Sorafenib, an orally active multi-
kinase inhibitor approved for the treatment of
hepatocellular carcinoma (HCC), is primarily metabolized both via
cytochrome P450 3A4 isoform (
CYP3A4) and UGT1A9. Due to the contribution of these two biotransformation pathways,
sorafenib is considered to be less susceptible than other agents to
CYP3A4 drug-drug interactions. This report discusses a clinically relevant pharmacokinetic
CYP3A4 drug-drug interaction between
sorafenib and
felodipine in an 80-year-old Caucasian patient with HCC. On day 15, after the introduction of
sorafenib (400 mg bid),
sorafenib plasma concentration was at 3.6 mg/L.
Felodipine (5 mg bid), an
anti-hypertensive agent that is exclusively
CYP3A4 substrate, was then introduced due to grade 2
sorafenib-related
hypertension. On day 30,
hypertension was well controlled. However,
sorafenib plasma concentration was 3-fold greater (11.4 mg/L) and the patient experienced grade-3
anorexia. Since neither
diarrhea nor cutaneous side effects were noticed at this time,
sorafenib treatment was continued at the same daily dosage. On day 45,
sorafenib plasma concentration was stable (10.8 mg/L) before declining on days 60 and 75 (7.0 mg/L and 7.4 mg/L, respectively), which was probably related to an occurrence of grade-2
diarrhea. This observation suggests a pharmacokinetic interaction involving
CYP3A4 inhibition by
felodipine. According to the Drug Interaction Probability Scale, this interaction was possible. Since
hypertension is a common toxicity of
sorafenib, clinicians should be aware of this possible interaction. The clinical relevance of pharmacokinetic interactions involving
CYP3A4 inhibition in HCC patients receiving
sorafenib is analyzed in this case report.