Ontogeny of Voriconazole Pharmaockinetics and Metabolism

描述（由申请人提供）：曲霉病的儿童死亡率超过50%。伏立康唑是治疗这种感染的一线药物，我们已经证明伏立康唑血药浓度和生存率之间存在高度显著的关系。然而，伏立康唑给药目前是经验性的，即使在静脉给药后，儿童之间的血浆暴露量也有400%或更多的差异。最多，CYP 2C 19基因型占这种变异性的40%。因此，量化年龄和疾病对CYP 2C 19、CYP 3A 4和黄素单加氧酶3（FMO 3）表型活性的影响至关重要，它们共同代谢>90%的伏立康唑，并优化和合理地给药这种关键药物。CYP 2C 19和CYP 3A 4代谢近一半的治疗药物，而FMO 3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，伏立康唑是最近的一个例子。因此，我们的实验室和统计方法的新组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，CYP 2C 19，CYP 3A 4和FMO 3的个体发育将与伏立康唑PK中观察到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，以最快地达到与生存相关的伏立康唑血药浓度。该项目有三个具体目的：1）表征儿童和青少年中的纵向CYP 2C 19、CYP 3A 4和FMO 3表型; 2）使用经验和生理模型描述伏立康唑PK; 3）使用基于模型的贝叶斯自适应控制优化患者伏立康唑给药。我们将在一项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2岁以下（n=10）、2-12岁（n=25）和12-18岁（n=25）分层。所有患者将开始静脉（IV）给药，并在临床指征时过渡至口服给药。我们将从每例患者中采集以下样本：1）用于检测已知影响酶活性的几种CYP 2C 19和FMO 3 SNP的血液样本; 2）IV和口服给药后最多9份稳态PK血液样本; 3）2次随访访视时给药后2小时的单次PK血液样本。在PK采样前IV伏立康唑给药时，我们还将单次IV微剂量埃索美拉唑、咪达唑仑和雷尼替丁作为混合药物，分别探测CYP 2C 19、CYP 3A 4和FOM 3活性。我们将在口服PK访视和两次随访访视前重复口服该混合药物。我们将估计DME表型使用探针药物代谢产物和母体药物的血浆时间浓度曲线（AUC）下的面积的比率，同时定量外周血单核细胞DME mRNA和蛋白质。我们将检测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.