Ontogeny of Voriconazole Pharmaockinetics and Metabolism

伏立康唑药代动力学和代谢的个体发育

基本信息

批准号：
8221696
负责人：
Michael N. Neely
金额：
$ 52.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/8221696
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: This study will enroll children and adolescents up to age 18 who are receiving therapy with the antifungal drug voriconazole. We will study why voriconazole concentrations in the body ("pharmacokinetics") are very different between children and adults, even when the dose is adjusted for body weight. As we learn more about this, we will put this information into computer software to improve our ability to pick the dose of voriconazole for individual patients so that they more reliably get the concentrations in their blood that have been shown to be good treatment for serious fungal infections.

描述（由申请人提供）：曲霉病儿童的死亡率超过50％。伏立康唑是这种感染的一线疗法，我们在伏立康唑血浆浓度和生存之间表现出了非常显着的关系。但是，伏立康唑的剂量目前是经验性的，即使在静脉注射后，儿童的血浆暴露也有400％或更多。 CYP2C19基因型最多占此变异性的40％。因此，量化年龄和疾病对CYP2C19，CYP3A4和黄素单氧酶3（FMO3）的表型活性的影响至关重要，该酶3（FMO3）共同代谢voriconazole> 90％的伏立康唑，并最佳地和合理地剂量剂量剂量。 CYP2C19和CYP3A4代谢了将近一半的治疗药物，而FMO3的广泛底物特异性表明其在小儿药物疗法中的作用已被忽略，Voriconazole作为最近的例子。因此，我们的新型实验室和统计方法组合将为改变范式变化的小儿药物开发和治疗剂量的方法奠定了基础。我们的创新和跨学科建议的假设是，CYP2C19，CYP3A4和FMO3的个体发育将与观察到的Voriconazole PK的年龄相关变化显着相关，并且将对剂量和策略产生重大影响，以迅速实现VoricOnazole plasma plasma浓度与生存相关。该项目有三个特定的目标：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来描述伏立康唑PK； 3）用基于模型的贝叶斯自适应控制优化患者伏立康唑的剂量。我们将在I/II期PK研究中招募60名需要Voriconazole的儿童/青少年，按2岁以下（n = 10），2-12岁（n = 25）和12-18岁（n = 25）分层。所有患者在临床表明时将以静脉内（IV）给药和过渡到口服剂量开始。从每个患者中，我们将收集以下内容：1）一个血液样本，用于检测几种CYP2C19和FMO3 SNP，已知会影响酶活性； 2）静脉注射和口服剂量后最多9个稳态的PK血液样本； 3）剂量后2小时进行2个随访访问。在PK采样之前静脉注射voriconazole剂量时，我们还将分别给出单次IV微剂量的埃索美丙唑，咪达唑仑和Ranitidine作为鸡尾酒，以探测CYP2C19，CYP3A4和FOM3活性。在口头PK访问和两次后续访问之前，我们将重复此鸡尾酒。我们将使用血浆时间浓度曲线（AUC）的探针药物代谢物和母体区域的比率估算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，Voriconazole PK参数，年龄，性别和疾病程度之间的关联。公共卫生相关性：这项研究将招募18岁以下的儿童和青少年接受抗真菌药物伏立康唑的治疗。我们将研究为什么儿童和成人之间体内体内的伏立康唑（“药代动力学”）也有很大不同，即使调整了体重的剂量。随着我们了解更多信息，我们将将这些信息放入计算机软件中，以提高我们为个别患者选择伏立康唑的能力证明是严重真菌感染的良好治疗方法。