Brown Jennifer, Plummer Ruth, Bauer Todd M, Anthony Stephen, Sarantopoulos John, De Vos Filip, White Mike, Schupp Marco, Ou Ying, Vaishampayan Ulka
Beatson West of Scotland Cancer Centre, 1053 Great Western Rd, Glasgow, Scotland G12 0YN UK.
Sir Bobby Robson Cancer Trials Research Centre, Freeman Hospital, Newcastle, England UK.
Exp Hematol Oncol. 2017 Oct 3;6:27. doi: 10.1186/s40164-017-0086-1. eCollection 2017.
Carfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function.
Patients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles. The primary objective was to assess the influence of hepatic impairment on carfilzomib PK following 27 and 56 mg/m doses.
The majority of patients enrolled in this study had solid tumors (n = 44) vs. MM (n = 2) since patients with multiple myeloma do not tend to have severe hepatic impairment in the same way as patients with solid tumors. A total of 11 normal and 17 mild, 14 moderate, and 4 severe hepatic impairment patients were enrolled. Compared with patients with normal hepatic function, patients with mild and moderate hepatic impairment had 44 and 26% higher carfilzomib AUC, respectively (27 mg/m dose); increases at the 56 mg/m dose were 45 and 21%, respectively. Considerable PK variability (% coefficient of variation in AUC ≤100%) was discerned and no consistent trend of increasing exposure resulting from increasing hepatic impairment severity (moderate vs. mild) was seen. The observed adverse event (AE) profile in patients of mostly solid tumors was consistent with the known safety profile of carfilzomib, with the exception of an increased frequency of AEs consistent with hepatic function abnormalities.
In this population of primarily advanced solid tumor patients, patients with mild and moderate hepatic impairment had approximately 20-50% higher carfilzomib AUC vs. normal hepatic function patients. These increases are unlikely to be clinically significant, in light of the intrinsic PK variability and exposure-response relationship of carfilzomib. http://clinicaltrials.gov NCT01949545; date of registration: September 6, 2013.
卡非佐米在美国和欧洲被批准用于治疗复发或难治性多发性骨髓瘤（MM）。本研究评估了卡非佐米在复发或进展性晚期恶性肿瘤且肝功能受损程度不同的患者中的药代动力学（PK）和安全性。
肝功能正常（正常）或肝功能损害（轻度、中度或重度）的患者接受卡非佐米静脉输注，每28天为一个周期。主要目的是评估肝功能损害对27毫克/平方米和56毫克/平方米剂量卡非佐米PK的影响。
本研究纳入的大多数患者患有实体瘤（n = 44），而MM患者（n = 2）较少，因为多发性骨髓瘤患者不像实体瘤患者那样容易出现严重肝功能损害。总共纳入了11名肝功能正常以及17名轻度、14名中度和4名重度肝功能损害患者。与肝功能正常的患者相比，轻度和中度肝功能损害患者的卡非佐米AUC分别高44%和26%（27毫克/平方米剂量）；56毫克/平方米剂量时的增幅分别为45%和21%。观察到了相当大的PK变异性（AUC变异系数百分比≤100%），且未发现随着肝功能损害严重程度增加（中度与轻度相比）导致暴露增加的一致趋势。大多数实体瘤患者观察到的不良事件（AE）谱与卡非佐米已知的安全性谱一致，但与肝功能异常相关的AE发生率有所增加。
在这个主要为晚期实体瘤患者的群体中，轻度和中度肝功能损害患者的卡非佐米AUC比肝功能正常的患者高约20 - 50%。鉴于卡非佐米固有的PK变异性和暴露 - 反应关系，这些增加在临床上不太可能具有显著意义。http://clinicaltrials.gov NCT01949545；注册日期：2013年9月6日。
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