The Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden.
Invest New Drugs. 2012 Apr;30(2):833-45. doi: 10.1007/s10637-010-9603-3. Epub 2010 Dec 14.
To improve the predictive capacity of a semi-mechanistic myelosuppression model for neutrophils as the model have shown to over-predict the nadir of neutrophils and, secondly, to develop a model describing the time-course of leukocytes and neutrophils simultaneously.
The study included 601 cancer patients treated with a 1 h infusion of docetaxel in monotherapy. A total of 3,549 pairwise observations of leukocytes and neutrophils from one treatment cycle were analyzed simultaneously in NONMEM.
A basic model was developed consisting of a neutrophil and a non-neutrophil model, each with the same structure as the semi-mechanistic myelosuppression model. The leukocytes were modeled as the sum of the predicted neutrophils and non-neutrophils. The model described the time-course of the leukocytes well, but was not able to capture the nadir of the neutrophils. Hence the model was further refined and the included modifications (p < 0.001) in the final model are a sigmoid Emax functions for the drug effect, feedback functions on the cell maturation time in bone-marrow and an optimized number of transit compartments for each of the two cell types.
A joint semi-mechanistic myelosuppression model describing the time-course of leukocytes and neutrophils following docetaxel administration was developed. The data supported a more complex model compared to the previous model developed by Friberg et al. (2002), and increased the model's capacity to accurately describe the time-course of neutrophils following docetaxel therapy. The combined model also illustrates the differences between the cell types and allows prediction of neutrophil counts from leukocyte measurements.
提高中性粒细胞的半机械性骨髓抑制模型的预测能力，因为该模型显示出过度预测中性粒细胞的最低点，其次，开发一个同时描述白细胞和中性粒细胞时间过程的模型。
该研究包括 601 例癌症患者，接受单药多西紫杉醇 1 小时输注治疗。在 NONMEM 中同时分析了来自一个治疗周期的白细胞和中性粒细胞的 3549 对配对观察值。
开发了一个基本模型，该模型由一个中性粒细胞模型和一个非中性粒细胞模型组成，每个模型的结构与半机械性骨髓抑制模型相同。白细胞被建模为预测中性粒细胞和非中性粒细胞的总和。该模型很好地描述了白细胞的时间过程，但不能捕捉到中性粒细胞的最低点。因此，对模型进行了进一步的改进，最终模型中包含的修改（p < 0.001）是药物效应的 S 型 Emax 函数、骨髓细胞成熟时间的反馈函数以及两种细胞类型中每个过渡隔室的优化数量。
开发了一个联合半机械性骨髓抑制模型，用于描述多西紫杉醇给药后白细胞和中性粒细胞的时间过程。与 Friberg 等人（2002 年）之前开发的模型相比，该数据支持更复杂的模型，并提高了模型准确描述多西紫杉醇治疗后中性粒细胞时间过程的能力。联合模型还说明了细胞类型之间的差异，并允许从白细胞测量值预测中性粒细胞计数。
