Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma

Takasaki, Shinya; Kawasaki, Yoshihide; Kikuchi, Masafumi; Tanaka, Masaki; Suzuka, Masato; Noda, Aoi; Sato, Yuji; Yamashita, Shinichi; Mitsuzuka, Koji; Saitō, Hideo; Ito, Akihiro; Yamaguchi, Hiroaki; Arai, Yoichi; Mano, Nariyasu

doi:10.1007/s10147-018-1302-7

Cited by 28 publications

(30 citation statements)

References 23 publications

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“…Sunitinib sum C trough was significantly higher in patients with sunitinib‐induced toxicity prior to dose reduction compared to patients without sunitinib‐induced toxicity requiring dose reductions (median 60 vs 44 ng/mL; P < 0.001). Interestingly, however, the dose regimen normalized median sunitinib sum C trough of patients with sunitinib‐induced toxicity leading to dose reduction (60 ng/mL) in our study was lower compared to thresholds for toxicity that were previously reported (>75 ng/mL) 20,29,30 . Similarly, median PFS in patients with RCC in our cohort (31 weeks) was slightly shorter compared to that previously reported in clinical trials (8.3‐11 months) 31,32 .…”

Section: Discussioncontrasting

confidence: 83%

The relationship between sunitinib exposure and both efficacy and toxicity in real‐world patients with renal cell carcinoma and gastrointestinal stromal tumour

Westerdijk¹,

Krens²,

Graaf

et al. 2020

Brit J Clinical Pharma

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Aim Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Because of the large interpatient pharmacokinetic variability and established exposure‐response and exposure‐toxicity relationships in clinical trial patients, therapeutic drug monitoring (TDM) seems promising for optimizing sunitinib exposure. We aimed to investigate the relationship between sunitinib exposure and treatment outcome in a real‐world patient cohort. Methods We performed a retrospective observational cohort study in 53 patients with metastatic RCC and 18 patients with metastatic GIST treated with sunitinib and receiving TDM‐guided dosing. Time on treatment – as a surrogate for progression‐free survival – in patients who achieved adequate sunitinib exposure was compared with patients who did not. Additionaly, the median sunitinib exposure was compared in patients with or without sunitinib‐induced toxicity leading to dose reduction. Results The median time on treatment in patients with RCC who achieved adequate sunitinib exposure (n = 39) was 32 weeks, compared to 15 weeks in patients who did not achieve adequate sunitinib exposure (n = 12) (P = 0.244). In 29 patients (41%) with toxicity leading to dose reduction, sunitinib sum plasma trough concentration (Ctrough) until dose reduction was significantly higher compared to patients without toxicity leading to dose reduction (median 60 ng/mL vs 44 ng/mL; P < 0.001) and reduced to comparable levels after dose reduction (44 ng/mL; P = 0.488). Conclusion In our real‐world patient cohort, patients with sunitinib‐induced toxicity requiring dose reduction had significantly higher sunitinib exposure compared to patients without toxicity. The threshold for toxicity, however, was lower compared to that previously described in clinical trials.

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Section: Discussioncontrasting

confidence: 83%

The relationship between sunitinib exposure and both efficacy and toxicity in real‐world patients with renal cell carcinoma and gastrointestinal stromal tumour

Westerdijk¹,

Krens²,

Graaf

et al. 2020

Brit J Clinical Pharma

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“…Following Faivre et al, who described DLT at sum C trough ≥ 100 ng/mL, four other studies described a correlation between a high C trough and the occurrence of AEs . Two studies described treatment discontinuation for AEs at sum C trough > 75 ng/mL and > 100 ng/mL, respectively …”

Section: Methodsmentioning

confidence: 96%

“…DLT at sum C trough ≥ 100 ng/mL, four other studies described a correlation between a high C trough and the occurrence of AEs. 6,11,[40][41][42] Two studies described treatment discontinuation for AEs at sum C trough > 75 ng/mL and > 100 ng/mL, respectively. 40,41 Interestingly, toxicity also seems to be related to the country where patients are treated Lee et al described substantial differences in the incidences of various AEs between Asian patients who were treated in Asia or in countries outside of Asia.…”

Section: Clinical Thresholds For Responsementioning

confidence: 99%

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Westerdijk¹,

Desar²,

Steeghs

et al. 2020

Brit J Clinical Pharma

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Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.

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“…58 A single center study of mRCC in Japan shows that whether the blood concentration of SU is higher than that of 50ng/mL has no significant difference on OS, but the toxicity should be considered. 59 Patients with a concentration of higher than 100 ng/mL had a higher incidence of grade 3 or more toxicity. If patients have serious adverse effects caused by excessive blood concentration of SU, Cmin of SU should be monitored regularly and adjusted appropriately.…”

Section: Dovepressmentioning

confidence: 96%

Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors

Xu¹,

Liu²

2021

OTT

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Relationships between sunitinib plasma concentration and clinical outcomes in Japanese patients with metastatic renal cell carcinoma

Cited by 28 publications

References 23 publications

The relationship between sunitinib exposure and both efficacy and toxicity in real‐world patients with renal cell carcinoma and gastrointestinal stromal tumour

The relationship between sunitinib exposure and both efficacy and toxicity in real‐world patients with renal cell carcinoma and gastrointestinal stromal tumour

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors

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