Voriconazole在血液科病人之群體藥動學研究

Abstract

背景 血液科病人之侵入性黴菌感染有極高的發病率與死亡率。而Voriconazole是治療侵入性黴菌感染的第一線藥物，在人體內主要經肝臟CYP2C19、CYP3A4、CYP2C9代謝。因voriconazole的血中濃度有極大的個體間變異與個體內變異，臨床使用上充滿挑戰性。本研究旨在探討血液科病人voriconazole的藥動學參數並分析影響voriconazole藥動學參數之因子。

方法 本研究於醫學中心進行收案，為單中心，回溯性分析之研究。研究對象為2012年1月1日到2016年12月31日期間，使用voriconazole且有血液疾病的病人。研究資料之voriconazole血中濃度值來自於療劑監測、係波谷濃度，不足以描敘藥物的分佈體積與吸收速率，故採回顧文獻在一室分佈的情況下固定藥物的分佈體積與吸收速率，藥品的清除情形評估用一級線性和非線性排除，尋找出最適當的個體間與個體內的變異模型；分析上利用non-linear mixed effect model去估算藥動學參數，年齡、身高、體重、性別、BMI、ALT、ALP、AST、T-bil、CRP、CYP2C19基因型、有無異體幹細胞移植、適應症、感染的嚴重程度、併用藥品等，均做為變項納入分析。

結果 本研究共納入123位病人，固定型個體內誤差和指數型個體間誤差為最適當的變異數模型，群體動態學估算出的模型為 CLi = CLpop x[1＋0.438(Allo-HSCT)] x[1- 0.00956（age - 53）]x[1- 0.051（CRP - 5.58）]x[1- 0.286（CYP2C19 genotype）] 群體的藥品清除率為5.52（L/h），年齡、CYP2C19 基因型、有無異體幹細胞移植、CRP值為顯著影響藥動參數的因子，納入因子之後個體間的誤差從80.9%下降到63.6%，代表此模型有較佳的預測效果。

結論 本研究發現年齡、CYP2C19 慢性代謝者、CRP值與voriconazole血中濃度呈正相關，而有無異體幹細胞移植則和voriconazole血中濃度呈負相關，此模型可供朝精準醫療邁進。

Background Invasive fungal infection (IFI) is a major cause of morbidity and mortality for patients with hematological patients. Voriconazole is first-line agent for the treatment of IFI and is metabolized by CYP2C19, CYP3A4, and CYP2C9. Given the high inter- and intra-subject variability in voriconazole serum concentrations, it is challenging for its routine use in clinical setting. The aim of this study was to characterize pharmacokinetics of voriconazole and to identify factors significantly associated with pharmacokinetic parameters in patients with hematological patients. Methods The data of adult patients diagnosed with hematological patients in NTUH were collected retrospectively from January 2012 to December 2016. In these patients, voriconazole was used for prophylaxis or the treatment of fungal infection. Serum samples were collected at steady-state during their clinical care. Non-linear mixed effect modeling using monolix was performed to estimate population pharmacokinetics. The data did not provide information about the rate of absorption and distribution processes so that absorption rate (ka) and apparent volume of distribution (Vd) were fixed according to the values from literature. One compartment open model with linear or nonlinear elimination pathway was used to estimate the clearance values. . Suitable models for interindividual variability and intraindividual error models were explored. Age, weight, height , BMI , ALT ,T-bil , ALP, CRP , CYP2C19 genotype, indication , patients with and without allogeneic hematopoietic stem cell transplantation (Allo-HSCT), co-medication and infectious disease severity were included for covariate evaluation. Results A total of 123 patients were enrolled in our study. Residual and inter-individual variabilities were best described by constant and exponential error models, respectively.The population clearance of voriconazole was estimated to be 5.52 L/h. The model indicated age, CRP, CYP2C19 genotype, and Allo-HSCT are statistically significant covariates influencing voriconazole pharmacokinetics. The final model was estimated to be CLi = CLpop x[1＋0.438(Allo-HSCT)] x[1- 0.00956（age-53）]x[1- 0.051（CRP-5.58）]x[1- 0.286（CYP2C19 genotype）] In addition, the standard deviation of CL has decreased from 0.809 to 0.636 as part of the inter-individual variability in CL explained by the covariate. Final model had better predicitive perferomance compared to base model. Conclusions Voriconazole concentrations are inversely associated with age, CRP, and CYP2C19 PM. Allo-HSCT are positively correlated with voriconazole exposure. The current model would provide a good way to optimize individual dosage for voriconazole.