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.

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.

Physiological pharmacokinetic model of children and its application of modeling software / 药学学报

Developmental changes in children can affect drug disposition and clinical effects. A physiologically-based pharmacokinetic (PBPK) model is a mathematical model that can be used to predict blood drug concentrations in children and gain insight into age-dependent physiological differences in drug disposition impact. Pediatric PBPK (P-PBPK) models have attracted attention over the past decade. With the concerted efforts of academia, pharmaceutical companies, and regulatory agencies, there are more and more examples of pediatric clinical studies using PBPK models. Nevertheless, the number of P-PBPK models and their predictive performance still lag behind adult models. By referring to the literature, we study the process of children adapting to adult absorption, distribution, metabolism, and excretion (ADME) parameters and analyze the general principles of P-PBPK model establishment. In addition, we summarize the functions and application examples of commonly used P-PBPK modeling software to provide a basis for the rational application of modeling software.

Anestesia total intravenosa libre de opioides guiada por qCON y qNOX en paciente obesa / Total Intravenous anesthesia in patients with intestinal occlusive syndrome

Introducción: En los últimos años la anestesia libre de opioides ha constituido una alternativa más a las técnicas tradicionales de anestesia general. Con la exclusión de este grupo de fármacos se evitan los múltiples efectos adversos y complicaciones asociados al mismo. A pesar de que la anestesia libre de opioides tiene sus indicaciones y que ha demostrado sus beneficios en cierto grupo de pacientes, existen aún controversias en relación con su utilidad en el paciente obeso. Características como la obesidad hacen que los modelos multimodales empleados para programar la anestesia libre de opioides sean cada vez más complejos. Objetivos: Describir un caso clínico realizado con la técnica de anestesia libre de opioides que constituye la primera experiencia en Ecuador. Presentación del caso: Se presenta el caso de una paciente obesa intervenida de colecistectomía laparoscópica mediante infusión de propofol, ketamina, lidocaína, sulfato de magnesio, y dexmedetomidina. La titulación de estos fármacos se realizó mediante cálculo de concentraciones plasmáticas a través de modelos farmacocinéticos y guiada por monitorización de profundidad anestésica y analgésica, con lo cual se logró optimizar el consumo de fármacos, disminuir las complicaciones y una evolución clínica favorable. Hasta donde se conoce a nivel local y de país (Ecuador) es la primera experiencia que se reporta con esta técnica. Conclusiones: La anestesia libre de opioides puede resultar una elección en el paciente obeso ya que asegura una adecuada recuperación sin efectos adversos asociados(AU)

Introduction: In recent years, opioid-free anesthesia has become another alternative in front of traditional general anesthesia techniques. The exclusion of this group of drugs avoids the numerous adverse effects and complications associated with its usage. Although opioid-free anesthesia has its indications and has showed its benefits in a certain group of patients, there is still controversy regarding its usefulness in the obese patient. Characteristics such as obesity make the multimodal models used to program opioid-free anesthesia increasingly complex. Objectives: To describe a clinical case involving the opioid-free anesthesia technique, which is the first experience in Ecuador. Case presentation: The case is presented of a female obese patient who underwent laparoscopic cholecystectomy by infusion of propofol, ketamine, lidocaine, magnesium sulfate and dexmedetomidine. Titration of these drugs was carried out by calculating plasma concentrations through pharmacokinetic models and guided by monitoring of anesthetic and analgesic depth, thus optimizing drug consumption, reducing complications and achieving a favorable clinical evolution. As far as known locally and in the country (Ecuador), this is the first reported experience with this technique. Conclusions: Opioid-free anesthesia may be a choice in the obese patient, since it ensures adequate recovery without associated adverse effects(AU)

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.

Establishment and validation of population pharmacokinetic model of docetaxel in malignant tumor patients / 中国药房

OBJECTIVE To establis h and validate a population pharmacokinetic model of docetaxel in malignant tumor patients. METHODS The clinical data of malignant tumor patients treated with chemotherapy regimen containing docetaxel in our hospital from June 2019 to December 2021 were retrospectively collected . According to the results of blood concentration detection ， based on the three -compartment model the nonlinear mixed effect model （NONMEM）was used ；covariates（age，weight，height， body surface area ，Karnofsky performance scale ，total protein ，albumin，total bilirubin ，aspartate aminotransferase ，alanine aminotransferase and serum creatinine ）affecting clearance （CL）were screened by “forward inclusion and backward exclusion ”； the population pharmacokinetic model of docetaxel was established . The model was tested for goodness -of-fit diagnosis and internal validation by Bootstrap . RESULTS A total of 264 measured blood concentrations of 132 patients with malignant tumors during chemotherapy were included . The covariates that had significant effect on CL of docetaxel were serum creatinine and total bilirubin （P＜0.01）. The results of Bootstrap analysis （parameter median values and 95% confidence intervals ）were close to predict results of the established model ；the final model estimated that the population typical value of docetaxel CL was 37.82 L/h. CONCLUSIONS The population pharmacokinetic model of docetaxel in malignant tumor patients is established successfully ， which can be used for the formulation and optimization of clinical individualized regimen .

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.

PKconverter: R package to convert the pharmacokinetic parameters

Population pharmacokinetic analysis and modeling procedures typically require estimates of both population and individual pharmacokinetic parameters. However, only some of these parameters are contained in models and only parameters in the model can be estimated. In this paper, we introduce a new R package, PKconverter, to calculate pharmacokinetic parameters using the relationships among them. After fitting the model, other parameters can be calculated from the functional relationship among the parameters. PKconverter provides the functions to calculate whole parameters along with a Shiny application for converting the parameters. With this package, it is also possible to calculate the standard errors of the other parameters that are not in the model and estimate individual parameters simultaneously.

Predictive performance and analysis of a vancomycin population pharmacokinetic model in Chinese pediatric patients / 药学学报

This study aimed to evaluate the predictive performance of a vancomycin population pharmacokinetic model in 0-10 year Chinese pediatric patients. This study was approved by the Ethics Research Committee of the First Affiliated Hospital of Guangxi Medical University, data from hospitalized children ≤ 10 years of age who receiving vancomycin were collected retrospectively. Individual predictive values (IPRED) were estimated by Bayesian Analysis based on a previous published population pharmacokinetic model, and compared with the observed steady state trough concentration. As results, a total of 371 vancomycin serum concentrations from 191 patients were taken for the external validation. The mean error (ME), the mean relative prediction error (ME%), the mean absolute error (MAE) and the root mean square error (RMSE) in individual prediction method for the total patients were -0.50 mg·L-1, 6.03%, 1.84 mg·L-1, 2.86 mg·L-1 respectively. The correlation coefficient between individual predictions and detection values was 0.95. The stability and the predictive performance of model were accepted by goodness-of-fit, visual predictive check (VPC) and Bland-Altman. The percentage of individual prediction error within ± 30% was 82.75%. The above results suggest that, this Chinese pediatric population pharmacokinetic model in 0-10 years old has a good prediction performance. It can be applied to the design of initial treatment plan and predicting the extent of drug exposure.

Application of a population pharmacokinetic model for vancomycin in patients with severe neurosurgical disease / 中国感染与化疗杂志

Objective This study was designed to validate the utility of a population pharmacokinetic model established for vancomycin in patients with severe neurosurgical disease . Methods The clinical data including patient gender , age , body weight ,serum creatinine and albumin were collected retrospectively from patients in Nanjing Drum Tower Hospital to calculate the steady trough concentration of vancomycin using the previously established pharmacokinetic model .The predicted value was compared with the actual value .Results During the period from March 2013 to March 2014 ,53 blood samples with serum trough concentration of vancomycin were collected from 42 patients .The average trough concentration of vancomycin was 10 .9 mg/L (range from 1 .6 to 49 .1 mg/L) .The predicted trough level of vancomycin based on the population pharmacokinetic model was significantly correlated to the actual value(r=0 .857 ,P<0 .001) .The mean absolute percentage error was 0 .407 9 . The confidence interval was 9 .36‐14 .07 for the predicted values ,and 8 .92‐14 .32 for the actual values .Conclusions The pharmacokinetic model is valid and useful for planning intravenous dose of vancomycin in patients with severe neurosurgical disease .Large error (about 30% ) was observed in estimation of body weight due to coma .Reduced renal function following contrast agent and/or diuretic drug has an impact on the predicted results . The accuracy of prediction can be increased to nearly 70% after adjusting the covariates .

Review of pharmacokinetic models for target controlled infusions in anesthesia.

Intravenous injection of anesthetic drugs dates back to the 17th Century when opium and chloral hydrate have been injected intravenously. It was not until the 1930s intravenous anesthesia became popular with the invention of barbiturates.Early intravenous anesthetic agents such as barbiturates were ideal for induction of anesthesia, but not suitable for maintenance of anesthesia. Most of these drugs accumulated significantly with increasing durations of infusion and also resulted in cardiorespiratory depression. The invention of propofol and shorter acting opioid analgesics such as remifentanil and alfentanil have revolutionized intravenous anesthesia. The rapid onset and offset of these drugs lends itself to being suitable agents for maintenance of anesthesia over prolonged periods of time. Detailed understanding of the pharmacokinetics of propofol and remifentanil, combined with technological advances in intravenous pumps capable of accurate delivery of drugs have resulted in great development of the field of total intravenous anesthesia and target controlled infusions. I would like to discuss, in this article, the pharmacokinetics and pharmacokinetic models behind these intravenous infusion pumps.

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.