Pediatric Surgery and Intensive Care, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
Pediatric Pharmacology and Pharmacometrics Research Center, University Children's Hospital Basel (UKBB), Basel, Switzerland.
Clin Pharmacokinet. 2020 Jan;59(1):97-110. doi: 10.1007/s40262-019-00799-5.
Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy.
PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (C) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated.
PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest C in the third trimester (median [interquartile range]: 4.5 [3.8-5.1] mg/L), while C was 6.7 [5.9-7.4], 5.6 [4.7-6.3], and 4.9 [4.1-5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1-13.4%]), followed by the second (9.0% [7.5-11.0%]) and third trimester (8.2% [6.8-10.1%]), compared with non-pregnant women (7.7% [6.4-9.4%]).
Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model.
关于孕期扑热息痛（对乙酰氨基酚）药代动力学的了解甚少。本研究旨在建立一种基于生理学的药代动力学（PBPK）模型，以预测整个孕期扑热息痛的药代动力学。
在非孕妇和孕妇中建立扑热息痛及其代谢物的 PBPK 模型。考虑了预期会影响扑热息痛药代动力学的孕妇的生理和酶学变化。通过拟合优度图和比较体内药代动力学数据来评估模型。预测结果说明了在每 6 小时给予 1000mg 后稳态时（C）的平均浓度值，作为疗效的指标。此外，作为潜在肝毒性的测量指标，估计了扑热息痛转化为 N-乙酰对苯醌亚胺（NAPQI）的摩尔剂量分数。
PBPK 模型成功预测了非孕妇和孕妇中扑热息痛及其代谢物的药代动力学。预测结果显示，在孕晚期（中位数[四分位距]：4.5[3.8-5.1]mg/L）的 C 值最低，而非孕妇、孕早期和孕中期的 C 值分别为 6.7[5.9-7.4]、5.6[4.7-6.3]和 4.9[4.1-5.5]mg/L。假设整个孕期细胞色素 P450 2E1 活性持续升高，NAPQI 转化的扑热息痛摩尔剂量分数在孕早期最高（中位数[四分位距]：11.0%[9.1-13.4%]），其次是孕中期（9.0%[7.5-11.0%]）和孕晚期（8.2%[6.8-10.1%]），而非孕妇为 7.7%[6.4-9.4%]。
与非孕妇相比，孕妇的扑热息痛暴露水平较低，且与妊娠持续时间有关。尽管有这些发现，但目前尚不能建议更高的剂量调整，因为尚不清楚妊娠是否会影响 NAPQI 的毒代动力学。需要了解怀孕期间谷胱甘肽的丰度和体内 NAPQI 的数据，以进一步完善所提出的模型。
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