多纳非尼和索拉非尼头对头一线治疗晚期肝细胞癌的药代动力学参数比较研究

Comparison study of pharmacokinetic parameters of donafenib and sorafenib in the first-line treatment of advanced hepatocellular carcinoma

目的多纳非尼是索拉非尼的新型氘代衍生物,治疗晚期肝细胞癌(HCC)患者具有更好的疗效和安全性。为了深入了解多纳非尼的作用特点,本课题组对Ⅱ/Ⅲ期临床研究中招募的部分HCC患者,进行了药代动力学(PK)特征的评估,比较多纳非尼与索拉非尼的药代动力学参数。方法在前瞻性、随机、平行对照、开放标签的多中心Ⅱ/Ⅲ期试验(ZGDH3研究,Clinicaltrial:NCT02645981)中,纳入既往未接受过系统治疗的不可切除或转移性HCC患者,随机(1∶1)接受多纳非尼(200 mg)或索拉非尼(400 mg)口服给药,每日两次(BID);主要终点为总生存期。分别在第1天和第14天,对于接受试验药物治疗、至少有一次药代动力学测量值且无重大方案偏离的患者进行了药代动力学参数(次要研究终点)研究,主要采用经过验证的液相色谱—串联质谱法测定原形药物和主要代谢产物的血浆浓度;并且通过Phoenix WinNonlin 7.0版软件采用非房室模型计算药代动力学参数。结果共20例患者(多纳非尼组16例和索拉非尼组4例)纳入此项PK子研究。给药后第1天时,多纳非尼原形药物的血浆峰浓度(C_(max))和给药后0~12 h的曲线下面积(AUC0-12h)均显著低于索拉非尼(C_(max):1.58μg/ml vs.2.78μg/ml,P=0.002;AUC0-12h:11.73μg·h/ml vs.22.04μg·h/ml,P=0.002),其M2代谢产物也类似(C_(max):0.35μg/ml vs.0.57μg/ml,P=0.021;AUC0-12h:2.48μg·h/ml vs.4.79μg·h/ml,P=0.013)。在给药后第14天时,多纳非尼原形药物的C_(max)和稳态曲线下面积(AUCss)均略高于索拉非尼,但是差异无统计学意义(C_(max):6.55μg/ml vs.4.98μg/ml,P=0.372;AUCss:45.38μg·h/ml vs.38.13μg·h/ml,P=0.505),同时其M2代谢产物也类似(C_(max):1.54μg/ml vs.1.32μg/ml,P=0.739;AUCss:11.44μg·h/ml vs.10.53μg·h/ml,P=0.819)。在达到稳态时,多纳非尼原形药物和M2代谢产物的血浆蓄积比约为索拉非尼及其M2代谢产物的3.5倍和6倍。结论达到稳态时,多纳非尼(200 mg BID)的血浆暴露量明显高于索拉非尼(400 mg BID)。多纳非尼具有良好的药代动力学特性,因此支持其一线治疗晚期HCC时,有效性和安全性均优于索拉非尼的结果。

Objective Donafenib,a novel deuterium derivative of sorafenib,has better efficacy and safetyin patients with advanced hepatocellular carcinoma(HCC).In order to gain a deeper understanding of the action characteristics of donafenib,the Collaboration Group evaluated the pharmacokinetic(PK)characteristics of some HCC patients recruited in the PhaseⅡ/Ⅲclinical study,and compared carefully the pharmacokinetic parameters of donafenib and sorafenib.Methods Patients with unresectable or metastatic HCC who had not previously received systemic therapy were randomized(1∶1)to donafenib(200 mg)or sorafenib(400 mg)orally twice daily(BID)in a randomized,parallel-controlled,open-label multi-center phaseⅡ/Ⅲtrial(ZGDH3 study,Clinicaltrial:NCT02645981).The primary endpoint was overall survival.Pharmaco-kinetic parameters(secondary study endpoint)study were performed on day 1 and 14 in patients receiving the experimental drug with at least one pharmacokinetic measurement and no signific-ant protocol deviation.The plasma concentrations of precursor drugs and major metabolites were determined by the validated liquid chromatography-tandem mass spectrometry.And Phoenix WinNonlin 7.0 software was used to calculate pharmacokinetic parameters by non-atrioventricular model.Results Twenty patients(16 in the donafenib group and 4 in the sorafenib group)were enrolled in the PK substudy.On day 1 after administration,the plasma peak concentration(C_(max))and the area under the curve(AUC0-12h)of donafenib were significantly lower than those of sorafenib(C_(max):1.58μg/ml vs.2.78μg/ml,P=0.002;AUC0-12h:11.73μg·h/ml vs.22.04μg·h/ml,P=0.002),and its M2 metabolites were similar(C_(max):0.35μg/ml vs.0.57μg/ml,P=0.021;AUC0-12 h:2.48μg·h/ml vs.4.79μg·h/ml,P=0.013).On day 14 after administration,the C_(max) and area under homeostasis curve(AUCss)of donafenib were slightly higher than those of sorafenib,but the differences were not statistically significant(C_(max):6.55μg/ml vs.4.98μg/ml,P=0.372;AUCss:45.38μg·h/ml vs.38.13μg·h/ml,P=0.505),and M2 metabolites were similar(C_(max):1.54μg/ml vs.1.32μg/ml,P=0.739;AUCss:11.44μg·h/ml vs.10.53μg·h/ml,P=0.819).However,at homeostasis,the plasma accumulation ratios of donafenib prototype drug and M2 metabolites were approximately 3.5 times and 6 times higher than those of sorafenib and M2 metabolites.Conclusion Plasma exposure to donafenib(200 mg BID,po)was significantly higher than that of sorafenib(400 mg BID,po)at homeostasis.The better pharmacokinetic properties of donafenib support its superior efficacy and safety results to sorafenib in the first-line treatment of advanced HCC.