title: Monitoring Serum Levels of Sorafenib and Its N-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma.
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 Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17).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 (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 ∙ day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC(N-oxide) ≤ 2.0 μg ∙ 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.
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital.
authors.forename: Miki
authors.initials: M
authors.lastname: Shimada
authors.forename: Hoshimi
authors.initials: H
authors.lastname: Okawa
authors.forename: Yasuteru
authors.initials: Y
authors.lastname: Kondo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maejima
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kataoka
authors.forename: Kanehiko
authors.initials: K
authors.lastname: Hisamichi
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Maekawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsuura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Jin
authors.forename: Masaru
authors.initials: M
authors.lastname: Mori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000188:drug therapy*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006207:Half-Life; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D010087:Oxides / Q000097:blood*; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012372:ROC Curve; D000077157:Sorafenib; D013997:Time Factors; D028761:Withholding Treatment
chemical_list: D010087:Oxides; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib