Kawai R, Lemaire M, Steimer J L, Bruelisauer A, Niederberger W, Rowland M
Drug Safety, Sandoz Pharma Ltd, Basel, Switzerland.
J Pharmacokinet Biopharm. 1994 Oct;22(5):327-65. doi: 10.1007/BF02353860.
The immunosuppressant, SDZ IMM 125 (IMM), is a derivative of cyclosporin A (CyA). The disposition kinetics of IMM in plasma, blood cells, and various tissues of the rat was characterized by a physiologically based pharmacokinetic (PBPK) model; the model was then applied to predict the disposition kinetics in dog and human. Accumulation of IMM in blood cell is high (equilibrium blood cell/plasma ratio = 8), although the kinetics of drug transference between plasma and blood cell is moderately slow, taking approximately 10 min to reach equilibrium, implying a membrane-limited distribution into blood cells. A local PBPK model, assuming blood-flow limited distribution and tissue/blood partition coefficient (KP) data, failed to adequately describe the observed kinetics of distribution, which were slower than predicted. A membrane transport limitation is therefore needed to model dynamic tissue distribution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, and glomerular filtration) of IMM were assessed at steady state in vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, which described closely the IMM concentration-time profiles in arterial blood as well as 14 organs/tissues of the rat after intravenous administration. The model was then scaled up to larger mammals by modifying physiological parameters, tissue distribution and elimination clearances; in vivo enzymatic activity was considered in the scale-up of metabolic clearance. The simulations agreed well with the experimental measurements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric relationship. In addition, the nonlinear increase in maximum blood concentration and AUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitatively link preclinical and clinical data.
免疫抑制剂SDZ IMM 125（IMM）是环孢素A（CyA）的衍生物。通过基于生理的药代动力学（PBPK）模型对IMM在大鼠血浆、血细胞及各种组织中的处置动力学进行了表征；然后将该模型应用于预测犬和人类的处置动力学。IMM在血细胞中的蓄积较高（平衡时血细胞/血浆比 = 8），尽管血浆和血细胞之间药物转移的动力学适中缓慢，大约需要10分钟达到平衡，这意味着药物向血细胞的分布受膜限制。一个局部PBPK模型，假设血流限制分布和组织/血液分配系数（KP）数据，未能充分描述观察到的分布动力学，其比预测的要慢。因此，需要膜转运限制来模拟动态组织分布数据。此外，一个缓慢相互作用的细胞内池对于充分描述某些器官中的分布动力学也是必要的。在体内稳态时评估了IMM的三种消除途径（代谢、胆汁分泌和肾小球滤过），并通过相应的清除率项进行了独立表征。根据这些发现建立了一个全身PBPK模型，该模型很好地描述了静脉给药后大鼠动脉血以及14个器官/组织中IMM的浓度-时间曲线。然后通过修改生理参数、组织分布和消除清除率将该模型放大到更大的哺乳动物；在代谢清除率放大过程中考虑了体内酶活性。尽管代谢清除率存在较大的种间差异且不遵循通常的异速生长关系，但模拟结果与犬和人类的实验测量结果吻合良好。此外，通过纳入已知的IMM与血细胞特异性结合的饱和度，定量地解释了健康志愿者静脉给药后最大血药浓度和AUC随剂量增加的非线性增加。总体而言，PBPK模型为定量关联临床前和临床数据提供了一个有前景的工具。
