Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Mailstop 28-3-B, Thousand Oaks, CA 91320-1799, USA.
Cancer Chemother Pharmacol. 2010 Nov;66(6):1151-8. doi: 10.1007/s00280-010-1456-0. Epub 2010 Sep 25.
To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between motesanib exposure and tumor response in a phase 2 study of motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer.
Data from patients (n = 184) who received motesanib 125 mg once daily were used for population pharmacokinetic/pharmacodynamic modeling. Motesanib concentrations were fitted to a 2-compartment population pharmacokinetic model. Observed change in tumor size was the drug response measure for the pharmacodynamic model. Exposure measures in the pharmacokinetic/pharmacodynamic model included dose, plasma concentration profile, or steady-state area under the concentration versus time curve (AUC( ss )). A longitudinal exposure-tumor response model of drug effect on tumor growth dynamics was used.
Motesanib oral clearance in patients with medullary thyroid cancer was 67% higher than in patients with differentiated thyroid cancer patients (73.7 vs. 44 L/h). Patients' disease type (medullary thyroid cancer vs. differentiated thyroid cancer) was the most important covariate for explaining interpatient variability in clearance. The objective response rates were 14 versus 2% for differentiated thyroid cancer and medullary thyroid cancer, respectively. Motesanib exposure measures (AUC( ss ) or concentration profile) were better predictors of tumor response than motesanib dose. The estimated motesanib concentration yielding tumor stasis (1.9 ng/mL) was lower than the observed trough concentrations in differentiated thyroid cancer and medullary thyroid cancer patients.
Differences in motesanib pharmacokinetics likely explain the difference in tumor response observed between differentiated thyroid cancer and medullary thyroid cancer patients. The population pharmacokinetic/pharmacodynamic model provides a tool for predicting tumor response to the drug to support the dosing regimen of motesanib in thyroid cancer patients.
建立群体药代动力学/药效学模型，描述在晚期分化型甲状腺癌或甲状腺髓样癌患者中接受莫特沙尼治疗的 2 期研究中莫特沙尼暴露与肿瘤反应之间的关系。
使用接受莫特沙尼 125mg 每日一次治疗的患者（n=184）的数据进行群体药代动力学/药效学建模。莫特沙尼浓度拟合至 2 室群体药代动力学模型。观察到的肿瘤大小变化是药效学模型的药物反应测量指标。药代动力学/药效学模型中的暴露测量指标包括剂量、血浆浓度曲线、或稳态浓度-时间曲线下面积（AUC(ss)）。采用药物对肿瘤生长动力学影响的纵向暴露-肿瘤反应模型。
甲状腺髓样癌患者的莫特沙尼口服清除率比分化型甲状腺癌患者高 67%（73.7 比 44 L/h）。患者的疾病类型（甲状腺髓样癌与分化型甲状腺癌）是解释清除率个体间差异的最重要协变量。客观缓解率分别为分化型甲状腺癌和甲状腺髓样癌患者的 14%和 2%。莫特沙尼暴露测量指标（AUC(ss)或浓度曲线）比莫特沙尼剂量更能预测肿瘤反应。预计使肿瘤停滞的莫特沙尼浓度（1.9ng/mL）低于分化型甲状腺癌和甲状腺髓样癌患者的实测谷浓度。
莫特沙尼药代动力学的差异可能解释了在分化型甲状腺癌和甲状腺髓样癌患者中观察到的肿瘤反应差异。群体药代动力学/药效学模型为预测药物对肿瘤的反应提供了工具，以支持甲状腺癌患者莫特沙尼的给药方案。
