Monitoring serum levels of sorafenib and its N-oxide is essential for long-term sorafenib treatment of patients with hepatocellular carcinoma

Miki Shimada, Hoshimi Okawa, Yasuteru Kondo, Takahiro Maejima, Yuta Kataoka, Kanehiko Hisamichi, Masamitsu Maekawa, Masaki Matsuura, Yuko Jin, Masaru Mori, Hiroyuki Suzuki, Tooru Shimosegawa, Nariyasu Mano

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUCsorafenib and AUCN-oxide, respectively). Inter-group comparison revealed that AUCN-oxide and AUC ratio (AUCN-oxide /AUCsorafenib) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUCN-oxide and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUCN-oxide: 2.0 μ g∙day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUCN-oxide ≤ 2.0 μ g∙day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.

Original languageEnglish
Pages (from-to)173-182
Number of pages10
JournalTohoku Journal of Experimental Medicine
Volume237
Issue number3
DOIs
Publication statusPublished - 2015 Oct 16

Keywords

  • Drug-induced toxicity
  • Hepatocellular carcinoma
  • Sorafenib
  • Sorafenib N-oxide
  • Therapeutic drug monitoring

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Monitoring serum levels of sorafenib and its N-oxide is essential for long-term sorafenib treatment of patients with hepatocellular carcinoma'. Together they form a unique fingerprint.

Cite this