Approaches to handling pharmacodynamic baseline responses
Approaches to handling pharmacodynamic baseline responses
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DOI：
10.1007/s10928-008-9088-2
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发表时间：
2008-06-01
影响因子：
2.5
通讯作者：
Karlsson, Mats O.
中科院分区：
文献类型：
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作者：
Dansirikul, Chantaratsamon;Silber, Hanna E.;Karlsson, Mats O.
一些处理基线反应的方法可用于药代动力学 (PK)-药效 (PD) 分析。它们包括：(方法 1-B1) 估计总体基线的典型值和个体间变异性 (IIV)，(B2) 将观察到的基线响应作为承认残余变异性的协变量，(B3) B2 的更通用版本，因为它还考虑了总体基线的 IIV，以及 (B4) 通过基线值对所有观测值进行标准化。本研究的目的是调查 B1-B4 的相对性能。单个给药间隔内的 PD 反应是通过间接反应模型进行模拟的，其中药物根据 Emax 模型通过刺激或抑制反应来发挥作用。 B1-B4 的性能在 22 种设计下进行了研究，每种设计包含 100 个数据集。 NONMEM VI beta 用于通过 FO 和 FOCE 方法估计模型参数。计算总体参数估计的平均误差（ME，％）和均方根误差（RMSE，％）并将其用作偏差和不精确性的指标。所有方法的绝对 ME（垂直条 ME 垂直条）和 RMSE 在同一设计中排名，排名值越低，方法性能越好。报告了所有设计中每种方法的平均排名。结果表明，使用 B1 和 FOCE，|ME| 的平均值所有典型个体参数和所有条件下的 RMSE 分别为 5.9% 和 31.8%。 |ME|的平均排名对于 B1、B2、B3 和 B4，FOCE 法为 3.7、3.8、3.3 和 5.2，FO 法为 4.6、4.3、4.7 和 6.4。使用 B1 时的不精确性最小（FO 的等级为 3.1，FOCE 的等级为 2.9），并且按顺序使用 B3（3.9-FO 和 3.6-FOCE）、B2（4.8-FO；4.7-FOCE）和 B4（6.4-FO；6.5-FOCE）增加不精确性。我们得出的结论是，在考虑偏差和不精确性时，B1 略好于 B3，而 B3 又好于 B2。这些方法之间的差异很小。 B4明显逊色。与 FO 方法相比，FOCE 方法导致较小的偏差，但参数估计的不精确性没有明显降低。
A few approaches for handling baseline responses are available for use in pharmacokinetic (PK)-pharmacodynamic (PD) analysis. They include: (method 1-B1) estimation of the typical value and interindividual variability (IIV) of baseline in the population, (B2) inclusion of the observed baseline response as a covariate acknowledging the residual variability, (B3) a more general version of B2 as it also takes the IIV of the baseline in the population into account, and (B4) normalization of all observations by the baseline value. The aim of this study was to investigate the relative performance of B1-B4. PD responses over a single dosing interval were simulated from an indirect response model in which a drug acts through stimulation or inhibition of the response according to an Emax model. The performance of B1-B4 was investigated under 22 designs, each containing 100 datasets. NONMEM VI beta was used to estimate model parameters with the FO and the FOCE method. The mean error (ME, %) and root mean squared error (RMSE, %) of the population parameter estimates were computed and used as an indicator of bias and imprecision. Absolute ME (vertical bar ME vertical bar) and RMSE from all methods were ranked within the same design, the lower the rank value the better method performance. Average rank of each method from all designs was reported. The results showed that with B1 and FOCE, the average of |ME| and RMSE across all typical individual parameters and all conditions was 5.9 and 31.8%. The average rank of |ME| for B1, B2, B3, and B4 was 3.7, 3.8, 3.3, and 5.2 for the FOCE method, and 4.6, 4.3, 4.7, and 6.4 for the FO method. The smallest imprecision was noted with the use of B1 (rank of 3.1 for FO, and 2.9 for FOCE) and increased, in order, with B3 (3.9-FO and 3.6-FOCE), B2 (4.8-FO; 4.7-FOCE), and B4 (6.4-FO; 6.5-FOCE). We conclude that when considering both bias and imprecision B1 was slightly better than B3 which in turn was better than B2. Differences between these methods were small. B4 was clearly inferior. The FOCE method led to a smaller bias, but no marked reduction in imprecision of parameter estimates compared to the FO method.