Purpose

The pharmacokinetic properties of plasma NO₃⁻ and its reduced metabolite, NO₂⁻, have been separately described, but there has been no reported attempt to simultaneously model their pharmacokinetics following NO₃⁻ ingestion. This report describes development of such a model from retrospective analyses of concentrations largely obtained from primary endpoint efficacy trials.

Methods

Linear and non-linear mixed effects analyses were used to statistically define concentration dependency on time, dose, as well as patient and study variables, and to integrate NO₃⁻ and NO₂⁻ concentrations from studies conducted at different times, locations, patient groups, and several studies in which sample range was limited to a few hours. Published pharmacokinetic studies for both substances were used to supplement model development.

Results

A population pharmacokinetic model relating NO₃⁻ and NO₂⁻ concentrations was developed. The model incorporated endogenous levels of the two entities, and determined these were not influenced by exogenous NO₃⁻ delivery. Covariate analysis revealed intersubject variability in NO₃⁻ exposure was partially described by body weight differences influencing volume of distribution. The model was applied to visualize exposure versus response (muscle contraction performance) in individual patients.

Conclusions

Extension of the present first-generation model, to ultimately optimize NO₃⁻ dose versus pharmacological effects, is warranted.

中文翻译：

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在混合患者群体中摄入无机硝酸盐后硝酸盐及其还原代谢物亚硝酸盐的同时药代动力学分析

目的

血浆 NO ₃ ^-及其还原代谢物 NO ₂ ^-的药代动力学特性已单独描述，但没有报道尝试同时模拟 NO ₃ ^-摄入后的药代动力学。本报告描述了从主要从主要终点疗效试验中获得的浓度的回顾性分析中开发这种模型。

方法

线性和非线性混合效应分析用于统计定义浓度对时间、剂量以及患者和研究变量的依赖性，并整合在不同时间、地点、患者组进行的研究中的NO ₃ ^-和 NO ₂ ^-浓度，以及几项研究，其中样本范围仅限于几个小时。已发表的两种物质的药代动力学研究用于补充模型开发。

结果

_{建立了与 NO 3} ^-和 NO ₂ ^-浓度相关的群体药代动力学模型。该模型结合了两个实体的内源性水平，并确定这些不受外源性 NO ₃ ^-递送的影响。协变量分析揭示了 NO ₃ ^-暴露的个体间变异性部分地通过影响分布体积的体重差异来描述。该模型用于可视化个体患者的暴露与反应（肌肉收缩性能）。

结论

有必要扩展目前的第一代模型，以最终优化 NO ₃ ^-剂量与药理作用。