypericum perforatum also known as St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations [see Dosage and Administration (2)].
CYP3A4 Inhibitors and CYP Isoform Substrates
In vitro data indicate that sorafenib is metabolized by CYP3A4 and UGT1A9 pathways. Ketoconazole (400 mg), a potent inhibitor of CYP3A4, administered once daily for 7 days did not alter the mean AUC of a single oral 50 mg dose of sorafenib in healthy volunteers. Therefore, sorafenib metabolism is unlikely to be altered by CYP3A4 inhibitors.
Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C19, CYP2D6, and CYP3A4 as indicated by Ki values of 17 µM, 22 µM, and 29 µM, respectively. Administration of NEXAVAR 400 mg twice daily for 28 days did not alter the exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate). This indicates that sorafenib is unlikely to alter the metabolism of substrates of these enzymes in vivo.
Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C9 with a Ki value of 7-8 µM. The possible effect of sorafenib on the metabolism of the CYP2C9 substrate warfarin was assessed indirectly by measuring PT-INR. The mean changes from baseline in PT-INR were not higher in NEXAVAR patients compared to placebo patients, suggesting that sorafenib did not inhibit warfarin metabolism in vivo [see Warnings and Precautions].
In Vitro Studies: CYP Enzyme Induction
CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 or CYP3A4.
Combination with Other Antineoplastic Agents
In clinical studies, NEXAVAR has been administered with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, oxaliplatin, paclitaxel and carboplatin, doxorubicin, docetaxel, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant use of paclitaxel (225 mg/m2) and carboplatin (AUC=6) with NEXAVAR (100, 200 or 400 mg twice daily), administered with a 3-day break in dosing around administration of paclitaxel/carboplatin, resulted in no significant effect on the pharmacokinetics of paclitaxel. See Drug Interactions (7.1, 7.2, 7.3 and 7.4) for information about interactions with irinotecan, docetaxel, doxorubicin and fluorouracil/leucovorin