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In recent years, modeling and simulation technology based on pharmacometrics has received increasing attention in the development of innovation drugs. In August of 2021, FDA issued a guidance named Pharmacokinetic-Based Criteria for Supporting Alternative Dosing Regimens of Programmed Cell Death Receptor-1 (PD-1) or Programmed Cell Death-Ligand 1 (PD-L1) Blocking Antibodies for Treatment of Patients with Cancer Guidance for Industry, claiming the necessity of using population PK-based simulation method for the optimization of dosing regimens, and the corresponding implementation standards. This article first summarized the existing therapeutic regimens of PD-1/PD-L1 blocking antibodies in clinic as well as the main content of the guidance, and then cited some actual examples where population PK-based simulation method did contribute to the approval of the alternative dosing regimens. Besides, some critical considerations for the dosing regimen optimization of PD-1/PD-L1 blocking antibodies were also analyzed. In our view, this guidance would have positive impacts on the development of PD-1/PD-L1 blocking antibodies in the future. We hope that this article may provide some references for the colleagues in China.
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ObjectⅣe To investigate the effect of sense and antisense TIMP-1 on the expression of FN and type Ⅳ collagen of rat glomerular mesangial cells in vitro. Methods Two recombinant retroviral vectors, pLXIN-TIMP-1 (PLT)encoding sense TIMP-1 and pLXIN-ATIMP-1 (PLA)encoding antisense TIMP-1 were constructed by using DNA recombining techniques. These two vectors were then introduced into the PA317 packaging cell line with lipofectin DOTAP. The high-titer retroviral supematants containing sense or antisense TIMP-1 were used to infect rat glomerular mesangial cells. PCR and Northern blot were used to detect the integration and expression of human TIMP-1. Northern blot and ELISA were employed to investigate the expression of endogenous TIMP-1, FN, and Ⅳ collagen. Results Both sense and antisense TIMP-1 were successfully integrated into rat mesangial cells and expressed the sense and antisense ITMP-1 RNA. Overexpression of TIMP-1 induced by sense TIMP-1 caused upregulation of FN and Ⅳ type collagen in protein level, in contrast, supprssion of TIMP-1 expression by antisense TIMP-1 caused downregulation of FN and Ⅳ type collagen protein; but neither sense nor antisense TIMP-1 infection had effects on the RNA level of FN and Ⅳ type collagen. Conclusion TIMP-1 suppresses the degradation of ECM in rat glomerular mesangial cells and antisense TIMP-1 may be available for renal fibrosis in the future.
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Objective To investigate the change of Na+ /dicarboxylate cotransporter (SDCT) 1 expression in renal tissues of rats with nephrolithiasis induced by ethylene glycol (EG) and the mechanism of potassium citrate prevention. Methods Male Wistar rats were divided into control, nephrolithiasis and potassium citrate treated groups. Calcium oxalate crystal deposition and histological changes in kidney were examined by anatomical and light microscope. The plasma and urinary biochemical parameters, such as citrate, oxalate etc., were analyzed by routine biochemical method. The expression of SDCT1 mRNA in kidneys was determined by Northern blot, and the change of SDCT1 protein abundance was detected by immunohistochemistry. Results On day 3, the animals in the nephrolithiasis group had a higher level of SDCT1 mRNA and protein abundance in kidneys, as well as a lower level of citrate in the urine when compared with the control group. However none of the rats in this group had obviously calcium oxalate crystal deposition in kidneys. On day 7 and 14, the expression of SDCT1 mRNA and protein abundance were shown further increase, when the urinary citrate concentration was decreased progressively, and 87. 5% to 100% of the rats in this group displayed a large quantity of calcium crystal deposition in the kidney. In the potassium citrate treated group, both the expression of SDCT1 mRNA and protein abundance were shown almost complete inhibited during the whole experiment time, meanwhile the urinary citrate level was significantly elevated with time; furthermore, the occurrence of the renal crystal deposition decreased to 37. 5% on day 14, and the pathologic changes such as tubular dilation and inflammatory cells infiltration were shown to be alleviated. Conclusions The upregulation of SDCT1 mRNA and protein abundance in kidney has a close relationship with hypocitraturia, which may play an important role in the development of nephroliathisis. The treatment with potassium citrate has a beneficial effect on the experimental nephrolithiasis rats through inhibiting the expression of SDCT1 in the renal tissue.