Association of drug exposure with toxicity and clinical response in metastatic renal cell carcinoma patients receiving an attenuated dosing regimen of sunitinib

Abstract

An attenuated dosing (AD) regimen of 37.5 mg daily in repeated 4 week on, 2 week off cycles has been proposed to ameliorate frequent dose modifications caused by the toxicity observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aimed to determine the effect of drug exposure on toxicity and clinical response in patients receiving this regimen. All mRCC patients receiving AD sunitinib were invited to participate. In week 4 of each cycle, toxicity and plasma levels were assessed. Clinical responses were assessed after two cycles. A total of 36 patients were recruited. Patients who manifested ≥grade 2 mucositis (126.46 vs 84.81 ng/mL, p = 0.04) and altered taste (159.91 vs 105.22 ng/mL, p = 0.05) had higher total exposure than those who had grade 1 or no toxicity. Twenty-six patients completed two treatment cycles; four (15%) had partial responses, 15 (58%) had a stable disease and 7 (27%) had progressive disease. No difference in the exposure levels was found among the patients with different clinical outcomes. The AD regimen of sunitinib in Asian mRCC patients provided sufficient drug exposure with a lower incidence of toxicity, with higher drug exposure being observed in patients who experienced toxicity.

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

“…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).…”

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…Dose‐limiting and Grade ≥3 toxicities of sunitinib have been associated with total C min ≥100 ng/mL 17, 72. Grade ≥2 mucositis and altered taste have also been related to higher total C min 73. A relationship was also found between sunitinib AUC and Grade ≥3 toxicity ( P = 0.0005) 74.…”

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

“…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 …”

“…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.…”