Hayashi N, Aso H, Higashida M, Kinoshita H, Ohdo S, Yukawa E, Higuchi S
Clinical Pharmacology Section, Clinical Research & Development Division, Chugai Pharmaceutical Co., Ltd., 1-9, Kyobashi 2-Chome, Chuo-Ku, 104-8301, Tokyo, Japan.
Eur J Pharm Sci. 2001 May;13(2):151-8. doi: 10.1016/s0928-0987(00)00219-0.
The clearance of recombinant human granulocyte-colony stimulating factor (rhG-CSF) is known to decrease with dose increase, and to be saturable. The average clearance after intravenous administration will be lower than that after subcutaneous administration. Therefore, the apparent absolute bioavailability with subcutaneous administration calculated from the AUC ratio is expected to be an underestimate. The absorption pharmacokinetics after subcutaneous administration was examined using the results of the bioequivalency study between two rhG-CSF formulations with a dose of 2 microg/kg. The analysis was performed using a modified Wagner-Nelson method with the nonlinear elimination model. The apparent absolute bioavailability for subcutaneous administration was 56.9 and 67.5% for each formulation, and the ratio between them was approximately 120%. The true absolute bioavailability was, however, estimated to be 89.8 and 96.9%, respectively, and the ratio was approximately 108%. The absorption pattern was applied to other doses, and the predicted clearance values for subcutaneous and intravenous administrations were then similar to the values for several doses reported in the literature. The underestimation of bioavailability was around 30%, and the amplification of difference was 2.5 times, from 8 to 20%, because of the nonlinear pharmacokinetics. The neutrophil increases for each formulation were identical, despite the different bioavailabilities. The reason for this is probably that the amount eliminated through the saturable process, which might indicate the amount consumed by the G-CSF receptor, was identical for each formulation.
已知重组人粒细胞集落刺激因子（rhG-CSF）的清除率会随着剂量增加而降低，且具有饱和性。静脉给药后的平均清除率低于皮下给药后的平均清除率。因此，根据AUC比值计算的皮下给药表观绝对生物利用度预计会被低估。使用两种剂量为2μg/kg的rhG-CSF制剂之间的生物等效性研究结果，研究了皮下给药后的吸收药代动力学。采用修正的Wagner-Nelson方法和非线性消除模型进行分析。每种制剂皮下给药的表观绝对生物利用度分别为56.9%和67.5%，两者之比约为120%。然而，真实的绝对生物利用度估计分别为89.8%和96.9%，两者之比约为108%。将吸收模式应用于其他剂量，然后皮下和静脉给药的预测清除率值与文献中报道的几种剂量的值相似。由于非线性药代动力学，生物利用度的低估约为30%，差异放大为2.5倍，从8%到20%。尽管生物利用度不同，但每种制剂的中性粒细胞增加情况相同。其原因可能是通过饱和过程消除的量，这可能表明G-CSF受体消耗的量，每种制剂是相同的。
