Latz Jane E, Rusthoven James J, Karlsson Mats O, Ghosh Atalanta, Johnson Robert D
Global Pharmacokinetics, Pharmacodynamics, and Trial Simulation, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Cancer Chemother Pharmacol. 2006 Apr;57(4):427-35. doi: 10.1007/s00280-005-0035-2. Epub 2005 Dec 2.
The objective of these analyses was to examine the effect of variations in the explanatory factors of neutropenic response, identified by semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) modeling, on clinically important features of the absolute neutrophil count (ANC)-time profile (e.g, the nadir of the ANC [NANC], its timing [T (Nadir)], and the timecourse of recovery [T (Rec)]).
Correlation analyses were used to evaluate the relationship of NANC, T (Nadir), and T (Rec) as a function of overall systemic exposure (AUC) and each of the covariates contained in the population PK/PD model. Simulations using the final PK/PD model were used to generate complete ANC-time profiles. Frequency counts of NANCs from the simulated profiles were used to quantitatively explore differences in the incidence and severity of neutropenia associated with a variety of scenarios (500 mg/m2 versus 600 mg/m2, normal vitamin deficiency markers versus elevated vitamin deficiency markers, and body surface area-based versus renal function-based dosing) and to evaluate the effect of individual explanatory factors with respect to neutropenic response.
Information obtained from correlation analysis and simulations was helpful in quantitatively exploring the impact of dose, exposure, and/or patient characteristics on neutropenic response. The information gained from these simulations provided supportive evidence for the decision to routinely include vitamin supplementation during pemetrexed treatment as a means of managing the risk of severe neutropenia secondary to pemetrexed administration. These techniques also provided information regarding the specific T (Nadir) and T( Rec) for inclusion in product labeling and suggested that a 14-day treatment cycle might be feasible for pemetrexed.
For population PK/PD models, to provide useful information for the practicing clinician or the clinical development team, it is not sufficient to look only at influences of covariates on model parameters. Rather, the modeling results need to be carefully investigated in terms of clinically relevant measures.
这些分析的目的是研究通过半机制-生理群体药代动力学/药效学（PK/PD）模型确定的中性粒细胞减少反应解释因素的变化对绝对中性粒细胞计数（ANC）-时间曲线的临床重要特征（例如，ANC的最低点[NANC]、其出现时间[T（最低点）]以及恢复时间进程[T（恢复）]）的影响。
采用相关性分析来评估NANC、T（最低点）和T（恢复）与总体全身暴露量（AUC）以及群体PK/PD模型中包含的每个协变量之间的关系。使用最终的PK/PD模型进行模拟以生成完整的ANC-时间曲线。来自模拟曲线的NANC频数用于定量探索与各种情况（500mg/m² 与600mg/m²、正常维生素缺乏标志物与升高的维生素缺乏标志物以及基于体表面积给药与基于肾功能给药）相关的中性粒细胞减少症的发生率和严重程度差异，并评估各个解释因素对中性粒细胞减少反应的影响。
从相关性分析和模拟中获得的信息有助于定量探索剂量、暴露和/或患者特征对中性粒细胞减少反应的影响。从这些模拟中获得的信息为培美曲塞治疗期间常规补充维生素作为管理培美曲塞给药继发严重中性粒细胞减少风险的一种手段的决策提供了支持性证据。这些技术还提供了关于纳入产品标签的特定T（最低点）和T（恢复）的信息，并表明14天的治疗周期对培美曲塞可能是可行的。
对于群体PK/PD模型，要为临床执业医生或临床开发团队提供有用信息，仅查看协变量对模型参数的影响是不够的。相反，需要根据临床相关指标仔细研究建模结果。
