Gandhi Khushboo A, Joshi Amit, Mehta Parsshava, Gurjar Murari, Rane Pallavi, Sharma Jyoti, Patil Anand, Nookala Manjunath, Noronha Vanita, Prabhash Kumar, Gota Vikram
Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Sector-22, Kharghar, Navi Mumbai, 410210, India.
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, 400012, India.
Cancer Chemother Pharmacol. 2022 Jun;89(6):751-759. doi: 10.1007/s00280-022-04432-4. Epub 2022 Apr 19.
Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). High variability in pharmacokinetics coupled with a proven exposure-effect relationship makes sunitinib an ideal candidate for therapeutic drug monitoring (TDM). The feasibility of TDM of sunitinib in patients with mRCC was evaluated in this prospective observational study in a real-world scenario.
Seventy patients with mRCC treated with sunitinib at a fixed dose of 50 mg per day were enrolled in the study. Total trough plasma level (TTL) of sunitinib (sunitinib and its active metabolite, SU12662), was measured between days 14/15 of cycle 1. The discriminatory potential of TTL of sunitinib for the prediction of responders and occurrence of grade ≥ 3 toxicity was determined using receiver operating characteristic (ROC) curve.
The median TTL of sunitinib was 76 ng/mL. Forty six out of 70 patients were evaluable for response, whereas 60 out of 70 patients were evaluable for toxicity. Threshold concentrations obtained from ROC analysis showed that TTL of 60.75 ng/mL and 82.3 ng/mL was discriminatory for response and occurrence of grade ≥ 3 toxicity respectively. 31/34 (91.7%) patients having TTL ≥ 60.75 ng/mL responded to treatment, while only 5/12 (41.6%) responded when TTL was < 60.75 ng/mL (P = 0.001). On the other hand, the incidence of grade ≥ 3 toxicity was 9/24 (37.7%) in patients with TTL ≥ 82.3 ng/mL compared to 4/36 (11.1%) in patients with TTL < 82.3 ng/mL (P = 0.024).
The TTL range of 60.75-82.3 ng/mL was found to be optimal in terms of safety and efficacy. More than 50% of patients in our cohort attained TTL of sunitinib outside the optimal range, thus demonstrating the feasibility of TDM to improve safety and efficacy of sunitinib in mRCC.
舒尼替尼是一种口服酪氨酸激酶抑制剂，已被批准用于治疗转移性肾细胞癌（mRCC）。其药代动力学具有高度变异性，且已证实存在暴露-效应关系，这使得舒尼替尼成为治疗药物监测（TDM）的理想候选药物。在这项前瞻性观察研究中，于真实世界场景下评估了mRCC患者中舒尼替尼TDM的可行性。
70例接受舒尼替尼治疗的mRCC患者入组本研究，舒尼替尼固定剂量为每日50mg。在第1周期的第14/15天测量舒尼替尼（舒尼替尼及其活性代谢产物SU12662）的总谷浓度（TTL）。使用受试者工作特征（ROC）曲线确定舒尼替尼TTL对预测反应者和≥3级毒性发生的鉴别潜力。
舒尼替尼的中位TTL为76ng/mL。70例患者中有46例可评估反应，70例患者中有60例可评估毒性。ROC分析得出的阈值浓度显示，TTL为60.75ng/mL和82.3ng/mL分别对反应和≥3级毒性的发生具有鉴别意义。TTL≥60.75ng/mL的患者中31/34（91.7%）对治疗有反应，而TTL<60.75ng/mL时只有5/12（41.6%）有反应（P=0.001）。另一方面，TTL≥82.3ng/mL的患者中≥3级毒性的发生率为9/24（37.7%），而TTL<82.3ng/mL的患者中为4/36（11.1%）（P=0.024）。
发现60.75 - 82.
