The HIV Pharmacology Data Repository (PDR): Setting a new standard for clinical and preclinical pharmacokinetic data sharing

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
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引用次数: 0

Abstract

21

The HIV Pharmacology Data Repository (PDR): Setting a new standard for clinical and preclinical pharmacokinetic data sharing

Mackenzie Cottrell1, Lauren Tompkins1, Adrian Khoei1, Alexander Tropsha1, Oleg Kapeljushnik2, Robert Hubal2, Julie Dumond1 and Angela Kashuba1

1UNC Eshelman School of Pharmacy; 2Renaissance Computing Institute at UNC

Background: Rapidly expanding clinical pharmacology modelling tools can be used to derive biological meaning through in silico study of archived pharmacokinetic (PK) data pools. Yet, a rate-limiting step to employing these approaches is the ability to access high-quality concentration vs. time (CvT) data, aggregated across disparate study designs in a way that is meaningful and usable for PK modelling. This is partly due to a lack of standardization for PK data description. To this end, we defined and applied a minimum information standard (MIS) for PK data description in the development of a web-based database—the HIV Pharmacology Data Repository (HIV PDR)—and demonstrate scientific utility through population PK modelling.

Materials/methods: We defined the MIS with key reportable variables divided into three categories: intervention (drug, route, time and quantify), system (species dosed and anatomical compartment sampled) and concentration (chemical entity and concentration units quantified, including pro-drugs, drugs and metabolites). We identified 610 archived CvT Excel datasets fulfilling this MIS and created data dictionaries to harmonize terminology. The resulting database is stored in an SQL server with the front-end developed using an ASP.NET core with Angular and the back-end on an SQL Server 2017. We extracted CvT values for tenofovir (TFV) and its active metabolite (tenofovir diphosphate; TFVdp) within human plasma and peripheral blood mononuclear cells (PBMC) from study participants dosed with tenofovir disoproxil fumarate (TDF) and fit a population PK model using NONMEMv7.4.

Results: Our data dictionaries collapsed 924 bioanalytical synonyms (analyte name and units) into 145 unique variables with units parsed in a separate column. Additionally, 246 descriptors of species and anatomical compartment were collapsed into 15 and 80 unique variables, respectively, with taxonomical and anatomical hierarchies. The final database aggregates 80 043 CvT datapoints of 77 chemically distinct compounds. Our extracted TDF dataset contained 913 plasma and 708 PBMC observations from 88 human study participants across three dosing levels (150, 300 and 600 mg) under first-dose and steady-state conditions. The final model fit first-order absorption (Ka) and elimination (CL) from the central compartment (Vc); a peripheral compartment (Vp and Q); one gut transit compartment (Ktr) to capture absorption delay; and a PBMC compartment to capture TFVdp formation and degradation (K35 and K53, respectively). Parameter estimates (%RSE) were; CL = 51.1 L/h (3.2%); Vc = 223 L (fixed), Vp = 687 L (4.7%), Q = 173 L/h (4.4%), Ka = 1 h−1 (fixed), K35 = 0.0255 h−1 (11.1%) and K53 = 0.0269 h−1 (11.5%). A 600 mg dose was associated with longer absorption delay (Ktr₁ = 1.36 h−1) compared to the lower doses (Ktr₂ = 6.1 h−1). Vc, Ka and Ktr depend on sampling near Cmax and were fixed to estimations from a separate model using a subset of data with rich PK sampling schemes.

Conclusions: We applied this MIS in curating PK CvT data collected from previously siloed studies into a user-friendly database to support data sharing, management and mining for the community of translational scientists working to optimize HIV therapeutics. Our observation of TFV's dose-dependent absorption delay is a novel finding from the pooled CvT analysis, demonstrating the power to derive new PK knowledge from resources like the HIV PDR.

艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。
21 HIV 药理数据储存库 (PDR):Mackenzie Cottrell1, Lauren Tompkins1, Adrian Khoei1, Alexander Tropsha1, Oleg Kapeljushnik2, Robert Hubal2, Julie Dumond1 and Angela Kashuba11UNC Eshelman 药学院;2Renaissance Computing Institute at UNC背景:快速发展的临床药理学建模工具可用于通过对归档的药代动力学 (PK) 数据库进行硅学研究来获得生物学意义。然而,采用这些方法的一个限制性步骤是获取高质量浓度与时间(CvT)数据的能力,这些数据在不同的研究设计中以有意义且可用于 PK 建模的方式汇总。部分原因是 PK 数据描述缺乏标准化。为此,我们在开发基于网络的数据库--HIV 药理学数据存储库(HIV PDR)时,定义并应用了 PK 数据描述的最低信息标准(MIS),并通过人群 PK 建模展示了其科学实用性:我们对 MIS 进行了定义,将可报告的关键变量分为三类:干预(药物、途径、时间和量化)、系统(用药物种和采样解剖区)和浓度(化学实体和量化浓度单位,包括原药、药物和代谢物)。我们确定了 610 个符合此管理信息系统的存档 CvT Excel 数据集,并创建了数据字典以统一术语。生成的数据库存储在 SQL 服务器中,前端使用 ASP.NET core 和 Angular 开发,后端使用 SQL Server 2017。我们提取了服用富马酸替诺福韦二吡呋酯(TDF)的研究参与者的人血浆和外周血单核细胞(PBMC)中替诺福韦(TFV)及其活性代谢物(替诺福韦二磷酸酯;TFVdp)的CvT值,并使用NONMEMv7.4拟合了一个群体PK模型:我们的数据字典将 924 个生物分析同义词(分析物名称和单位)合并为 145 个独特的变量,单位在单独的一列中解析。此外,我们还将 246 个物种和解剖分区描述符分别整理为 15 个和 80 个唯一变量,并按分类学和解剖学进行了分级。最终数据库汇总了 77 种化学性质不同的化合物的 80 043 个 CvT 数据点。我们提取的 TDF 数据集包含来自 88 名人类研究参与者的 913 个血浆和 708 个 PBMC 观察数据,这些数据来自三个剂量水平(150、300 和 600 毫克)的首次剂量和稳态条件。最终模型拟合了中心区室(Vc)的一阶吸收(Ka)和消除(CL);外周区室(Vp 和 Q);一个肠道转运区室(Ktr)以捕捉吸收延迟;以及一个 PBMC 区室以捕捉 TFVdp 的形成和降解(分别为 K35 和 K53)。参数估计值(%RSE)为:CL = 51.1 L/h(3.2%);Vc = 223 L(固定值),Vp = 687 L(4.7%),Q = 173 L/h(4.4%),Ka = 1 h-1(固定值),K35 = 0.0255 h-1(11.1%),K53 = 0.0269 h-1(11.5%)。与低剂量(Ktr₂ = 6.1 h-1)相比,600 毫克剂量的吸收延迟时间更长(Ktr₁ = 1.36 h-1)。Vc、Ka和Ktr取决于Cmax附近的取样,并固定为使用具有丰富PK取样方案的数据子集的单独模型的估计值:我们将这一管理信息系统应用于将从以前各自为政的研究中收集的 PK CvT 数据整理成一个用户友好型数据库,以支持致力于优化 HIV 治疗的转化科学家社区的数据共享、管理和挖掘。我们观察到 TFV 的吸收延迟与剂量有关,这是从集合 CvT 分析中得出的新发现,证明了从 HIV PDR 等资源中获取新 PK 知识的能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.30
自引率
8.80%
发文量
419
审稿时长
1 months
期刊介绍: Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.
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