Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (A.C.O., J.K., B.W., A.P., S.F., N.P., K.U.); Drug Delivery and Disposition Laboratory, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (A.C.O., A.P., P.A.); BioNotus GCV, Niel, Belgium (P.A.); Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland (S.K.); Department of Clinical Research (S.K.) and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences (S.K.), University of Basel, Basel, Switzerland.
Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (A.C.O., J.K., B.W., A.P., S.F., N.P., K.U.); Drug Delivery and Disposition Laboratory, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium (A.C.O., A.P., P.A.); BioNotus GCV, Niel, Belgium (P.A.); Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland (S.K.); Department of Clinical Research (S.K.) and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences (S.K.), University of Basel, Basel, Switzerland
Drug Metab Dispos. 2024 Jun 17;52(7):614-625. doi: 10.1124/dmd.123.001635.
Hepatic impairment, due to liver cirrhosis, decreases the activity of cytochrome P450 enzymes (CYPs). The use of physiologically based pharmacokinetic (PBPK) modeling to predict this effect for CYP substrates has been well-established, but the effect of cirrhosis on uridine-glucuronosyltransferase (UGT) activities is less studied and few PBPK models have been reported. UGT enzymes are involved in primary -glucuronidation of midazolam and glucuronidation of 1'-OH-midazolam following CYP3A hydroxylation. In this study, Simcyp was used to establish PBPK models for midazolam, its primary metabolites midazolam--glucuronide (UGT1A4) and 1'-OH midazolam (CYP3A4/3A5), and the secondary metabolite 1'-OH-midazolam--glucuronide (UGT2B7/2B4), allowing to simulate the impact of liver cirrhosis on the primary and secondary glucuronidation of midazolam. The model was verified in noncirrhotic subjects before extrapolation to cirrhotic patients of Child-Pugh (CP) classes A, B, and C. Our model successfully predicted the exposures of midazolam and its metabolites in noncirrhotic and cirrhotic patients, with 86% of observed plasma concentrations within 5th-95th percentiles of predictions and observed geometrical mean of area under the plasma concentration curve between 0 hours to infinity and maximal plasma concentration within 0.7- to 1.43-fold of predictions. The simulated metabolic ratio defined as the ratio of the glucuronide metabolite AUC over the parent compound AUC (AUC/AUC, metabolic ratio [MR]), was calculated for midazolam--glucuronide to midazolam (indicative of UGT1A4 activity) and decreased by 40% (CP A), 48% (CP B), and 75% (CP C). For 1'-OH-midazolam--glucuronide to 1'-OH-midazolam, the MR (indicative of UGT2B7/2B4 activity) dropped by 35% (CP A), 51% (CP B), and 64% (CP C). These predicted MRs were corroborated by the observed data. This work thus increases confidence in Simcyp predictions of the effect of liver cirrhosis on the pharmacokinetics of UGT1A4 and UGT2B7/UGT2B4 substrates. SIGNIFICANCE STATEMENT: This article presents a physiologically based pharmacokinetic model for midazolam and its metabolites and verifies the accurate simulation of pharmacokinetic profiles when using the Simcyp hepatic impairment population models. Exposure changes of midazolam--glucuronide and 1'-OH-midazolam--glucuronide reflect the impact of decreases in UGT1A4 and UGT2B7/2B4 glucuronidation activity in cirrhotic patients. The approach used in this study may be extended to verify the modeling of other uridine glucuronosyltransferase enzymes affected by liver cirrhosis.
肝功能损害，由于肝硬化，降低细胞色素 P450 酶（CYPs）的活性。使用基于生理的药代动力学（PBPK）模型来预测 CYP 底物的这种作用已经得到很好的建立，但是肝硬化对尿苷-葡萄糖醛酸基转移酶（UGT）活性的影响研究较少，报道的 PBPK 模型也很少。UGT 酶参与咪达唑仑的初级 -葡萄糖醛酸化和 CYP3A 羟化后的 1'-OH-咪达唑仑的葡萄糖醛酸化。在这项研究中，Simcyp 用于建立咪达唑仑、其主要代谢物咪达唑仑--葡萄糖醛酸（UGT1A4）和 1'-OH 咪达唑仑（CYP3A4/3A5）以及次要代谢物 1'-OH-咪达唑仑--葡萄糖醛酸（UGT2B7/2B4）的 PBPK 模型，允许模拟肝硬化对咪达唑仑初级和次级葡萄糖醛酸化的影响。在将模型外推至 Child-Pugh（CP）A、B 和 C 级的肝硬化患者之前，该模型在非肝硬化患者中进行了验证。我们的模型成功预测了非肝硬化和肝硬化患者中咪达唑仑及其代谢物的暴露情况，86%的观察到的血浆浓度在预测的第 5 至 95 百分位数范围内，观察到的几何平均 AUC 至无穷大与最大血浆浓度之间的比值和预测值的 0.7 至 1.43 倍。模拟的代谢比定义为葡萄糖醛酸代谢物 AUC 与母体化合物 AUC 的比值（AUC/AUC，代谢比[MR]），用于咪达唑仑--葡萄糖醛酸与咪达唑仑（指示 UGT1A4 活性），下降 40%（CP A），48%（CP B）和 75%（CP C）。对于 1'-OH-咪达唑仑--葡萄糖醛酸与 1'-OH-咪达唑仑，MR（指示 UGT2B7/2B4 活性）下降 35%（CP A），51%（CP B）和 64%（CP C）。这些预测的 MR 得到了观察数据的证实。这项工作因此增加了对 Simcyp 预测肝硬化对 UGT1A4 和 UGT2B7/UGT2B4 底物药代动力学影响的信心。意义陈述：本文提出了咪达唑仑及其代谢物的基于生理的药代动力学模型，并验证了使用 Simcyp 肝损伤人群模型准确模拟药代动力学特征。咪达唑仑--葡萄糖醛酸和 1'-OH-咪达唑仑--葡萄糖醛酸的暴露变化反映了肝硬化患者中 UGT1A4 和 UGT2B7/2B4 葡萄糖醛酸化活性降低的影响。在这项研究中使用的方法可以扩展到验证其他受肝硬化影响的尿苷葡萄糖醛酸基转移酶的建模。
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