Novartis Healthcare Pvt. Ltd., Hyderabad, India (R.S.); and Novartis Institutes for Biomedical Research, East Hanover, New Jersey (H.G., D.Y.C., H.J.E.).
Novartis Healthcare Pvt. Ltd., Hyderabad, India (R.S.); and Novartis Institutes for Biomedical Research, East Hanover, New Jersey (H.G., D.Y.C., H.J.E.)
Drug Metab Dispos. 2018 Jan;46(1):26-32. doi: 10.1124/dmd.117.077834. Epub 2017 Oct 16.
The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (P450) inhibitor in vitro, a P450-mediated drug interaction may be likely when clofazimine is coadministered with substrates of these enzymes. The P450-mediated drug interaction potential of clofazimine was evaluated using both static [estimation of the and area under the plasma concentration-time curve ratio (AUCR) values] and dynamic [physiologically based pharmacokinetics (PBPK)] modeling approaches. For static and dynamic predictions, midazolam, repaglinide, and desipramine were used as probe substrates for CYP3A4/5, CYP2C8, and CYP2D6, respectively. The AUCR static model estimations for clofazimine with the substrates midazolam, repaglinide, and desipramine were 5.59, 1.34, and 1.69, respectively. The fold increases in the area under the curve (AUC) predicted for midazolam, repaglinide, and desipramine with clofazimine (based on PBPK modeling) were 2.69, 1.60, and 1.47, respectively. Clofazimine was predicted to be a moderate-to-strong CYP3A4/5 inhibitor and weak CYP2C8 and CYP2D6 inhibitor based on the calculated AUCR by static and PBPK modeling. Additionally, for selected antiretroviral, antitubercular, antihypertensive, antidiabetic, antileprotics, and antihyperlipidemic CYP3A4/5 substrate drugs, approximately 2- to 6-fold increases in the AUC were predicted with static modeling when coadministered with 100 mg of clofazimine. Therefore, the possibility of an increase in the AUC of CYP3A4/5 substrates when coadministered with clofazimine cannot be ignored.
2016 年世界卫生组织（WHO）耐多药结核病（DR-TB）治疗推荐意见将氯法齐明定位为核心二线药物。氯法齐明在体外被鉴定为细胞色素 P450（CYP450）抑制剂，当与这些酶的底物同时给药时，可能会发生 CYP450 介导的药物相互作用。使用静态（估计 和 血浆浓度-时间曲线下面积比值（AUCR）值）和动态（基于生理的药代动力学（PBPK））建模方法评估了氯法齐明的 CYP450 介导的药物相互作用潜力。对于静态和动态预测，咪达唑仑、瑞格列奈和去甲替林分别用作 CYP3A4/5、CYP2C8 和 CYP2D6 的探针底物。氯法齐明与咪达唑仑、瑞格列奈和去甲替林底物的 AUCR 静态模型估算值分别为 5.59、1.34 和 1.69。根据 PBPK 建模预测，氯法齐明使咪达唑仑、瑞格列奈和去甲替林的 AUC 增加了 2.69、1.60 和 1.47 倍。根据静态和 PBPK 建模计算的 AUCR，氯法齐明被预测为中度至强 CYP3A4/5 抑制剂和弱 CYP2C8 和 CYP2D6 抑制剂。此外，对于选定的抗逆转录病毒、抗结核、抗高血压、抗糖尿病、抗麻风病和抗高血脂 CYP3A4/5 底物药物，当与 100mg 氯法齐明同时给药时，静态模型预测 AUC 增加了 2 至 6 倍。因此，不能忽视与氯法齐明同时给药时 CYP3A4/5 底物 AUC 增加的可能性。
