Division of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Albert Einstein Cancer Center, Montefiore Medical Center, 111 E 210th Street, Bronx, NY, 10567, USA.
Cancer Chemother Pharmacol. 2018 Jan;81(1):73-80. doi: 10.1007/s00280-017-3469-4. Epub 2017 Nov 3.
Dovitinib is an orally available multi tyrosine kinase inhibitor which inhibits VEGFR 1-3, FGFR 1-3, and PDGFR. This study was performed to investigate the potential drug-drug interaction of dovitinib with the CYP1A2 inhibitor fluvoxamine in patients with advanced solid tumors.
Non-smoking patients of ≥ 18 years with advanced solid tumors, excluding breast cancer, were included. Patients were treated with a dose of 300 mg in 5 days on/2 days off schedule. Steady-state pharmacokinetic assessments of dovitinib were performed with or without fluvoxamine.
Forty-five patients were enrolled; 24 were evaluable for drug-drug interaction assessment. Median age was 60 years (range 30-85). At steady state the geometric mean for dovitinib (coefficient of variation%) of the area under the plasma concentration-time curve (AUC) and maximum concentration (C ) were 2880 ng/mL h (47%) and 144 ng/mL (41%), respectively. Following administration of dovitinib in combination with fluvoxamine the geometric mean of dovitinib AUC and C were 8290 ng/mL h (60%) and 259 ng/mL (45%), respectively. The estimated geometric mean ratios for dovitinib AUC and C (dovitinib + fluvoxamine vs. dovitinib alone) were 2.88 [90% confidence interval (CI) 2.58, 3.20] and 1.80 (90% CI 1.66, 1.95). This effect is considered a moderate drug-drug interaction.
Fluvoxamine co-administration resulted in a 80% increase in C and a 188% increase in AUC of dovitinib. Given the increase in exposure to dovitinib observed, patients are at risk of dovitinib related toxicity. Dovitinib should, therefore, not be co-administered with moderate and strong CYP1A2 inhibitors, without dose reduction.
多韦替尼是一种口服多酪氨酸激酶抑制剂，可抑制 VEGFR 1-3、FGFR 1-3 和 PDGFR。本研究旨在研究多韦替尼与 CYP1A2 抑制剂氟伏沙明在晚期实体瘤患者中的潜在药物相互作用。
纳入非吸烟、年龄≥18 岁的晚期实体瘤患者（乳腺癌除外），给予 300mg 剂量，每 5 天服用 1 天，2 天停药。使用或不使用氟伏沙明进行多韦替尼稳态药代动力学评估。
共纳入 45 例患者；24 例可用于药物相互作用评估。中位年龄为 60 岁（范围 30-85 岁）。在稳态下，多韦替尼的几何平均（变异系数%）血浆浓度-时间曲线下面积（AUC）和最大浓度（C ）分别为 2880ng/mL·h（47%）和 144ng/mL（41%）。多韦替尼与氟伏沙明联合给药后，多韦替尼 AUC 和 C 的几何平均分别为 8290ng/mL·h（60%）和 259ng/mL（45%）。多韦替尼 AUC 和 C 的估计几何平均比值（多韦替尼+氟伏沙明与多韦替尼单药相比）分别为 2.88（90%置信区间[CI]2.58，3.20）和 1.80（90%CI 1.66，1.95）。这种作用被认为是一种中度的药物相互作用。
氟伏沙明联合用药使多韦替尼的 C 增加 80%，AUC 增加 188%。鉴于观察到多韦替尼暴露增加，患者有发生多韦替尼相关毒性的风险。因此，多韦替尼不应与中度和强效 CYP1A2 抑制剂联合使用，而无需减少剂量。
