Ontogeny of Voriconazole Pharmaockinetics and Metabolism

描述（由申请人提供）：儿童曲霉病死亡率超过50%。伏立康唑是这种感染的一线治疗，我们已经证明伏立康唑血浆浓度与生存之间存在高度显著的关系。然而，伏立康唑的剂量目前是经验性的，儿童之间的血浆暴露量相差400%或更多，即使在静脉给药后也是如此。最多，CYP2C19基因型占这种变异的40%。因此，确定年龄和疾病对CYP2C19、CYP3A4和黄素单加氧酶3 （FMO3）表型活性的影响，以及优化合理给药至关重要。CYP2C19和CYP3A4代谢了近一半的治疗药物，而FMO3广泛的底物特异性表明其在儿科药物治疗中的作用被忽视了，伏立康唑就是最近的一个例子。因此，我们的实验室和统计方法的新颖结合将为儿科药物开发和治疗剂量的范式改变方法奠定基础。我们的创新和跨学科建议的假设是，CYP2C19、CYP3A4和FMO3的个体发生将与观察到的伏立康唑PK的年龄相关变化显著相关，并将对剂量和策略产生重大影响，以最快速地达到与生存相关的伏立康唑血浆浓度。该项目有三个具体目标：1)表征儿童和青少年CYP2C19、CYP3A4和FMO3的纵向表型；2)利用经验和生理模型描述伏立康唑的PK；3)采用基于模型的贝叶斯自适应控制优化患者伏立康唑剂量。我们将在I/II期PK研究中招募60名需要伏立康唑的儿童/青少年，按年龄分为2岁以下（n=10）、2-12岁（n=25）和12-18岁（n=25）。所有患者将开始静脉（IV）给药，并在临床指征时过渡到口服给药。从每位患者中，我们将收集以下内容：1)血液样本用于检测几种已知影响酶活性的CYP2C19和FMO3 snp；2)静脉和口服给药后最多9个稳态PK血样；3) 2次随访，给药后2小时单次PK血样。在PK取样前静脉注射伏立康唑时，我们还将单次静脉注射微剂量的埃索美拉唑、咪达唑仑和雷尼替丁作为鸡尾酒，分别检测CYP2C19、CYP3A4和FOM3的活性。我们将在口服PK访问和两次随访之前重复口服剂量的鸡尾酒。我们将利用血浆时间浓度曲线（AUCs）下探针药物代谢物与亲本区域的比值来估计DME表型，同时定量外周血单核细胞DME mRNA和蛋白。我们将测试DME表型、mRNA、蛋白质、伏立康唑PK参数、年龄、性别和疾病程度之间的相关性。

DESCRIPTION (provided by applicant): Mortality in children from aspergillosis is more than 50%. Voriconazole is the first-line therapy for this infection, and we have shown a highly significant relationship between voriconazole plasma concentrations and survival. However, voriconazole dosing is currently empirical, and plasma exposure varies between children by 400% or more, even after intravenous dosing. At most, CYP2C19 genotype accounts for 40% of this variability. Therefore it is crucial to quantify the impact of age and illness on the phenotypc activity of CYP2C19, CYP3A4 and flavin mono-oxygenase 3 (FMO3), which together metabolize >90% of voriconazole, and to optimally and rationally dose this critical drug. CYP2C19 and CYP3A4 metabolize nearly half of therapeutic drugs, while the broad substrate specificity of FMO3 suggests its role in pediatric pharmacotherapy has been overlooked, voriconazole serving as a recent example. Therefore, our novel combination of laboratory and statistical methods will set the stage for paradigm-changing methods of pediatric drug development and therapeutic dosing. The hypothesis of our innovative and cross-disciplinary proposal is that the ontogeny of CYP2C19, CYP3A4 and FMO3 will significantly correlate with observed age-related changes in voriconazole PK and will have a major impact on dosing and strategies to most rapidly achieve voriconazole plasma concentrations that are associated with survival. There are three Specific Aims for the project: 1) to characterize the longitudinal CYP2C19, CYP3A4, and FMO3 phenotypes in children and adolescents; 2) to describe voriconazole PK using empirical and physiological models; and 3) to optimize patient voriconazole dosing with model-based Bayesian adaptive control. We will enroll 60 children/adolescents requiring voriconazole in a phase I/II PK study, stratified by age under 2 years (n=10), 2-12 years (n=25) and 12-18 years (n=25). All patients will begin with intravenous (IV) dosing and transition to oral dosing when clinically indicated. From each patient we will collect the following: 1) a blood sample for detection of several CYP2C19 and FMO3 SNPs known to affect enzyme activity; 2) up to 9 steady-state PK blood samples after IV and oral doses; and 3) single PK blood samples 2 hours post-dose at 2 follow-up visits. At the time of the IV voriconazole dose prior to the PK sampling, we will also give single IV microdoses of esomeprazole, midazolam, and ranitidine as a cocktail to probe CYP2C19, CYP3A4, and FOM3 activity, respectively. We will repeat this cocktail with oral doses before the oral PK visit and two follow-up visits. We will estimate DME phenotype using ratios of probe drug metabolite and parent areas under the plasma time concentration curves (AUCs) and simultaneously quantify peripheral blood mononuclear cell DME mRNA and protein. We will test associations between DME phenotype, mRNA, protein, voriconazole PK parameters, age, sex, and degree of illness.