Monitoring Serum Levels of Sorafenib and Its <i>N</i>-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 Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17).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.

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

“…Recently, another observational study has shown that sorafenib‐related adverse events were associated with a relatively higher exposure of the N‐oxide metabolite after 400 mg b.i.d. dosing 44. Therefore, a decreased frequency and/or severity of adverse events may be expected in patients with AML with a lower dosing regimen, such as the proposed dose of 200 mg b.i.d.…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…Optimal cutoffs were 5.78 mg/L for hand‐foot syndrome and 4.78 mg/L for hypertension 69. In a small cohort of 25 hepatocellular carcinoma patients, the AUC‐ratio of sorafenib and its metabolites resulted in even better prediction of toxicity ( P = 0.002) 70. The same cohort found that not sorafenib AUC but that of its metabolite seemed significantly associated with dose reduction or discontinuation ( P = 0.031) and increased PFS ( P = 0.048) 70.…”

“…In a small cohort of 25 hepatocellular carcinoma patients, the AUC‐ratio of sorafenib and its metabolites resulted in even better prediction of toxicity ( P = 0.002) 70. The same cohort found that not sorafenib AUC but that of its metabolite seemed significantly associated with dose reduction or discontinuation ( P = 0.031) and increased PFS ( P = 0.048) 70. A study in Japanese patients ( n = 91) found a trend toward increased OS in hepatocellular carcinoma patients at a sorafenib C max of ≥4.78 mg/L (12.0 vs. 6.5 months, P = 0.08) 69…”

Simultaneous analysis of oral anticancer drugs for renal cell carcinoma in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry

“…The ability to analyze many drug levels in blood simultaneously would resolve this problem, allowing adequate therapeutic management of RCC. However, the therapeutic windows of those four TKIs are different from each other (Faivre et al, ; Fukudo et al, ; Kato et al, ; Noda et al, ; Shimada et al, ; Suttle et al, ), and it is difficult to measure their plasma concentrations under the same conditions using LC/ESI‐MS/MS. Recently, we have demonstrated the usefulness of a linear range‐shifting technique using in‐source collision‐induced dissociation (CID), and shown that this technique is capable of analyzing the concentrations of a drug and its metabolites in human plasma simultaneously (Ishii, Shimada, et al, ; Ishii, Yamaguchi, & Mano, ; Ishii et al, ).…”