Tohoku J. Exp. Med., 2015 November, 237(3)

Monitoring Serum Levels of Sorafenib and Its N-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

MIKI SHIMADA,^1,2,* HOSHIMI OKAWA,² YASUTERU KONDO,³ TAKAHIRO MAEJIMA,¹ YUTA KATAOKA,¹ KANEHIKO HISAMICHI,¹ MASAMITSU MAEKAWA,¹ MASAKI MATSUURA,¹ YUKO JIN,⁴ MASARU MORI,¹ HIROYUKI SUZUKI,¹ TOORU SHIMOSEGAWA³ and NARIYASU MANO^1,2

¹Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi, Japan
²Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan
³Department of Gastroenterology, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
⁴Division of Nursing, Tohoku University Hospital, Sendai, Miyagi, Japan

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 Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17).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 (AUC_sorafenib and AUC_N-oxide, respectively). Inter-group comparison revealed that AUC_N-oxide and AUC ratio (AUC_N-oxide /AUC_sorafenib) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC_N-oxide and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC_N-oxide: 2.0 μg�Eday/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC_N-oxide ≤ 2.0 μg�Eday/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.

keywords —— drug-induced toxicity; hepatocellular carcinoma; sorafenib; sorafenib N-oxide; therapeutic drug monitoring

© 2015 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2015, 237, 173-182

Correspondence: Miki Shimada, Ph.D., Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

e-mail: shimada@hosp.tohoku.ac.jp

*Present address: Department of Hospital Pharmacy, Tottori University Hospital, 36-1 Nishi-cho, Yonago, Tottori 683-8504, Japan.

e-mail: shimada@med.tottori-u.ac.jp