Search

Infected aortic aneurysms account for 0.7%-3% of all aortic aneurysms and are associated with a 26%-44% mortality rate (1). No consensus exists about appropriate antimicrobial therapy and treatment duration for [...]

The pharmacokinetics (PKs) of mycophenolic acid (MPA) exhibit considerable complexity and large variability. We developed a population pharmacokinetic (popPK) model to predict the complex PK of MPA by examining an absorption model. Forty‐two patients who had undergone renal transplantation were included in this study. popPK analysis, incorporating several absorption models, was performed using the nonlinear mixed‐effects modeling program NONMEM. The MPA area under the concentration‐time curve at 0–12 h (AUC0–12) was simulated using the final model to calculate the recommended dose. The PK of MPA was adequately described using a two‐compartment model incorporating sequential zero‐ and first‐order absorption with lag time. Total body weight, renal function (RF), and posttransplantation day (PTD) were included as covariates affecting MPA PK. The final model estimates were 7.56, 11.6 L/h, 104.0 L, 17.3 L/h, 169.0 L, 0.0453, 0.283, and 1.95 h for apparent nonrenal clearance, apparent renal clearance, apparent central volume of distribution, apparent intercompartmental clearance, apparent peripheral volume of distribution, absorption half‐life, lag time, and duration of zero‐order absorption, respectively. Simulation results showed that a dose regimen of 500–1000 mg twice daily is recommended during the early posttransplantation period. However, dose reduction could be required with increased PTD and decreased RF. The complex PK of MPA was explained using an absorption model. The developed popPK model can provide useful information regarding individual dosing regimens based on PTD and RF. [ABSTRACT FROM AUTHOR]

Posaconazole is a globally approved broad‐spectrum triazole antifungal compound. In Japanese patients, posaconazole has identical dosing regimens as those approved globally for both tablet and intravenous formulations. This article aims to describe a model‐informed approach for dose justification of posaconazole in the Japanese population as either high‐risk patients with fungal infections (prophylaxis patients) or patients with fungal infections (treatment patients). A simultaneous population pharmacokinetic (PK) model for tablet and intravenous formulation was developed on the basis of a data set including Japanese data from healthy participants and treatment patients. The PK profiles and exposure distributions in Japanese patients were predicted and compared against foreign patients, that is, patients outside of Japan. Relationships between the post hoc posaconazole exposures and frequently observed clinical adverse events were evaluated. Although clinical trials for Japanese prophylaxis patients were not conducted, PK profiles in Japanese prophylaxis patients were predicted using the population PK model and demographic covariate information obtained from the published literature. Based upon the globally approved dosing regimen, posaconazole exposure distribution was predicted to be the highest in Japanese treatment patients, and generally similar between Japanese and foreign prophylaxis patients. Exposures in Japanese patients exceeded the efficacy target level (500 ng/mL). Safety profiles in Japanese treatment patients with the highest exposures were clinically acceptable without specific concerns to Japanese patients and appeared to have no relationship with posaconazole exposures. From PK, safety, and efficacy perspectives, the use of the same dosing regimen as in foreign patients was justified in Japanese prophylaxis and treatment patients. [ABSTRACT FROM AUTHOR]

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug‐target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally, making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended to provide a guide to modellers in their model endeavours to simplify these complicated models. [ABSTRACT FROM AUTHOR]

Experiment was conducted to investigate the effects of dietary diosgenin (Dio), a plant-derived sapogenin, on indomethacin (Indo)-induced rats. Bile secretion, intestinal inflammation and blood chemistry were assessed in anesthetized rats three days after two subcutaneous injections of Indo given 24 h apart. dio (>80 mg.kg-1-day-1) pretreatment significantly inhibited weight and food intake decreases and intestinal inflammation. Dio significantly increased biliary cholesterol output and prevented the decreases in bile flow, bile acid output and biliary alpha-muricholic acid.