Exposure–Toxicity Relationship of Sorafenib in Japanese Patients with Renal Cell Carcinoma and Hepatocellular Carcinoma

Fukudo, Masahide; Ito, Takuma; Mizuno, Tomoyuki; Shinsako, Keiko; Hatano, Etsuro; Üemoto, Shinji; Kamba, Tomomi; Yamasaki, Toshinari; Ogawa, Osamu; Seno, Hiroshi; Chiba, Tsutomu; Matsubara, Kazuo

doi:10.1007/s40262-013-0108-z

Cited by 77 publications

(65 citation statements)

References 39 publications

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“…Different PK/PD studies have documented the relationship between severe drug-induced toxicities and plasma concentration of tyrosine kinase inhibitors such as sunitinib, erlotinib, sorafenib [7,8,[21][22][23][24]. The present study is the first to show that an increased concentration of vemurafenib is associated with an increased risk of grade≥2 skin rash in the first 3 months of treatment.…”

Section: Discussionsupporting

confidence: 48%

Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma

et al. 2015

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Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF (V600) -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0-6.0) and 11.0 (95% CI 7.0-16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21-1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG ≥ 1 (odds ratio 4.67; 95 % CI 1.39-15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5-5.5] vs. 4.5 [2-undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p < 0.0001). These results suggest that early plasma drug monitoring may help identify outpatients at high risk of non-response or grade ≥ 2 skin rash.

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Section: Discussionsupporting

confidence: 48%

Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma

et al. 2015

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“…Severe HFSR (grade ≥2) has been reported to be related to plasma drug concentration, cumulative drug area under the curve, and maintenance dose [21][22][23][24]. In the present study, no statistical difference was observed between non-HFSR and HFSR groups with regard to the initial doses patients received (data not shown).…”

Section: Discussioncontrasting

confidence: 60%

Association of Single Nucleotide Polymorphisms in STAT3 with Hand-Foot Skin Reactions in Patients with Metastatic Renal Cell Carcinoma Treated with Multiple Tyrosine Kinase Inhibitors: A Retrospective Analysis in Japanese Patients

et al. 2015

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“…Sorafenib steady‐state concentrations were found to be higher in patients with Grade ≥2 hand‐foot syndrome and hypertension than in those not experiencing these AEs ( P = 0.0045 and 0.0453, respectively). 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.…”

Section: Practical Recommendations For Tdm Of Kis In Oncologymentioning

confidence: 99%

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Verheijen

Schellens

et al. 2017

Clin Pharma and Therapeutics

228

287

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Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs.

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Exposure–Toxicity Relationship of Sorafenib in Japanese Patients with Renal Cell Carcinoma and Hepatocellular Carcinoma

Cited by 77 publications

References 39 publications

Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma

Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma

Association of Single Nucleotide Polymorphisms in STAT3 with Hand-Foot Skin Reactions in Patients with Metastatic Renal Cell Carcinoma Treated with Multiple Tyrosine Kinase Inhibitors: A Retrospective Analysis in Japanese Patients

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

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