Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
Department of Internal Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Oncologist. 2019 Aug;24(8):1137-1145. doi: 10.1634/theoncologist.2018-0336. Epub 2019 Feb 1.
Vinorelbine has demonstrated anticancer activity and is primarily metabolized in the liver. This single-institution, phase I pilot study describes the safety and pharmacokinetics of vinorelbine in patients with varying degrees of hepatic impairment.
Patients with treatment-refractory solid tumors were enrolled into treatment arms based on vinorelbine dose (weekly infusions of 7.5-30 mg/m) and liver function (normal liver function, mild, moderate, or severe liver dysfunction). Vinorelbine pharmacokinetics were evaluated to describe its relationship with liver function. Indocyanine green (ICG) clearance was assessed for correlation with pharmacokinetics.
Forty-seven patients were enrolled, and a total of 108 grade 3-4 treatment-related adverse events (AEs) occurred. Of these, grade 3-4 myelosuppression was the most common (34.3%). Thirty-three (30.6%), 22 (20.4%), and 9 (8.3%) grade 3-4 AEs were observed in the vinorelbine 20 mg/m/severe, 15 mg/m/moderate, and 7.5 mg/m/severe liver dysfunction groups, respectively, with the majority being nonhematologic toxicities. ICG clearance decreased as liver function worsened. Vinorelbine pharmacokinetics were not correlated with ICG elimination or the degree of liver dysfunction.
For patients with severe liver dysfunction (bilirubin >3.0 mg/dL), vinorelbine doses ≥7.5 mg/m are poorly tolerated. The high incidence of grade 3-4 AEs with 15 mg/m vinorelbine in moderate liver dysfunction (bilirubin 1.5-3.0 mg/dL) raises concerns for its safety in this population. Vinorelbine pharmacokinetics are not affected by liver dysfunction; however, levels of the active metabolite 4-O-deacetylvinorelbine were not measured and may be higher in patients with liver dysfunction if its elimination is impacted by liver impairment to a greater degree than the parent drug.
Vinorelbine remains widely prescribed in advanced malignancies and is under development in immunotherapy combinations. Given vinorelbine is primarily hepatically metabolized, understanding its safety and pharmacokinetics in liver dysfunction remains paramount. In this phase I pilot study, weekly vinorelbine at doses ≥7.5 mg/m is poorly tolerated in those with severe liver dysfunction. Furthermore, a high incidence of grade 3-4 toxicities was observed with vinorelbine at 15 mg/m in those with moderate liver dysfunction. Vinorelbine pharmacokinetics do not appear affected by degree of liver dysfunction. Further evaluation of levels of the free drug and active metabolites in relationship to liver function are warranted.
长春瑞滨具有抗癌活性，主要在肝脏中代谢。这项单机构、I 期试验研究描述了长春瑞滨在不同程度肝功能损害患者中的安全性和药代动力学。
患有难治性实体瘤的患者根据长春瑞滨剂量（每周输注 7.5-30mg/m）和肝功能（正常肝功能、轻度、中度或重度肝功能障碍）分为治疗臂。评估长春瑞滨的药代动力学以描述其与肝功能的关系。评估吲哚菁绿（ICG）清除率与药代动力学的相关性。
共纳入 47 例患者，共发生 108 例 3-4 级与治疗相关的不良事件（AE）。其中，最常见的是 3-4 级骨髓抑制（34.3%）。20mg/m/重度、15mg/m/中度和 7.5mg/m/重度肝功能障碍组分别观察到 33（30.6%）、22（20.4%）和 9（8.3%）例 3-4 级 AE，大多数为非血液学毒性。ICG 清除率随着肝功能恶化而降低。长春瑞滨药代动力学与 ICG 消除或肝功能障碍程度无关。
对于肝功能严重障碍（胆红素＞3.0mg/dL）的患者，7.5mg/m 以上的长春瑞滨剂量难以耐受。在中度肝功能障碍（胆红素 1.5-3.0mg/dL）中，15mg/m 长春瑞滨的 3-4 级 AE 发生率较高，令人担忧其在该人群中的安全性。长春瑞滨药代动力学不受肝功能障碍的影响；然而，由于其消除受肝功能损害的影响大于母体药物，因此如果其消除受到肝功能障碍的影响程度大于母体药物，则活性代谢物 4-O-去乙酰长春瑞滨的水平可能更高，但尚未进行测量。
长春瑞滨在晚期恶性肿瘤中仍广泛应用，并在免疫治疗联合治疗中得到进一步开发。鉴于长春瑞滨主要在肝脏中代谢，了解其在肝功能障碍患者中的安全性和药代动力学仍然至关重要。在这项 I 期试验研究中，严重肝功能障碍患者每周 7.5mg/m 以上的长春瑞滨剂量耐受性差。此外，在中度肝功能障碍患者中，15mg/m 长春瑞滨观察到较高的 3-4 级毒性发生率。长春瑞滨药代动力学似乎不受肝功能障碍程度的影响。进一步评估与肝功能相关的游离药物和活性代谢物的水平是必要的。
