Jiang Sibo, Madrasi Kumpal, Samant Tanay, Lagishetty Chakradhar, Vozmediano Valvanera, Chiew Angela, Abdel-Rahman Susan M, James Laura P, Schmidt Stephan
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, Florida, USA.
Department of Clinical Toxicology Prince of Wales Hospital, Randwick, NSW, Australia.
J Clin Pharmacol. 2020 May;60(5):595-604. doi: 10.1002/jcph.1555. Epub 2019 Dec 4.
Acetaminophen protein adducts (adducts) are a well-established biomarker to diagnose acetaminophen toxicity. To date, the quantitative relationship between acetaminophen exposure, which drives adduct formation, and adduct exposure remains to be established. Our study characterized the adduct formation and disposition in adults using the approach of population parent-metabolite modeling. It demonstrated formation-limited pharmacokinetics (PK) for adducts in healthy subjects. This finding expands the existing knowledge on adduct PK that showed an apparent long elimination half-life. We then allometrically scaled the adduct PK model to children, simulated the adduct profiles, and compared these simulated profiles with those observed in an independent cohort of children. The scaled model significantly overpredicted the adduct concentrations in children early on in treatment and underpredicted concentrations following repeated acetaminophen doses. These results suggest that children demonstrate different adduct PK behavior from that of adults, most likely because of increased reactive metabolite detoxification in children. In summary, we described the first PK model linking acetaminophen and acetaminophen protein adduct concentrations, which provides a semimechanistic understanding of varying profiles of adduct exposure in adults and children.
对乙酰氨基酚蛋白加合物（加合物）是一种公认的用于诊断对乙酰氨基酚毒性的生物标志物。迄今为止，驱动加合物形成的对乙酰氨基酚暴露与加合物暴露之间的定量关系仍有待确定。我们的研究采用群体母体 - 代谢物建模方法，对成年人中加合物的形成和处置进行了表征。研究表明，健康受试者中加合物的药代动力学（PK）受形成限制。这一发现扩展了现有的关于加合物PK的知识，此前显示其消除半衰期明显较长。然后，我们将加合物PK模型按体表面积进行缩放以适用于儿童，模拟了加合物的变化情况，并将这些模拟结果与在一个独立儿童队列中观察到的结果进行比较。缩放后的模型在治疗早期显著高估了儿童体内的加合物浓度，而在重复给予对乙酰氨基酚剂量后则低估了浓度。这些结果表明，儿童的加合物PK行为与成人不同，很可能是因为儿童体内活性代谢物的解毒作用增强。总之，我们描述了第一个将对乙酰氨基酚与对乙酰氨基酚蛋白加合物浓度联系起来的PK模型，该模型为理解成人和儿童中加合物暴露的不同变化情况提供了半机制性的认识。
