Invest New Drugs (2011) 29:1511–1514 DOI 10.1007/s10637-010-9514-3
SHORT REPORT
Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma Charline Gomo & Romain Coriat & Lionel Faivre & Olivier Mir & Stanislas Ropert & Bertrand Billemont & Alain Dauphin & Michel Tod & Francois Goldwasser & Benoit Blanchet
Received: 8 June 2010 / Accepted: 27 July 2010 / Published online: 13 August 2010 # Springer Science+Business Media, LLC 2010
Summary 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 C. Gomo : R. Coriat : L. Faivre : O. Mir : S. Ropert : B. Billemont : A. Dauphin : F. Goldwasser : B. Blanchet Centre évaluation et de recours des inhibiteurs de l’angiogénèse (CERIA), GH Cochin- Hôtel Dieu, 27 rue faubourg Saint Jacques, Paris 75014, France C. Gomo : L. Faivre : A. Dauphin : B. Blanchet (*) Laboratoire de Pharmacologie-Toxicologie, Service de Pharmacie, GH Cochin- Hôtel Dieu, Paris, France e-mail:
[email protected] R. Coriat : O. Mir : S. Ropert : B. Billemont : F. Goldwasser Service d’oncologie Médicale, GH Cochin- Hôtel Dieu, Paris, France R. Coriat : O. Mir : S. Ropert : F. Goldwasser
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 sorafenibrelated hypertension. On day 30, hypertension was well controlled. However, sorafenib plasma concentration was 3fold greater (11.4 mg/L) and the patient experienced grade3 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. Keywords Sorafenib . CYP3A4 drug-drug interaction . Felodipine . Hypertension
EA 1833, faculté de médecine Paris Descartes, Paris V, Paris, France M. Tod Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France M. Tod Université de Lyon, F69008 Lyon, France
Introduction Sorafenib is an oral multikinase inhibitor that targets Raf as well as VEGF and PDGF tyrosine kinase receptors [1–3]. Sorafenib has demonstrated preclinical and clinical activity in a broad range of solid tumors [2, 4]. Sorafenib is currently
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approved in the United States and the European Union for the treatment of hepatocellular carcinoma (HCC) at the recommended dosage of 400 mg, twice daily (bid) [5]. The most frequent toxicities of sorafenib include diarrhea, skin toxicity, asthenia, anorexia and hypertension [6]. Sorafenib is subjected to two biotransformation pathways in humans: cytochrome P450 3A4 (CYP3A4)–mediated oxidation and UGT1A9–mediated glucuronidation [7]. Due to the contribution of these two biotransformation pathways, sorafenib is considered less susceptible than other agents to CYP3A4 drug–drug interactions. The case report analyzes the first case of a CYP3A4 drug-drug interaction involving sorafenib and the anti-hypertensive agent felodipine in a patient with HCC.
Invest New Drugs (2011) 29:1511–1514
Fig. 1 Follow-up of plasma sorafenib concentrations before and after felodipine introduction in a patient treated with sorafenib (400 mg twice daily) for hepatocellular carcinoma
Case report An 80-year-old Caucasian man (73 kg, 1.70 m), with a history of hepatitis B virus infection since 1998, was diagnosed in July 2003 with HCC. From November 2003 to April 2008, he underwent four sessions of radiofrequency ablation and three sessions of transarterial chemoembolization. In May 2008, a progressive liver disease was diagnosed. Our multidisciplinary staff for Digestive Oncology recommended the introduction of sorafenib, which was started in June 2008 at the recommended dosage (400 mg bid). Subsequently, daily dosages of sorafenib were adjusted based on clinical response and adverse events and not on plasma exposure to sorafenib. At sorafenib initiation (day 0), cirrhosis was categorized as Child-Pugh class A and liver tests were as follows: total bilirubin concentration 9 μmol/L (normal values : 3–17), serum albumin concentration 35 g/L (35–50), ALT 27 IU/L (10–45), AST 47 IU/L (10–45) and PAL 185 IU/L (35–120). Chronic medications included adefovir dipivoxil 100 mg/day, lamivudine 100 mg/day, furosemide 40 mg/day and propanolol 40 mg/day. On day 15, plasma sorafenib concentration assessed by high performance liquid chromatography [8] was at 3.6 mg/L. The patient experienced a weight loss of 3 kg, and developed grade-2 hypertension according to the Common Terminology Criteria for adverse events (version 3.0) from the National Cancer Institute. Subsequently, felodipine, a calcium channel blocker, was introduced at 5 mg twice daily to control hypertension. Two weeks later (day 30), hypertension was well controlled and remained so thereafter. The sorafenib plasma concentration increased to 11.4 mg/L (Fig. 1). Concomitantly, the patient experienced grade-3 anorexia, resulting in a loss of 13 kg over 1 month since the introduction of sorafenib. As neither diarrhea nor cutaneous side effects were noticed, sorafenib treatment was continued at the same daily dosage. On day 45, the 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)
without any daily dosage adjustment for sorafenib or felodipine. From day 45 to the treatment discontinuation, patient experienced grade-2 diarrhea (5 stools per day). By day 75, the patient had gained 4 kg over the past month. Within the following weeks, except grade-2 diarrhea, sorafenib treatment was better tolerated (grade-1 hoarseness and grade-1 asthenia). Sorafenib was discontinued on day 85 due to disease progression. The patient expired 5 months later.
Discussion Drug interactions are an important issue in the treatment of cancer patients, and could contribute to the intra-individual variability in sorafenib exposure. Lathia et al. reported that ketoconazole, a strong inhibitor of CYP3A4, did not significantly alter sorafenib exposure in healthy volunteers receiving a single-dose of sorafenib [9]. As the fraction of sorafenib metabolized by Phase I is low (
