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首页> 外文期刊>臨床薬理: Japanese journal of clinical pharmacology >Markov Chain Monte Carlo Bayesian Analysis for Population Pharmacokinetics of Dasatinib in Japanese Adult Subjects with Chronic Myeloid Leukemia and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
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Markov Chain Monte Carlo Bayesian Analysis for Population Pharmacokinetics of Dasatinib in Japanese Adult Subjects with Chronic Myeloid Leukemia and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

机译：马尔可夫链蒙特卡罗·贝叶斯贝叶斯贝叶斯·贝叶松分析日本成人对象慢性骨髓白血病和费城染色体阳性急性淋巴细胞白血病

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摘要

This study evaluated the population pharmacokinetics of dasatinib in Japanese subjects with imatinib-resistant or -intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph~+ALL) enrolled in 3 Japanese clinical trials, and compared individual PK estimates to that of non-Japanese subjects in global database. A full Markov Chain Monte Carlo Bayesian analysis method in NONMEM 7 was utilized for the estimation of model parameters. In terms of covariate model selection, baseline demographic and clinical laboratory covariates were assessed on oral clearance (CL/F). The food effect and the dose effect were also tested on the relative bioavailability (F_R) and CL/F, respectively. A total of 706 observations were obtained from 63 Japanese subjects who received twice daily administration of dasatinib at 50, 70 and 90 mg, and once daily administration at 100 mg. Consistent with a PPK model in non-Japanese subjects, plasma concentration-time data were well described by alinear two-compartment model with the inter-occasion variability (IOV) on the relative bioavailability (FR) ， which is to account for between-visit difference of dasatinib exposure within a subject apparently observed in a phase 1/2 study in Japanese subjects. Comparable exposures of individual Japanese subjects with that of non-Japanese subjects were obtained. Investigation of covariates revealed neither marked trends nor clinically relevant effect on CL/F or F_R. These results indicated that no dose adjustment is warranted for Japanese CML and Ph+ALL patients, based on their body size, age, or gender.
机译：本研究评估了含有伊马替尼抗性或 - 耐药慢性骨髓白血病（CML）和费城染色体阳性急性淋巴细胞白血病（pH〜+全部）中的达沙替尼的人口药代动力学，参加了3日日本临床试验，并将个别PK估计进行了比较全球数据库中的非日本科目。 NONMEM 7中的全马尔可夫链蒙特卡罗·贝叶斯分析方法用于估计模型参数。就协变量的模型选择而言，在口腔清除（Cl / F）上评估基线人口统计和临床实验室协变量。还在相对生物利用度（F_R）和Cl / F上测试食物效果和剂量效应。从63名日本受试者获得了总共706个观察结果，该受试者每天每天施用Dasatinib在50,70和90毫克，并且每日施用100毫克。与非日本受试者的PPK模型一致，血浆浓度 - 时间数据通过来自相对生物利用度（FR）的场合间变异性（IOV）进行了很好的描述，这是为了考虑访问之间的访问在日本科目的1/2期研究中，达斯替尼暴露的差异显然观察到。获得了具有非日本科目的各个日本科目的可比较暴露。协变量的调查既不明显趋势也没有对CL / F或F_R的临床相关影响。这些结果表明，对于日本CML和pH +所有患者，无需调整任何剂量调整，基于身体规模，年龄或性别。

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