Optimization of dosage regimen using a mechanism-based pharmacokinetic-pharmacodynamic modeling

降糖药物的药代动力学（PK）和药效学（PD）可能受到给药时间的影响，因为血糖水平具有明显的昼夜节律。本研究的目的是评估昼夜节律变化对SU药物甲苯磺丁脲（TB）在大鼠体内PK-PD关系的影响。生理水平的血浆葡萄糖表现出昼夜节律与顶相结束的光相（约。15：00小时）。使用二室模型描述了6：00和18：00 h静脉推注给药后游离TB的血浆浓度，未观察到PK参数随给药时间的变化。TB在18：00 h静脉给药后的降血糖作用大于6：00 h剂量。采用Link和E_模型建立了具有昼夜节律的PK-PD模型<max>。然而，回归曲线不能同时很好地拟合在两个给药时间观察到的降血糖作用。从血浆胰岛素水平和胰岛释放量来看，TB在18：00时胰岛素分泌量较6：00时增加。因此，TB的剂量转化为胰岛素的表观剂量。为了评估TB剂量与降血糖效果之间的关系，然后使用血浆胰岛素水平代替TB构建另一模型。模型估计的效应解释了同时在两个给药时间观察到的数据。这些结果表明，当SU药物持续使用很长一段时间时，由于某些生物昼夜节律，可能会发生无法通过血浆药物浓度预测的药理学变化。

Pharmacokinetics (PK) and pharmacodynamics (PD) of hypoglycemic drugs may be influenced by dosage time, because plasma glucose level shows a remarkable circadian rhythm. The purpose of the present investigation was to evaluate the effect of circadian changes on the PK-PD relationship of tolbutamide (TB), a SU agent, in rats. Physiological level in plasma glucose showed a circadian rhythm with acrophase in the end of the light phase (ca.15:00 h). Plasma concentrations of free TB after i.v. bolus administration at 6:00 and 18:00 h were described using a two-compartment model, and no change of the PK parameters by the administration time was observed. The hypoglycemic effect after i.v. administration of TB at 18:00 h was larger than the 6:00 h dosage. The PK-PD model was constructed using link and E_<max> models with a circadian rhythm. However, the regression curves did not fit simultaneously the observed hypoglycemic effects at both dosage times well. For the insulin secretion by TB, plasma level and release from isolated pancreatic islets indicated that the spiked secretion of insulin enhanced at 18:00 h comparing with 6:00 h. The dosage of TB was therefore translated into the apparent dosage of insulin. To evaluate the relationship between the dosage of TB and the hypoglycemic effect, another model was then constructed using plasma level of insulin instead of TB. The model-estimated effect explained the observed data at both administration times simultaneously. These results suggest that a pharmacological change, which cannot be predicted from plasma drug concentration, might occur because of some biological circadian rhythms when SU agents are continued for a long time.