Satoshi Noda1, Daiki Hira2,3, Rie Osaki4, Takehide Fujimoto4, Hiroya Iida5, Sachiko Tanaka-Mizuno6, Akira Andoh4, Masaji Tani5, Yoshito Ikeda2,7, Shin-Ya Morita2, Tomohiro Terada2. 1. Department of Pharmacy, Shiga University of Medical Science Hospital, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan. snoda@belle.shiga-med.ac.jp. 2. Department of Pharmacy, Shiga University of Medical Science Hospital, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan. 3. College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Japan. 4. Department of Gastroenterology, Shiga University of Medical Science, Otsu, Japan. 5. Department of Surgery, Shiga University of Medical Science, Otsu, Japan. 6. Department of Medical Statistics, Shiga University of Medical Science, Otsu, Japan. 7. Laboratory of Medicinal Cell Biology, Kobe Pharmaceutical University, Kobe, Japan.
Abstract
PURPOSE: Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS). RESULTS: The median sorafenib concentration was 2.91 μg/mL (range 0.74-8.8 μg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 μg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40 μg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45 µg/mL had a tendency to be longer than those of patients administered < 1.40 μg/mL and ≥ 3.45 μg/mL [median 17.8 months (1.40-3.45 μg/mL) vs. 5.3 months (< 1.40 μg/mL) and 9.5 months (≥ 3.45 μg/mL)]. CONCLUSIONS: From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 μg/mL in patients with HCC.
PURPOSE: Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS). RESULTS: The median sorafenib concentration was 2.91 μg/mL (range 0.74-8.8 μg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 μg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40 μg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45 µg/mL had a tendency to be longer than those of patients administered < 1.40 μg/mL and ≥ 3.45 μg/mL [median 17.8 months (1.40-3.45 μg/mL) vs. 5.3 months (< 1.40 μg/mL) and 9.5 months (≥ 3.45 μg/mL)]. CONCLUSIONS: From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 μg/mL in patients with HCC.
Authors: John C Panetta; Olivia Campagne; Jessica Gartrell; Wayne Furman; Clinton F Stewart Journal: Clin Transl Sci Date: 2021-06-01 Impact factor: 4.689