This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.
Complex pathophysiology of diabetic wounds causes a delayed wound healing response. Advanced wound dressing materials that deliver biochemical cues are of particular interest in wound healing research. Here, we developed a dual-function delivery vehicle for drug and cell delivery applications
to treat diabetic wounds. The delivery system was developed via electrospinning of polycaprolacton/cellulose acetate solution containing fenugreek extract. The produced delivery vehicle was characterized using microstructural studies, cell viability assay, cytoprotection assay, cell migration
assay, In Vitro anti-inflammatory assay, free radical scavenging assay, tensile strength studies, swelling studies, and protein adsorption test. Scaffolds were then seeded with 30000 unrestricted somatic stem cells and transplanted into the rat model of excisional diabetic wound. Wound
healing assay showed that the co-delivery of fenugreek extract and unrestricted somatic stem cells led to a substantial improvement in the healing activity of electrospun dressings, as evidenced by higher wound contraction, epithelial thickness, and collagen deposition in this group compared
with other experimental groups. Gene expression analysis showed that dual-function delivery system could increase the expression level of VEGF, b-FGF, and collagen type II genes. Furthermore, the tissue expression level of IL-1β and glutathione peroxidase genes was significantly
reduced in this group compared with other groups. This study shows that the developed system may be considered as a potential treatment modality for diabetic wounds in the clinic.
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