Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-β-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Establishment and application of the physiologically-based pharmacokinetic model of amikacin in elderly patients with renal insufficiency / 中国药房

OBJECTIVE To establish a physiologically-based pharmacokinetic （PBPK） model of amikacin in elderly patients with renal insufficiency. METHODS PK-SIM® software was adopted for model building， optimization and simulation. The physical and chemical properties and pharmacokinetic parameters related to amikacin were collected by literature review. The PBPK model on adults was established and extrapolated to the elderly population based on the built-in human model. Data from clinical PK studies were used to optimize and validate the model. The goodness of fit， relative residual， and mean folding error （MFE） were used to evaluate the performance of forecasting. The final model was employed to simulate the exposure of amikacin in the elderly population with renal insufficiency， and the efficacy and safety of commonly used clinical dosing regimens were evaluated， and the recommended regimens were proposed. RESULTS The established PBPK model of amikacin had good prediction performance in both adult and elderly populations， with the absolute mean of relative residual value of 25%； the MFE of peak concentration （cmax） and area under the plasma concentration curve （AUC0－∞） in all simulation occasions ranged ＞0.5-＜2. The simulation results showed that， compared with healthy adults， no significant clinical difference in cmax was observed in the elderly with renal insufficiency at the same dosing regimen， but the trough concentration increased significantly due to accumulation. Prolonging the administration interval of amikacin rather than reducing the dosage was more helpful to ensure the efficacy and to reduce the occurrence of nephrotoxicity. CONCLUSIONS The PBPK model for amikacin is successfully established in the elderly patient with renal insufficiency， and shows good predictive performance.

Application of Physiologically Based Pharmacokinetic Modeling of Lamotrigine Using PK-Sim in Predicting the Impact of Drug Interactions and Dosage Adjustment

Objectives To build a lamotrigine (LTG) physiologically based pharmacokinetic (PBPK) model (LTG PBPK) and compare it to the clinical data from South Asian Indian patients and use this model to understand the drug interactions of LTG and explore the optimal doses. Methods and Material The PBPK model was developed using the PK-Sim software platform and qualified with LTG plasma concentration data from an Indian study. The European population database was chosen as the patient setting in the software. Physiochemical data of LTG and enzyme kinetic data were incorporated from the literature. Dosing protocols were as per the previous study. Interaction models for drug interactions with carbamazepine and valproate were also simulated. Results Most of the model predicted concentration-time profiles of LTG at steady-state were well within the observed concentrations. The developed models were suitably qualified. The drug interaction model was used to assess the impact of induction and inhibition of the pharmacokinetic profile of LTG. Conclusions The predicted plasma concentrations of the developed PBPK models using the European population database were very similar to the data from Indian patients. The developed LTG PBPK models are applicable in predicting the impact of drug interactions and can yield appropriate LTG doses to be administered.

Evaluation on the efficacy of moxifloxacin hydrochloride based on physiological pharmacokinetic models / 药学学报

This study is to establish and validation in vivo models of moxifloxacin based on the theory of physiologically based pharmacokinetics (PBPK), and then to predict the distribution of moxifloxacin in human venous return and organ such as lung, spleen and so on. The efficacy of moxifloxacin and its pharmaceutical preparations were quantified by comparing the pharmacokinetic parameters with the minimum inhibitory concentration of related pathogenic bacterium. The results showed that the anti-infection efficacy of pharmaceutical moxifloxacin preparation in the corresponding organs was basically the same. The PBPK model of moxifloxacin preparations can be more accurately described the pharmacokinetic of anti-infective drugs in human, it is suitable for the efficacy evaluation of anti-infective drugs and provides a strong basis for the corresponding scientific research and scientific supervision.

Application of physiologically based pharmacokinetic model in drug development and several questions being thought / 中国临床药理学与治疗学

Physiologically based pharmacokinetic (PBPK) model is based on physiology, anatomy, enzymes for drug metabolism, characteristic of drug transport, physicochemical property of drug and drug-body interaction. Thus, PBPK model may quantitatively predict: concentration-time profiles of drug and its metabolites in plasma and tissues; pharmacokinetics of drug under disease status; pharmacokinetics of drug in special population; pharmacokinetics of drugs in human derived from experimental animals; in vivo pharmacokinetics of drugs based on in vitro parameters for metabolism and transport; pharmacokinetics of drugs from different formations; pharmacodynamics or toxicity of drugs based on in vitro parameters for metabolism, transport, activity or toxicity of drug; drug-drug interaction; individual contributions of enzymes and transporters to in vivo drug disposition. Here, we would review applications of PBPK model in drug development and several questions which should be thought through a series of examples.

Establishment and application of physiologically based pharmacokinetic model in patients with hepatic impairment / 中国临床药理学与治疗学

Physiologically based pharmacokinetic (PB-PK) model simulates the circulation of blood flow in systemic organs by using mathematical model to quantitatively describe the behavior characteristics of drugs in the body. The application of PB-PK model to special population to predict the pharmacokinetic behavior of drugs in special populations can provide support for clinical rational drug use. In recent years, chronic liver disease has gradually become an important health problem. Due to the impairment of patients' liver function, the disposal process of drug in vivo will change to some extent. Therefore, it is necessary to evaluate the impact of liver dysfunction on the drug absorption, distribution, metabolism, elimination (ADME) in order to ensure the safety and effectiveness of drug use. PB-PK model can accurately determine the ADME process of drugs in patients according to the level of liver function, and play an important role in guiding clinical rational drug use. This review will start from the impact of liver function on the process of drug ADME, summarize and discuss how PB-PK model can build a model according to the physiological and pathological changes of patients with liver dysfunction for more accurate extrapolation prediction.

A physiologically-based pharmacokinetic model adequately predicted the human pharmacokinetic profiles of ZSP1601, a novel pan-phosphodiesterase inhibitor / 药学学报

ZSP1601, a novel pan-phosphodiesterase inhibitor is in development for the treatment of nonalcoholic steatohepatitis. A physiologically-based pharmacokinetic (PBPK) model was developed to predict the pharmacokinetics of ZSP1601 in human. The PBPK model following intravenous and oral dose of ZSP1601 in rats and dogs was firstly built using preclinical in vitro and in vivo data. The PBPK model in human was then built based on models in animal. The in vitro-in vivo extrapolation (IVIVE) method and some allometric scaling methods were used to predict the clearance in human, respectively. The PBPK models using IVIVE and allometry of unbound CL plus the rule of exponents methods predicted the pharmacokinetics of ZSP1601 in healthy Chinese subjects successfully. The predicted parameters Cmax and AUC following single oral dose administration were within 0.5-2 folds of the observed data. The model was optimized and the final model was used to predict the pharmacokinetics of ZSP1601 in North European Caucasian, Geriatrics, Obese and Morbidly Obese, respectively. Animal studies were approved by the Animal Management and Use Committee of Suzhou AppTec Inc., and the approved No. is SZ20140916.

Physiologically Based Pharmacokinetic Models for Use in Risk Assessment of Xylene / 环境与健康杂志

As a mature tool for estimating tissue dosimetry,physiologically based pharmacokinetic (PBPK) models are being used to simulate the process from an external chemical exposure to an internal exposure at a target site,for supporting quantitative predictions of risks to human health. This paper reviewed these models from three aspects: the general steps of model construction,the criteria of model evaluation,the use of model in risk assessment and taking xylene as an example particularly described the third aspect.