Wang Xiaofeng, Owzar Kouros, Gupta Pankaj, Larson Richard A, Mulkey Flora, Miller Antonius A, Lewis Lionel D, Hurd David, Vij Ravi, Ratain Mark J, Murry Daryl J
University of Iowa, Iowa City, IA, USA.
Br J Clin Pharmacol. 2014 Nov;78(5):1005-13. doi: 10.1111/bcp.12427.
Vatalanib is an oral anti-angiogenesis agent that inhibits vascular endothelial growth factor receptor tyrosine kinases, which in patients showed auto induction of metabolism and variability in pharmacokinetic (PK) disposition. The objective was to characterize the population PK and time-dependent change in vatalanib clearance and assess exposure-toxicity relationship in patients with myelodysplastic syndrome (MDS).
This was an open-label phase II study of vatalanib in MDS patients receiving 750-1250 mg once daily in 28-day cycles. Serial blood samples were obtained and plasma vatalanib concentrations measured by HPLC. Population PK analysis was performed using nonmem 7.2 with FO estimation since FOCE failed. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive check.
Pharmacokinetic data were complete for 137 patients (86 M, 51 F), of median age 70 years (range 20-91). A one-compartment model with lagged first-order absorption and time-dependent change in oral clearance was fitted to the vatalanib plasma concentration versus time data. The population means for pre-induction and post-induction oral clearance were 24.1 l h(-1) (range: 9.6-45.5) and 54.9 l h(-1) (range: 39.8-75.6), respectively. The apparent oral clearance increased 2.3-fold, (range: 1.7-4.1-fold) from first dose to steady state. Our data did not identify a significant relationship of the predefined covariates with vatalanib pharmacokinetics, although power to detect such a relationship was limited.
Vatalanib pharmacokinetics were highly variable and the extent of auto induction was not determined to correlate with any of the pre-defined covariates.
凡他尼布是一种口服抗血管生成药物，可抑制血管内皮生长因子受体酪氨酸激酶，在患者中显示出代谢的自身诱导以及药代动力学（PK）处置的变异性。目的是描述凡他尼布清除率的群体PK和时间依赖性变化，并评估骨髓增生异常综合征（MDS）患者的暴露-毒性关系。
这是一项凡他尼布的开放标签II期研究，研究对象为接受凡他尼布治疗的MDS患者，剂量为750 - 1250mg，每日一次，每28天为一个周期。采集系列血样，用高效液相色谱法测定血浆凡他尼布浓度。由于FOCE失败，使用带有FO估计的非参数模型7.2进行群体PK分析。使用拟合优度图、自抽样分析和可视化预测检验对最终模型进行评估。
137例患者（86例男性，51例女性）的药代动力学数据完整，中位年龄70岁（范围20 - 91岁）。将具有滞后一级吸收和口服清除率时间依赖性变化的单室模型拟合到凡他尼布血浆浓度与时间的数据。诱导前和诱导后口服清除率的群体均值分别为24.1 l h⁻¹（范围：9.6 - 45.5）和54.9 l h⁻¹（范围：39.8 - 75.6）。从首剂到稳态，表观口服清除率增加了2.3倍（范围：1.7 - 4.1倍）。我们的数据未发现预定义协变量与凡他尼布药代动力学之间存在显著关系，尽管检测这种关系的效能有限。
凡他尼布的药代动力学具有高度变异性，且自身诱导程度与任何预定义协变量均未确定存在相关性。
