PDF(Pubmed)
Abstract：
Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the root causes have not been fully studied. This study aims to investigate the mechanisms behind CBZ\'s nonlinear PK and its induction potential on CYP3A4 and CYP2C9 enzymes. To achieve this, we developed and validated a physiologically based pharmacokinetic (PBPK) parent-metabolite model of CBZ and its active metabolite Carbamazepine-10,11-epoxide in GastroPlus®. The model was utilized for Drug-Drug Interaction (DDI) prediction with CYP3A4 and CYP2C9 victim drugs and to further explore the underlying mechanisms behind CBZ\'s nonlinear PK. The model accurately recapitulated CBZ plasma PK. Good DDI performance was demonstrated by the prediction of CBZ DDIs with quinidine, dolutegravir, phenytoin, and tolbutamide; however, with midazolam, the predicted/observed DDI AUClast ratio was 0.49 (slightly outside of the two-fold range). CBZ\'s nonlinear PK can be attributed to its nonlinear metabolism caused by autoinduction, as well as nonlinear absorption due to poor solubility. In further applications, the model can help understand DDI potential when CBZ serves as a CYP3A4 and CYP2C9 inducer.
摘要：
卡马西平（CBZ）通常用于治疗癫痫，并经常用于多种药物治疗。然而,引起人们对其诱导其他药物代谢的能力的担忧，包括自己,可能导致共同用药的治疗不足。此外,CBZ表现出非线性药代动力学（PK），但是根本原因尚未得到充分研究。本研究旨在探讨CBZ非线性PK背后的机制及其对CYP3A4和CYP2C9酶的诱导潜力。为了实现这一点，我们在GastroPlus®中开发并验证了CBZ及其活性代谢产物卡马西平-10,11-环氧化物的生理药代动力学（PBPK）母体代谢模型。该模型用于CYP3A4和CYP2C9受害者药物的药物-药物相互作用（DDI）预测，并进一步探索CBZ非线性PK背后的潜在机制。该模型准确地概括了CBZ血浆PK。通过对奎尼丁的CBZDDIs的预测证明了良好的DDI性能，dolutegravir,苯妥英,和甲苯磺丁脲；然而，咪达唑仑,预测/观察到的DDIAUClast比率为0.49(略微超出2倍范围).CBZ的非线性PK可以归因于其由自感应引起的非线性代谢，以及由于溶解度差导致的非线性吸收。在进一步的应用中,当CBZ充当CYP3A4和CYP2C9诱导剂时，该模型可以帮助理解DDI潜力。
