Ontogeny of Voriconazole Pharmaockinetics and Metabolism

伏立康唑药代动力学和代谢的个体发育

• 批准号: 8754114
• 负责人: Michael N. Neely
• 金额: $ 39.54万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-22 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754114
• 关键词: Accounting; Adolescent; Adult; Affect; Age; Algorithms; Antifungal Agents; Area; Aspergillosis; Biological Assay; Blood; Blood specimen; Body Weight; CYP2C19 gene; CYP3A4 gene; Child; Childhood; Computer Assisted; Computer software; Detection; Dose; Drug Kinetics; Enrollment; Enzymes; Esomeprazole; Flavins; Future; Genotype; Growth; Hour; Individual; Infection; Intravenous; Intravenous infusion procedures; Laboratories; Lansky Play-Performance Status; Lead; Learning; Measures; Messenger RNA; Metabolic; Metabolism; Methods; Midazolam; Modeling; Mono-S; Mycoses; Oral; Oxygenases; Parents; Patients; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenotype; Physiological; Plasma; Population; Proteins; Ranitidine; Research Personnel; Role; Sampling; Simulate; Staging; Statistical Methods; Substrate Specificity; Testing; Therapeutic; Time; Update; Visit; Voriconazole; age effect; age related; base; bench to bedside; cohort; drug development; enzyme activity; follow-up; improved; innovation; mRNA Expression; mortality; novel; sex; tool

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.

描述（由申请人提供）：曲霉病儿童死亡率超过 50%。伏立康唑是这种感染的一线治疗方法，我们已经证明伏立康唑血浆浓度与生存率之间存在高度显着的关系。然而，目前伏立康唑的给药剂量是经验性的，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。 CYP2C19 基因型最多占这种变异的 40%。因此，量化年龄和疾病对 CYP2C19、CYP3A4 和黄素单加氧酶 3 (FMO3) 表型活性的影响至关重要，这些酶共同代谢超过 90% 的伏立康唑，并优化、合理地调整这种关键药物的剂量。 CYP2C19 和 CYP3A4 代谢近一半的治疗药物，而 FMO3 广泛的底物特异性表明它在儿科药物治疗中的作用被忽视，伏立康唑就是最近的一个例子。因此，我们实验室和统计方法的新颖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提案的假设是，CYP2C19、CYP3A4 和 FMO3 的个体发育将与观察到的伏立康唑 PK 的年龄相关变化显着相关，并将对最快速达到伏立康唑血浆浓度的剂量和策略产生重大影响。与生存有关。该项目有三个具体目标：1）表征儿童和青少年的纵向 CYP2C19、CYP3A4 和 FMO3 表型； 2) 使用经验和生理模型描述伏立康唑 PK； 3) 通过基于模型的贝叶斯自适应控制优化患者伏立康唑剂量。我们将招募 60 名需要伏立康唑的儿童/青少年进行 I/II 期 PK 研究，按年龄分层：2 岁以下 (n=10)、2-12 岁 (n=25) 和 12-18 岁 (n=25)。所有患者都将从静脉 (IV) 给药开始，并在临床指征时过渡到口服给药。我们将从每位患者身上收集以下信息：1) 血液样本，用于检测已知影响酶活性的几种 CYP2C19 和 FMO3 SNP； 2) 静脉注射和口服给药后多达 9 个稳态 PK 血液样本； 3) 2 次随访时服药后 2 小时的单一 PK 血液样本。在 PK 采样前静脉注射伏立康唑剂量时，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混合物，分别探测 CYP2C19、CYP3A4 和 FOM3 活性。在口服 PK 访视和两次随访访视之前，我们将通过口服剂量重复这种鸡尾酒。我们将使用血浆时间浓度曲线 (AUC) 下探针药物代谢物和亲本面积的比率来估计 DME 表型，并同时量化外周血单核细胞 DME mRNA 和蛋白质。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关联。