Background and Objective

Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy.

Methods

Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM^®, version 7.5).

Results

In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33–0.77) and 0.2 1/h (95% confidence interval 0.09–0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48–0.92), suggesting full xanthine oxidoreductase inhibition during the period studied.

Conclusions

This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.

中文翻译：

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窒息新生儿次黄嘌呤、黄嘌呤和尿酸代谢的半机械模型

背景和目标

以前，我们在患有缺氧缺血性脑病的新生儿中开发了别嘌醇、氧嘌呤醇和生物标志物、次黄嘌呤、黄嘌呤和尿酸的药代动力学-药效学模型，其中观察到高初始生物标志物水平表明缺氧的影响。然而，在我们之前的研究中无法阐明完整的药效学。目前的研究包括来自 ALBINO 研究 (NCT03162653) 安慰剂组的额外数据，旨在描述患有缺氧缺血性脑病的新生儿的次黄嘌呤、黄嘌呤和尿酸的动态特征。

方法

接受别嘌醇或安慰剂甘露醇的 ALBINO 研究的新生儿也包括在内。基于嘌呤代谢机制开发了扩展群体药代动力学-药效学模型，其中描述了通过黄嘌呤氧化还原酶途径的合成、补救和降解。生物标志物的初始水平是内源性周转和高疾病相关量的组合。模型开发是通过非线性混合效应建模（NONMEM® ^， 7.5 版）完成的。

结果

总共有 20 名接受别嘌醇治疗的新生儿和 17 名接受甘露醇治疗的新生儿被纳入该分析。由于前体耗尽，生物标志物的内源性合成每小时减少 0.43%。次黄嘌呤很容易被回收或降解为黄嘌呤，速率常数分别为 0.5 1/h（95% 置信区间 0.33-0.77）和 0.2 1/h（95% 置信区间 0.09-0.31）。在与其作用机制一致的别嘌醇治疗组中发现了更大的挽救。高缺氧诱导的生物标志物初始水平被量化，与轻度缺氧缺血性脑病的新生儿相比，中度至重度缺氧缺血性脑病的新生儿高 1.2 至 2.9 倍。

结论

这种扩展的药代动力学-药效学模型充分描述了缺氧缺血性脑病新生儿中复杂的次黄嘌呤、黄嘌呤和尿酸代谢，表明别嘌醇对这些生物标志物有积极影响。表征了缺氧对其动力学的影响，强调了更高的缺氧相关初始暴露和更严重的缺氧缺血性脑病状态。