Journal of Pharmacokinetics and Pharmacodynamics最新文献

{"title":"International society of Pharmacometrics Mentorship Program (IMP): feedback survey from the first cohort of mentor-mentee pairs.","authors":"Patrick O Hanafin,&nbsp;Ananya Murthy,&nbsp;Dhananjay Marathe,&nbsp;John K Diep,&nbsp;Anu Shilpa Krishnatry,&nbsp;Hoi-Kei Lon,&nbsp;Dhaval K Shah,&nbsp;Sihem Ait-Oudhia,&nbsp;Gauri G Rao","doi":"10.1007/s10928-023-09880-w","DOIUrl":"https://doi.org/10.1007/s10928-023-09880-w","url":null,"abstract":"<p><p>The International Society of Pharmacometrics (ISoP) Mentorship Program (IMP) aims to help professionals at all career stages to transition into the pharmacometrics field, move to a different role/area within pharmacometrics, or expand their skillsets. The program connects mentees at various stages of their careers with mentors based on established criteria for mentor-mentee matching. Pairing mentees with appropriate mentors ensures strong alignment between mentees' interests and mentors' expertise as this is critical to the success and continuation of the relationship between the mentor and mentee. Once mentors and mentees are connected, they are strongly encouraged to meet at least once per month for an hour. The mentor and mentee have the freedom to tailor their sessions to their liking, including frequency, duration, and topics they choose to focus on. Mentees are encouraged to clearly define their goals to help direct their mentor-mentee relationship and conversations. Mentees and mentors alike are given the opportunity to provide feedback about the program to the ISoP Education Committee through surveys and testimonials. Due to the program's infancy, structured guidelines for mentor-mentee sessions are still being developed and instituted using the program evaluation described in this paper.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 4","pages":"243-250"},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10260442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Operational characteristics of full random effects modelling ('frem') compared to stepwise covariate modelling ('scm').","authors":"Lisa F Amann,&nbsp;Sebastian G Wicha","doi":"10.1007/s10928-023-09856-w","DOIUrl":"https://doi.org/10.1007/s10928-023-09856-w","url":null,"abstract":"<p><p>An adequate covariate selection is a key step in population pharmacokinetic modelling. In this study, the automated stepwise covariate modelling technique ('scm') was compared to full random effects modelling ('frem'). We evaluated the power to identify a 'true' covariate (covariate with highest correlation to the pharmacokinetic parameter), precision, and accuracy of the parameter-covariate estimates. Furthermore, the predictive performance of the final models was assessed. The scenarios varied in covariate effect sizes, number of individuals (n = 20-500) and covariate correlations (0-90% cov-corr). The PsN 'frem' routine provides a 90% confidence intervals around the covariate effects. This was used to evaluate its operational characteristics for a statistical backward elimination procedure, defined as 'frem_posthoc' and to facilitate the comparison to 'scm'. 'Frem_posthoc' had a higher power to detect the true covariate with lower bias in small n studies compared to 'scm', applied with commonly used settings (forward p < 0.05, backward p < 0.01). This finding was vice versa in a statistically similar setting. For 'frem_posthoc', power, precision and accuracy of the covariate coefficient increased with higher number of individuals and covariate effect magnitudes. Without a backward elimination step 'frem' models provided unbiased coefficients with highly imprecise coefficients in small n datasets. Yet, precision was superior to final 'scm' model precision obtained using common settings. We conclude that 'frem_posthoc' is also a suitable method to guide covariate selection, although intended to serve as a full model approach. However, a deliberated selection of automated methods is essential for the modeller and using those methods in small datasets needs to be taken with caution.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 4","pages":"315-326"},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9903183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Joint longitudinal model-based meta-analysis of FEV₁ and exacerbation rate in randomized COPD trials.","authors":"Carolina Llanos-Paez,&nbsp;Claire Ambery,&nbsp;Shuying Yang,&nbsp;Misba Beerahee,&nbsp;Elodie L Plan,&nbsp;Mats O Karlsson","doi":"10.1007/s10928-023-09853-z","DOIUrl":"https://doi.org/10.1007/s10928-023-09853-z","url":null,"abstract":"<p><p>Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV₁) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV₁ data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV₁ and mean annual exacerbation rate.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 4","pages":"297-314"},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9897184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of sequential and joint nonlinear mixed effects modeling of tumor kinetics and survival following Durvalumab treatment in patients with metastatic urothelial carcinoma.","authors":"Ting Chen,&nbsp;Yanan Zheng,&nbsp;Lorin Roskos,&nbsp;Donald E Mager","doi":"10.1007/s10928-023-09848-w","DOIUrl":"https://doi.org/10.1007/s10928-023-09848-w","url":null,"abstract":"<p><p>Standard endpoints such as objective response rate are usually poorly correlated with overall survival (OS) for treatment with immune checkpoint inhibitors. Longitudinal tumor size may serve as a more useful predictor of OS, and establishing a quantitative relationship between tumor kinetics (TK) and OS is a crucial step for successfully predicting OS based on limited tumor size measurements. This study aims to develop a population TK model in combination with a parametric survival model by sequential and joint modeling approaches to characterize durvalumab phase I/II data from patients with metastatic urothelial cancer, and to evaluate and compare the performance of the two modeling approaches in terms of parameter estimates, TK and survival predictions, and covariate identification. The tumor growth rate constant was estimated to be greater for patients with OS ≤ 16 weeks as compared to that for patients with OS > 16 weeks with the joint modeling approach (k_g= 0.130 vs. 0.0551 week^-1, p-value < 0.0001), but similar for both groups (k_g = 0.0624 vs.0.0563 week^-1, p-value = 0.37) with the sequential modeling approach. The predicted TK profiles by joint modeling appeared better aligned with clinical observations. Joint modeling also predicted OS more accurately than the sequential approach according to concordance index and Brier score. The sequential and joint modeling approaches were also compared using additional simulated datasets, and survival was predicted better by joint modeling in the case of a strong association between TK and OS. In conclusion, joint modeling enabled the establishment of a robust association between TK and OS and may represent a better choice for parametric survival analyses over the sequential approach.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 4","pages":"251-265"},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9902687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implementation of non-linear mixed effects models defined by fractional differential equations.","authors":"Christos Kaikousidis,&nbsp;Aristides Dokoumetzidis","doi":"10.1007/s10928-023-09851-1","DOIUrl":"https://doi.org/10.1007/s10928-023-09851-1","url":null,"abstract":"<p><p>Fractional differential equations (FDEs), i.e. differential equations with derivatives of non-integer order, can describe certain experimental datasets more accurately than classic models and have found application in pharmacokinetics (PKs), but wider applicability has been hindered by the lack of appropriate software. In the present work an extension of NONMEM software is introduced, as a FORTRAN subroutine, that allows the definition of nonlinear mixed effects (NLME) models with FDEs. The new subroutine can handle arbitrary user defined linear and nonlinear models with multiple equations, and multiple doses and can be integrated in NONMEM workflows seamlessly, working well with third party packages. The performance of the subroutine in parameter estimation exercises, with simple linear and nonlinear (Michaelis-Menten) fractional PK models has been evaluated by simulations and an application to a real clinical dataset of diazepam is presented. In the simulation study, model parameters were estimated for each of 100 simulated datasets for the two models. The relative mean bias (RMB) and relative root mean square error (RRMSE) were calculated in order to assess the bias and precision of the methodology. In all cases both RMB and RRMSE were below 20% showing high accuracy and precision for the estimates. For the diazepam application the fractional model that best described the drug kinetics was a one-compartment linear model which had similar performance, according to diagnostic plots and Visual Predictive Check, to a three-compartment classic model, but including four less parameters than the latter. To the best of our knowledge, it is the first attempt to use FDE systems in an NLME framework, so the approach could be of interest to other disciplines apart from PKs.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 4","pages":"283-295"},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9903157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An exploratory analysis of the performance of methylphenidate regimens based on a PKPD model of dopamine and norepinephrine transporter occupancy.","authors":"Sara Soufsaf,&nbsp;Philippe Robaey,&nbsp;Fahima Nekka","doi":"10.1007/s10928-023-09854-y","DOIUrl":"https://doi.org/10.1007/s10928-023-09854-y","url":null,"abstract":"<p><p>Methylphenidate (MPH) is a psychostimulant which inhibits the uptake of dopamine and norepinephrine transporters, DAT and NET, and is mostly used to treat Attention Deficit/Hyperactivity Disorder. The current dose optimization is done through titration, a cumbersome approach for patients. To assess the therapeutic performance of MPH regimens, we introduce an in silico framework composed of (i) a population pharmacokinetic model of MPH, (ii) a pharmacodynamic (PD) model of DAT and NET occupancy, (iii) a therapeutic box delimited by time and DAT occupancy, and (iv) a performance score computation. DAT occupancy data was digitized (n = 152) and described with Emax models. NET occupancy was described with a KPD model. We used this integrative framework to simulate the performance of extended-release (18-99 mg) and tid MPH regimens (25-40 mg). Early blood samples of MPH seem to lead to higher DAT occupancy, consistent with an acute tolerance observed in clinical rating scales. An Emax model with a time-dependent tolerance was fitted to available data to assess the observed clockwise hysteresis. Peak performance is observed at 63 mg. While our analysis does not deny the existence of an acute tolerance, data precision in terms of formulation and sampling times does not allow a definite confirmation of this phenomenon. This work justifies the need for a more systematic collection of DAT and NET occupancy data to further investigate the presence of acute tolerance and assess the impact of low MPH doses on its efficacy.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 4","pages":"267-281"},"PeriodicalIF":2.5,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10258236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the prospects of using gestational diabetes mellitus model to find means of pharmacological correction of the disorders in rat offspring","authors":"A. Solomina, A. Rodina, K. Kachalov, A. D. Zakharov, A. Durnev","doi":"10.37489/2587-7836-2023-2-45-53","DOIUrl":"https://doi.org/10.37489/2587-7836-2023-2-45-53","url":null,"abstract":"Imbalance of glucose homeostasis in the mother-placenta-fetus system in case of gestational diabetes mellitus (GDM) leads to pre- and postnatal abnormalities in offspring. Lack of universally recognized GDM-model complicates the search for pathogenetic means to prevent and correct abnormalities in offspring. A model using food load (high-calorie diet) in combination with low doses of diabetogen streptozotocin (HCD-STZ model) seems to be one of the closest in causes, mechanisms of development and clinical findings. Hence, the aim was to work out and assess the suitability of HCD-STZ model of GDM in order to register abnormalities in the offspring and determine the possibility of their pharmacological correction. Rats and its fetuses were the objects of the study. Modeling of GDM involved keeping rats on a high-calorie diet (NCD) for at least 10 weeks followed by a single injection of low-dose STZ on the first day of gestation. The hyperglycemia characteristic of GDM is recorded in less than 40 % of animals in HCD group combined with streptozotocin at a dose of 25 mg/kg. This fact does not allow a reliable assessment of abnormalities of antenatal and postnatal development of offspring. Thus, the model used is not promising for finding means of pharmacological correction of the effect of GDM on offspring.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"8 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82571591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Method for quantitative analysis of the marker substrate ABCB1-protein fexofenadine in Caco-2 cell lysate","authors":"M. A. Kopanitsa, Yu. S. Tranova, I. V. Chernykh, A. Shchulkin, P. Mylnikov, O. V. Kalinkina, E. Yakusheva","doi":"10.37489/2587-7836-2023-2-60-68","DOIUrl":"https://doi.org/10.37489/2587-7836-2023-2-60-68","url":null,"abstract":"One way to analyze the activity of the ABCB1 protein is to assess the accumulation of its substrate fexofenadine (F.) inside the test cells. The goal is to develop and validate a method for the quantitative analysis of F. in Caco-2 cell lysate using HPLC-MS/MS. Materials and methods. Caco-2 cell lysate was used as a matrix. The analysis was performed on an \"Ultimate 3000\" chromatograph with a TSQ Fortis triple quadrupole mass detector, a UCT Selectra C18 4.6 mm*100 mm 5 µm column in a gradient elution mode. The mobile phase rate was 0.3 ml/min, the sample volume was 20 µl, the ionization mode was positive, and the internal standard was amantadine (ng/ml). Sample preparation — precipitation of cell lysate protein with acetonitrile. The method was validated for the following parameters: selectivity, linearity, lower limit of quantitation (LLOQ), correctness, precision, sample transfer and sample stability. Results. Chromatograms of the blank lysate of Caco-2 cells showed no peaks with retention times characteristic of F. (5.70 min) and amantadine (3.58 min). NPKO F. was 0.5 ng/ml. F.'s transfer did not exceed 20% of NPKO, and amantadine — 5%. Based on the results of the analysis of three series of calibration standards (0.5; 1; 1.5; 5; 10; 25; 40; 50 ng/ml), linear regression equations were obtained, the correlation coefficients exceeded 0.99. Accuracy and precision were assessed within and between cycles by analyzing F. solutions in the matrix (0.5; 1.5; 25 and 40 ng/ml) within three cycles. The parameters did not exceed 20% for LLPO and 15% for other points. The stability of F. solutions (1.5 and 40 ng/ml) in the lysate was analyzed during storage at room temperature, after 3-fold freezing-thawing, storage at -80 °C for 60 days, after sample preparation and being in the autosampler for 24 hours. The accuracy was within 15% of the nominal values. Conclusions. A method for the quantitative determination of F. in Caco-2 cell lysate using HPLC-MS/MS has been developed and validated.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"12 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84333001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of the effect of food on the bioavailability, safety and tolerability of Aterixen® 100 mg tablet in healthy volunteers","authors":"V. B. Vasilyuk, Y. Dzhurko, A. Globenko, L. N. Schitov, V. N. Shabrov, M. Pasko, O. Kovchan, A. Kapashin, A. I. Bashkatova","doi":"10.37489/2587-7836-2023-2-37-44","DOIUrl":"https://doi.org/10.37489/2587-7836-2023-2-37-44","url":null,"abstract":"The aim. The primary objective of the study was to evaluate the effect of food on the bioavailability of Aterixen® 100 mg tablet after single oral dose under fasting or fed conditions. The secondary objective was to evaluate the pharmacokinetic parameters, safety, and tolerability of Aterixen® 100 mg tablet after single oral dose under fasting or fed conditions. Materials and methods. Healthy male and female volunteers aged 18 to 45 years were included in the study. Due to lack of data about intra-individual variability of the main pharmacokinetic parameters of the active substance in Aterixen® (XC221GI, 1-[2-(1-Methylimidazol-4-yl)-ethyl]perhydroazin-2,6-dione), an adaptive group sequential approach was used in the study. At Stage I, 24 volunteers were randomized into 2 groups (12 in each group): Group 1 (sequence AAB) received treatment A (administration of the drug under fasting conditions) during period I, treatment A during period II and treatment B (administration of the drug under fed conditions) during period III, Group 2 (sequence BBA) received therapy B during period I, therapy B during period II, and therapy A during period III. In each study period, serial blood samples were collected before and throughout 12 h after administration of the study drug. The quantification of the active substance XC221GI in plasma samples was performed using a validated high-performance liquid chromatography method with mass spectrometric detection. Safety evaluation was performed on the basis of frequency and severity of adverse events (AEs) and serious adverse events (SAEs), which were registered based on complaints, physical examination, laboratory tests, and electrocardiography (ECG). Drug tolerability was evaluated in terms of proportion of volunteers who prematurely discontinued participation in the study due to AE/SAE. Results. 24 randomized volunteers completed the study in compliance with the approved study protocol. The averaged pharmacokinetic curves profiles of XC221GI had similar shapes under fasting and fed conditions. Confidence intervals for the ratio of the geometric means for the primary parameters (AUC(0-t) and Cmax) of XC221GI and AUC(0-∞) were within the 80-125 % acceptance interval, while a small in absolute value, but statistically significant differences were noted in time until Cmax is reached. Throughout the study, 2 volunteers reported AEs (low RBC count, low hemoglobin concentration, and low hematocrit value) after receiving the study drug under fed conditions. All reported AEs were mild. The relationship between AEs and the study drug product was assessed by investigator as doubtful. Conclusion. The results of this study indicate that food does not affect the bioavailability of Aterixen® 100 mg, tablets, and the single oral dose of 100 mg was safe and well tolerated by healthy volunteers.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"5 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88625249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of a high-carbohydrate diet and streptozotoc in for modeling type 2 diabetes in Wistar rats","authors":"S. Ivanov, R. Ostrovskaya","doi":"10.37489/2587-7836-2023-2-54-59","DOIUrl":"https://doi.org/10.37489/2587-7836-2023-2-54-59","url":null,"abstract":"Relevance. To conduct a preclinical evaluation of the effectiveness of antidiabetic drugs, models simulating the pathogenesis and main manifestations of diabetes mellitus (DM) in humans are needed. The streptozotocin (STZ) model, which has received the most widespread use in the experiment, does not allow reproducing the stepwise multifactorial development of type 2 diabetes. Goal. To develop a model of type 2 diabetes using a high-carbohydrate diet in combination with a subthreshold dose of STZ in Wistar rats, characterized by hyperglycemia and insulin resistance. Methods. The animals of the control group (n = 20) received water as a drink, and the experimental group (n = 20) received a 10 % solution of fructose. After 14 days, 10 animals from each group were injected with STZ at a dose of 35 mg/kg. The blood glucose level was determined weekly. To assess insulin resistance, a oral glucose tolerance test was performed before and after the administration of STZ. Results. It was found that keeping rats on a high-carbohydrate diet for two weeks leads to a violation of glucose tolerance, which indicates insulin resistance. The introduction of STZ at a subthreshold dose of 35 mg/kg to animals on a standard diet causes an increase in the glycemic drop to 13.2 mmol/l, while the same dose of STZ against the background of a high-carbohydrate diet causes an increase in the level of hyperglycemia to 22.9 mmol/l and increases insulin resistance. Conclusion. The synergism of a high-carbohydrate diet and low doses of STZ makes it possible to obtain a model of type 2 diabetes mellitus that reproduces not only basal hyperglycemia, but also impaired glucose tolerance, which more fully corresponds to the process of developing type 2 diabetes in humans.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"9 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90367990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}