Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Development and Regeneration, and Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
Clin Pharmacokinet. 2022 Nov;61(11):1545-1558. doi: 10.1007/s40262-022-01164-9. Epub 2022 Aug 30.
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.
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).
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.
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.
此前，我们开发了一种别嘌醇、氧嘌呤醇和生物标志物（次黄嘌呤、黄嘌呤和尿酸）在患有缺氧缺血性脑病的新生儿中的药代动力学-药效学模型，其中观察到高初始生物标志物水平表明缺氧有影响。然而，在我们之前的研究中，无法充分阐明全部药效动力学。本研究纳入了来自 ALBINO 研究（NCT03162653）安慰剂组的额外数据，旨在描述缺氧缺血性脑病新生儿中次黄嘌呤、黄嘌呤和尿酸的动态变化。
纳入接受别嘌醇或安慰剂甘露醇治疗的 ALBINO 研究的新生儿。基于嘌呤代谢的机制，建立了一个扩展的群体药代动力学-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与疾病相关的大量物质的组合。通过非线性混合效应模型（NONMEM，版本 7.5）进行模型开发。
总共纳入了 20 例接受别嘌醇治疗的新生儿和 17 例接受甘露醇治疗的新生儿。由于前体耗尽，生物标志物的内源性合成以每小时 0.43%的速度减少。次黄嘌呤可迅速被补救或降解为黄嘌呤，其速率常数分别为 0.51/h（95%置信区间为 0.33-0.77）和 0.21/h（95%置信区间为 0.09-0.31）。在别嘌醇治疗组中发现了更多的补救作用，这与其作用机制一致。量化了高缺氧诱导的生物标志物初始水平，与轻度缺氧缺血性脑病相比，中重度缺氧缺血性脑病新生儿的生物标志物初始水平高 1.2 倍至 2.9 倍。半最大黄嘌呤氧化还原酶抑制作用在 0.68mg/L 的联合别嘌醇和氧嘌呤醇浓度下达到（95%置信区间为 0.48-0.92），表明在研究期间完全抑制了黄嘌呤氧化还原酶。
该扩展的药代动力学-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。还对其动态变化的缺氧影响进行了特征描述，强调了更严重的缺氧缺血性脑病状态下与缺氧相关的初始暴露更高。
