图卡替尼是一种高选择性、口服、可逆、人表皮生长因子受体 2 (HER2) 特异性酪氨酸激酶抑制剂。 Tucatinib 被批准在成人中以 300 mg 每日两次的剂量与曲妥珠单抗和卡培他滨联合治疗晚期 HER2 阳性 (HER2 ) 不可切除或转移性乳腺癌，并与曲妥珠单抗联合治疗 RAS 野生型 HER2 不可切除或转移性结直肠癌。本研究旨在描述健康志愿者和 HER2 转移性乳腺癌或结直肠癌患者中图卡替尼的药代动力学 (PK) 特征并评估 PK 变异的来源。基于四项健康参与者研究和三项研究的数据开发了群体药代动力学模型。使用非线性混合效应建模方法对患有 HER2 转移性乳腺癌或转移性结直肠癌的患者进行研究。评估临床相关协变量以评估其对暴露的影响，并通过预测校正的视觉预测检查评估整体模型性能。具有线性消除和一级吸收的两室药代动力学模型充分描述了图卡替尼药代动力学特征151 名健康参与者和 132 名患者。肿瘤类型被确定为影响图卡替尼生物利用度和清除率的显着协变量，导致 HER2 转移性结直肠癌和 HER2 转移性乳腺癌中图卡替尼稳态暴露量（浓度-时间曲线下面积）增加 1.2 倍和 2.1 倍，分别与健康参与者相比。没有其他协变量，包括轻度肾或肝损伤，对图卡替尼药代动力学产生影响。所确定的具有统计学意义的协变量的影响不被认为具有临床意义。无需根据最终群体药代动力学模型中测试的协变量调整图卡替尼剂量。NCT03723395、NCT03914755、NCT03826602、NCT03043313、NCT01983501、NCT02025192。© 2024。作者。

Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers.A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks.A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics.The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model.NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.© 2024. The Author(s).