The University of Sydney, Sydney Pharmacy School, Pharmacy and Bank Building (A15), Camperdown, NSW, 2006, Australia.
University of South Australia, School of Pharmacy and Medical Sciences, Adelaide, SA, 5001, Australia.
Clin Pharmacokinet. 2019 Jul;58(7):911-926. doi: 10.1007/s40262-019-00736-6.
Herb-drug interactions with St John's wort (SJW) have been widely studied in numerous clinical studies. The objective of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for hyperforin (the constituent of SJW responsible for interactions), which has the potential to provide unique insights into SJW interactions and allow prediction of the likely extent of interactions with SJW compared to published interaction reports.
A PBPK model of hyperforin accounting for the induction of cytochrome P450 (CYP) 3A, CYP2C9 and CYP2C19 was developed in the Simcyp Simulator (version 17) and verified using published, clinically observed pharmacokinetic data. The predictive performance of this model based on the prediction fold-difference (expressed as the ratio of predicted and clinically observed change in systemic exposure of drug) was evaluated across a range of CYP substrates.
The verified PBPK model predicted the change in victim drug exposure due to the induction by SJW (expressed as area under the plasma concentration-time curve (AUC) ratio) within 1.25-fold (0.80-1.25) of that reported in clinical studies. The PBPK simulation indicated that the unbound concentration of hyperforin in the liver was far lower than in the gut (enterocytes). Simulations revealed that induction of intestinal CYP enzymes by hyperforin was found to be more pronounced than the corresponding increase in liver CYP activity (15.5- vs. 1.1-fold, respectively, at a hyperforin dose of 45 mg/day).
In the current study, a PBPK model for hyperforin was successfully developed, with a predictive capability for the interactions of SJW with different CYP3A, CYP2C9 and CYP2C19 substrates. This PBPK model is valuable to predict the extent of herb-drug interactions with SJW and help design the clinical interaction studies, particularly for new drugs and previously unstudied clinical scenarios.
圣约翰草（SJW）与药物的相互作用已在许多临床研究中广泛研究。本研究的目的是开发和评估一种超高效（SJW 中负责相互作用的成分）的基于生理学的药代动力学（PBPK）模型，该模型有可能提供对 SJW 相互作用的独特见解，并允许与已发表的相互作用报告相比，预测 SJW 相互作用的可能程度。
在 Simcyp Simulator（版本 17）中开发了一种超高效的 PBPK 模型，该模型考虑了细胞色素 P450（CYP）3A、CYP2C9 和 CYP2C19 的诱导作用，并使用已发表的临床观察到的药代动力学数据进行了验证。该模型基于预测折叠差异（表示为药物系统暴露的预测和临床观察变化之比）的预测性能在一系列 CYP 底物中进行了评估。
经过验证的 PBPK 模型预测了 SJW 诱导引起的受试药物暴露的变化（表示为 AUC 比值），在 1.25 倍（0.80-1.25）内与临床研究报告的结果一致。PBPK 模拟表明，超高效在肝脏中的未结合浓度远低于肠道（肠细胞）。模拟表明，超高效诱导肠道 CYP 酶的作用比相应的肝 CYP 活性增加更为明显（超高效剂量为 45mg/天时，分别为 15.5-和 1.1 倍）。
在本研究中，成功开发了一种超高效的 PBPK 模型，具有预测 SJW 与不同 CYP3A、CYP2C9 和 CYP2C19 底物相互作用的能力。该 PBPK 模型对于预测 SJW 与草药的相互作用程度以及帮助设计临床相互作用研究具有重要意义，特别是对于新药和以前未研究的临床情况。
