Agios Pharmaceuticals, Inc., Cambridge, MA, USA.
Certara UK Limited, Sheffield, UK.
Cancer Chemother Pharmacol. 2020 Nov;86(5):619-632. doi: 10.1007/s00280-020-04148-3. Epub 2020 Sep 25.
Develop a physiologically based pharmacokinetic (PBPK) model of ivosidenib using in vitro and clinical PK data from healthy participants (HPs), refine it with clinical data on ivosidenib co-administered with itraconazole, and develop a model for patients with acute myeloid leukemia (AML) and apply it to predict ivosidenib drug-drug interactions (DDI).
An HP PBPK model was developed in Simcyp Population-Based Simulator (version 15.1), with the CYP3A4 component refined based on a clinical DDI study. A separate model accounting for the reduced apparent oral clearance in patients with AML was used to assess the DDI potential of ivosidenib as the victim of CYP3A perpetrators.
For a single 250 mg ivosidenib dose, the HP model predicted geometric mean ratios of 2.14 (plasma area under concentration-time curve, to infinity [AUC]) and 1.04 (maximum plasma concentration [C]) with the strong CYP3A4 inhibitor, itraconazole, within 1.26-fold of the observed values (2.69 and 1.0, respectively). The AML model reasonably predicted the observed ivosidenib concentration-time profiles across all dose levels in patients. Predicted ivosidenib geometric mean steady-state AUC and C ratios were 3.23 and 2.26 with ketoconazole, and 1.90 and 1.52 with fluconazole, respectively. Co-administration of the strong CYP3A4 inducer, rifampin, predicted a greater DDI effect on a single dose of ivosidenib than on multiple doses (AUC ratios 0.35 and 0.67, C ratios 0.91 and 0.81, respectively).
Potentially clinically relevant DDI effects with CYP3A4 inducers and moderate and strong inhibitors co-administered with ivosidenib were predicted. Considering the challenges of conducting clinical DDI studies in patients, this PBPK approach is valuable in ivosidenib DDI risk assessment and management.
利用健康受试者(HP)的体外和临床药代动力学(PK)数据以及伊维替尼与酮康唑的临床数据,开发伊维替尼的基于生理学的药代动力学(PBPK)模型,并对其进行修正,然后建立急性髓细胞白血病(AML)患者的模型,并应用该模型预测伊维替尼的药物-药物相互作用(DDI)。
在 Simcyp 基于人群的模拟器(版本 15.1)中开发 HP PBPK 模型,并用临床 DDI 研究对 CYP3A4 成分进行修正。使用单独的模型来解释 AML 患者中表观口服清除率降低的情况,以评估伊维替尼作为 CYP3A 效应物的 DDI 潜力。
对于单次 250mg 伊维替尼剂量,与酮康唑合用的强 CYP3A4 抑制剂伊维替尼,HP 模型预测的血浆浓度-时间曲线下面积(AUC)和最大血浆浓度(C)几何均值比值分别为 2.14 和 1.04,在观察值的 1.26 倍以内(分别为 2.69 和 1.0)。AML 模型合理地预测了患者所有剂量水平的伊维替尼浓度-时间曲线。与酮康唑合用时,预测的伊维替尼稳态 AUC 和 C 的几何均值比值分别为 3.23 和 2.26,与氟康唑合用时,分别为 1.90 和 1.52。与强 CYP3A4 诱导剂利福平合用时,预测伊维替尼单剂量的 DDI 效应大于多剂量(AUC 比值为 0.35 和 0.67,C 比值为 0.91 和 0.81)。
预测了伊维替尼与 CYP3A4 诱导剂和中效及强效抑制剂联合使用时可能具有临床相关性的 DDI 效应。考虑到在患者中进行临床 DDI 研究的挑战,这种 PBPK 方法在伊维替尼 DDI 风险评估和管理方面具有重要价值。