Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction
Inducers of metabolic enzymes
Administration of rifampicin for 5 days before administration of a single dose of sorafenib resulted in an average 37 % reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/or glucuronidation (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.

CYP3A4 inhibitors

Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest that clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.

CYP2B6, CYP2C8 and CYP2C9 substrates

Sorafenib inhibited CYP2B6, CYP2C8 and CYP2C9 in vitro with similar potency. However, in clinical pharmacokinetic studies, concomitant administration of sorafenib 400 mg twice daily with cyclophosphamide, a CYP2B6 substrate, or paclitaxel, a CYP2C8 substrate, did not result in a clinically meaningful inhibition. These data suggest that sorafenib at the recommended dose of 400 mg twice daily may not be an in vivo inhibitor of CYP2B6 or CYP2C8.
Additionally, concomitant treatment with sorafenib and warfarin, a CYP2C9 substrate, did not result in changes in mean PT-INR compared to placebo. Thus, also the risk for a clinically relevant in vivo inhibition of CYP2C9 by sorafenib may be expected to be low. However, patients taking warfarin or phenprocoumon should have their INR checked regularly (see section 4.4).

CYP3A4, CYP2D6 and CYP2C19 substrates

Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates for cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, did not alter the exposure of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes are unlikely.


UGT1A1 and UGT1A9 substrates

In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of this finding is unknown (see below and section 4.4).

In vitro studies of 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 and CYP3A4.

P-gp substrates

In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). Increased plasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitant treatment with sorafenib.

Combination with other anti-neoplastic agents

In clinical studies sorafenib has been administered with a variety of other anti-neoplastic agents at their commonly used dosing regimens including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, irinotecan, docetaxel and cyclophosphamide.
Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin or cyclophosphamide.


Paclitaxel/carboplatin o     Administration of paclitaxel (225 mg/m2) and carboplatin (AUC = 6) with sorafenib (≤ 400 mg twice daily), administered with a 3-day break in sorafenib dosing (two days prior to and on the day of paclitaxel/carboplatin administration), resulted in no significant effect on the pharmacokinetics of paclitaxel.
o      Co-administration of paclitaxel (225 mg/m2, once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6- OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.

These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered with sorafenib with a 3-day break in sorafenib dosing (two days prior to and on the day of paclitaxel/carboplatin administration). The clinical significance of the increases in sorafenib and paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.

Capecitabine

Co-administration of capecitabine (750-1050 mg/m2 twice daily, Days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure when co-administered with sorafenib is unknown.

Doxorubicin/Irinotecan

Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolised 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 (see section 4.4).
Docetaxel

Docetaxel (75 or 100 mg/m2 administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a 21-day cycle 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 sorafenib is co-administered with docetaxel (see section 4.4).
Combination with other agents

Neomycin
Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal flora, interferes with the enterohepatic recycling of sorafenib (see section 5.2, Metabolism and Elimination), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day regimen of neomycin the average exposure to sorafenib decreased by 54%. Effects of other antibiotics have not been studied, but will likely depend on their ability to interfere with microorganisms with glucuronidase activity.