The main drug-drug interactions associated with sorafenib include

CYP3A4 Inhibitors/ Inducers

CYP3A4 Inducers

Continuous co-administration of sorafenib and rifampicin resulted in an average 37% reduction of sorafenib AUC.1-3 Other inducers of CYP3A4 activity (for example, St. John’s wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations.1,2,4

CYP3A4 Inhibitors and CYP Isoform Substrates

In vitro and in vivo data suggest that: 1) sorafenib is unlikely to be altered by CYP3A inhibitors, and 2) sorafenib is unlikely to alter the metabolism of substrates of CYP2C19, CYP2D6, and CYP3A4.1,2,4

QT Prolongators

QTc Interval-Prolonging Drugs

Sorafenib prolongs the QT interval, hence, concomitant administration with patients taking certain anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, e.g. certain anti-arrhythmic drugs, should be used with caution.1,3

Other Drug-drug Interactions

Sorafenib and Neoplastic Agents

When used concomitantly with carboplatin and paclitaxel, sorafenib has been observed to increase the AUC of paclitaxel, and the AUC of sorafenib also increased. Sorafenib can also cause increases in plasma concentrations of doxorubicin, irinotecan, docetaxel, fluorouracil, and paclitaxel.1,2,5 Sorafenib is contraindicated in patients with squamous cell lung cancer, as a result of observed increased mortality with the addition of sorafenib.1,2

Sorafenib and CYP Inhibitors and Substrates

Sorafenib inhibits CYP2B6 and CYP2C8 in vitro. Systemic exposure to substrates of CYP2B6 and CYP2C8 is therefore expected to increase when co-administered with sorafenib.1,2

UGT1A1 and UGT1A9 Substrates

Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways.1,2 Systemic exposure to substrates of UGT1A1 and UGT1A9, such as acetaminophen, may therefore increase when co-administered with sorafenib.1,2,5 In clinical studies, when sorafenib was 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.1,2,4

P-glycoprotein Substrates

Sorafenib has been shown to inhibit p-glycoprotein. Hence, increased plasma concentrations of p-glycoprotein substrates, such as digoxin, may potentially occur if they are given concomitantly with sorafenib.1,2,4

Other Drug-Drug Interactions

The exposure of sorafenib was reduced by 54% in healthy volunteers who received neomycin.1,2,5

References

  1. European Medicines Agency. Sorafenib (NEXAVAR). Summary of Product Characteristics. 2015.
  2. Food and Drug Administration. Sorafenib (Nexavar) Prescribing information. 2015.
  3. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315-326.
  4. Pajares B, Torres E, Trigo JM et al. Tyrosine kinase inhibitors and drug interactions: a review with practical recommendations. Clin Transl Oncol 2012; 14: 94-101.
  5. Thomas-Schoemann A, Blanchet B, Bardin C et al. Drug interactions with solid tumour-targeted therapies. Crit Rev Oncol Hematol 2014; 89: 179-196.

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