ABSTRACT
Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the “fit for purpose” application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in C(max) of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds.
Subject(s)
Humans , Area Under Curve , Caffeine , Ciprofloxacin , Computer Simulation , Drug Discovery , In Vitro Techniques , Permeability , Pharmacokinetics , Solubility , Tissue DistributionABSTRACT
No abstract available.
ABSTRACT
In 1974, bipolar endoprosthesis was first introduced by Bateman & Giliberty. It has theoretical advantages including minimizing acetabular wear, possible reduction of incidence of stem loosening, lessening of dislocation and easy revision procedure. Various methods for the treatment of fracture of the femur neck have been developed & performed, but it is still called “the unsolved fracture” in certain situation. But the role of it as primary treatment of fracture of the femur neck continues to be controversial. Current clinical results encourage its continued use and expansion of indication. Authors reviewed and analysed 21 cases of bicentric endoprosthesis and 1 case of Giliberty endoprosthesis those have been operated at the Department of Orthopaedic Surgery, National Medical Center from 1981 to 1983. Following results were obtained, l. According to disorder distribution, 14 cases were neglected fracture of femur neck, 2 old fracture, 1 idiopathic femoral head necrosis and 2 avascular necrosis & 1 non-union complicated by femoral neck fracture. 2. Among 20 cases, 8 cases were operated within 1/2 1 month after injury and 6 cases within 1 3months 3. Harris lateral appmach was used in 16 cases (80%) and Modified Gibson approach in 4 cases (20%). There were no significant differences in morbidity during operation and postoperative complication. 4. We used femoral stems those head diameter was 22 and 32mm(Charnley & Miiller type) and head pieces those diameter was 48-51 mm in male and 44–48 mm in Ifemale. 5. 3 cases were stiff in inner bearing without acetabular erosion. 6. In 6 cases more than 2 years followup 1 degree CE angle of Wiberg was increased in 2 cases of youngage respectively without associated hip joint pain. 7. Although inclination of head piece was vertical in 8 cases, fracture and dislocation were not found. 8. The circumference of head piece and opposite femoral head was measured and compared. There were 12 cases (mean 12.6 mm) that of head piece larger than opposite femoral head and 3 cases smaller than opposite femoral head. 9. There was 4 cases of complication (3 patients) and still no reoperation and revision converted to T.H.R. 10. With regard to average 18 months of follow-up, 7 cases of 81–90 Harris hip-rating score, 6 of 91–100, 4 of 71–80 and 3 of 61–70.