目的 建立卡博替尼的生理药动学及其主要靶点的靶点占有率联用(PBPK-TO)模型,并预测CYP3A4的调节剂(抑制剂和诱导剂)对其PK/PD的影响。方法 通过运用公式和收集参数,建立卡博替尼的PBPK模型,利用文献实测值进行验证,并联合主要靶点的结合、解离速率常数(kon、koff)搭建成PBPK-TO模型;通过结合CYP3A4竞争型抑制剂酮康唑、时间依赖抑制剂地拉韦啶和诱导剂利福平的PBPK模型,研究其对卡博替尼的PK/PD的影响。结果 成功建立了卡博替尼PBPK-TO模型;联合用药时,酮康唑、地拉韦啶和利福平对卡博替尼最大血药浓度(cmax)和激酶靶点的最大靶点占有率(TOmax)均无显著性影响;酮康唑能使卡博替尼血浆药物浓度-时间曲线下面积(AUC0-t)增加34%,3个主要靶点的靶点占有率大于60%的持续时间(DTO>60%)均增加30%以上;地拉韦啶能使卡博替尼AUC0-t增加16%,3个主要靶点的DTO >60%均增加20%以上;利福平能使卡博替尼AUC和靶点的DTO >60%减少70%以上。此外,也研究了联合用药时临床合理的剂量调整方案,当单独使用卡博替尼60 mg作为治疗剂量时,与酮康唑联用剂量需要降低至40 mg;与地拉韦啶联用,不需要调整剂量;与利福平联用时,剂量需要增加到80 mg。结论 建立的PBPK-TO模型能较好地预测CYP3A4抑制剂、诱导剂对卡博替尼PK/PD的影响,为药物相互作用模型研究和临床使用剂量调整提供新思路。
Abstract
OBJECTIVE To establish a PBPK-TO model by combining physiologically based pharmacokinetics of cabozantinib with occupancy ratio of its main targets, and to predict the effects of CYP3A4 inhibitors and inducers on its PK/PD. METHODS The PBPK model of cabozantinib was established by formulas and collected parameters, and verified by measured values from literatures. Then the model was developed into a PBPK-TO model with the combination of kon and koff. The PBPK model of CYP3A4 competitive inhibitor ketoconazole, time-dependent inhibitor delavirdine and inducer rifampicin were taken together with cabozantinibs′ to study their effect on the PK and PD of cabozantinib. RESULTS The PBPK-TO model of cabozantinib was established successfully. When used in combination, ketoconazole, delavirdine and rifampin had no significant effect on the cmax of cabozantinib and TOmax of kinase targets; ketoconazole increased the AUC0-t of cabozantinib by 34%, and DTO >60% of three main targets by more than 30%. Delavirdine increased the AUC of cabozantinib by 16%, and DTO >60% of three main targets by more than 20%. Rifampicin reduced the AUC of cabozantinib and DTO >60% of targets by more than 70%. In addition, the dosing regimens were also determined when co-administered with CYP3A4 inhibitors and inducer. For single administration of 60 mg cabozantinib, dosing needed be adjusted to 40 mg with ketoconazole, no needed to be adjusted with delavirdine, and needed to be increased to 80 mg with rifampicin. CONCLUSION The established PBPK-TO model can predict the effect of CYP3A4 inhibitors and inducers on the PK/PD of cabozantinib successfully, and provide new ideas for drug-drug interaction model research and clinical dose justment.
关键词
卡博替尼 /
靶点占有率 /
PBPK-TO模型 /
药物相互作用 /
蛋白激酶抑制剂
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Key words
cabozantinib /
target occupancy /
PBPK-TO model /
drug-drug interaction /
protein kinase inhibitor
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