This report describes the case of a 70 year old patient on warfarin for atrial fibrillation, who experienced elevated INRs and haemorrhage following the addition of sorafenib.

The patient was started on warfarin in April 2007 and stabilised on a dose of 36mg weekly. He was diagnosed with hepatocellular carcinoma and began treatment with sorafenib 200mg daily in September 2007. The patient arrived at the emergency room one month later with an INR of 39.5 and was admitted for lower-extremity haemorrhage and diagnosed with warfarin toxicity. Sorafenib and warfarin was discontinued. He was discharged on warfarin 3mg daily and in November, warfarin was increased to 36mg weekly, and his INR values stabilised. In late November, he was restarted on sorafenib 200mg daily and approximately two weeks later, his INR had increased to 4.7. Sorafenib was discontinued permanently. Both the Naranjo et al. probability scale score and the drug interaction probability scale score suggested that there was a probable interaction between warfarin and sorafenib.

The authors note that warfarin is hepatically metabolised via the cytochrome P-450 (CYP) system, including the isoenzymes 1A2, 2C9, 2C19, 2C18, and 3A4, and is 99% protein bound, whilst sorafenib undergoes oxidative metabolism mediated by CYP3A4 and glucuronidation mediated by UGT1A9 and is 99.5% protein bound. Furthermore, in vitro studies indicate that sorafenib is an inhibitor of CYP2C19, CYP2D6, and CYP3A4. They postulate that competitive inhibitors of CYP3A4 might decrease the metabolism of warfarin and lead to increased anticoagulant effects, and it is also possible that displacement from plasma proteins may occur if these two highly protein-bound medications are used concurrently.