AAPS Journal最新文献_第5页

Establishing Clinically Relevant Specifications for Carbamazepine Tablets Using Physiologically Based Pharmacokinetic Modeling. 利用基于生理的药代动力学模型建立卡马西平片的临床相关规格。

IF 5 3区医学

AAPS Journal Pub Date : 2025-05-02 DOI: 10.1208/s12248-025-01074-1

Xiaofeng Wang, Longjie Li, Hongyi Yang, Qingfeng He, Xiao Zhu, Jiajing Wang, Bo Sun, Peng Liu, Xiaoqiang Xiang

{"title":"Establishing Clinically Relevant Specifications for Carbamazepine Tablets Using Physiologically Based Pharmacokinetic Modeling.","authors":"Xiaofeng Wang, Longjie Li, Hongyi Yang, Qingfeng He, Xiao Zhu, Jiajing Wang, Bo Sun, Peng Liu, Xiaoqiang Xiang","doi":"10.1208/s12248-025-01074-1","DOIUrl":"10.1208/s12248-025-01074-1","url":null,"abstract":"The purpose of this study was to establish a clinically relevant specification for carbamazepine (CBZ) tablets, a classic narrow therapeutic index drug (NTID), within the Chinese population. By integrating physiologically based pharmacokinetic (PBPK) modeling with in vitro dissolution profiles and corresponding pharmacokinetic (PK) data, we developed an in vitro-in vivo relationship (IVIVR) by selecting an appropriate dissolution model, and the IVIVR model was validated using in vitro and in vivo data from external sources to ensure the reliability of the method. Parameter sensitivity analysis was used to examine how the critical parameters influence the drug's absorption fraction (Fa). Additionally, the sensitivity of Tmax, Cmax, and AUC to physiological and formulation parameters was quantitatively evaluated. Based on the validated model, we also developed and validated a virtual bioequivalence (VBE) approach. Additionally, the safety space of the dissolution (Q60 min ≥ 80% meanwhile 50% ≤ Q15 min ≤ 85% and the assay (95 ~ 105%) for carbamazepine tablets (100 mg) were successfully explored depending on the VBE study. This study provides a valuable reference for establishing clinically relevant specifications for NTIDs through PBPK model-informed research.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"87"},"PeriodicalIF":5.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Reference-Corrected Visual Predictive Check: A More Intuitive Diagnostic for Non-Linear Mixed Effects Models. 参考校正视觉预测检查：非线性混合效应模型的更直观诊断。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-29 DOI: 10.1208/s12248-025-01065-2

Moustafa M A Ibrahim, E Niclas Jonsson, Martin Bergstrand

{"title":"The Reference-Corrected Visual Predictive Check: A More Intuitive Diagnostic for Non-Linear Mixed Effects Models.","authors":"Moustafa M A Ibrahim, E Niclas Jonsson, Martin Bergstrand","doi":"10.1208/s12248-025-01065-2","DOIUrl":"10.1208/s12248-025-01065-2","url":null,"abstract":"The prediction-corrected visual predictive check (pcVPC) is an informative model diagnostic that can offer advantages over the standard visual predictive check (VPC) when heterogenous study designs and adaptive dosing are used. However, a drawback with these plots is that prediction correction often results in y-axis values and trends that are unintuitive, difficult to explain, and challenging to communicate even among experts. The reference-corrected visual predictive check (rcVPC) offers a solution to these problems by leveraging a user-defined set of independent variables, for a more intuitive model diagnostic and an efficient communication of results to a wider audience. The rcVPC methodology is based on the definition of a reference dataset. Simulations are conducted with this reference dataset and the observed dataset, and then the simulated and the observed dependent variables are normalized by the population prediction for the user-defined independent variables in the reference dataset. The opportunity to manipulate time in the reference dataset is a unique feature that gives rcVPC the ability to visually characterize exposure-response relationships with delayed effect onset. The rcVPC approach was compared to pcVPCs and traditional VPCs for a range of examples inspired by real data. The rcVPC methodology was demonstrated to offer a more intuitive interpretation and more effective guidance to model development in a way that is not possible for VPC or pcVPC plots.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"86"},"PeriodicalIF":5.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Use of Surrogate Matrix for Calibrators in the Analysis of Dried Blood Samples - A Feasibility Study. 在干燥血液样本分析中使用替代基质校准器的可行性研究。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-29 DOI: 10.1208/s12248-025-01040-x

Dong Hun Lee, Iris Xie, Matthew Solomon, Ming Wang, Linlin Luo, Eric Woolf

引用次数: 0

Model-informed Drug Development (MIDD) Approach to Support Biopharmaceutical Development of Iberdomide. 基于模型的药物开发（MIDD）方法支持Iberdomide的生物制药开发。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-29 DOI: 10.1208/s12248-025-01071-4

Caroline Sychterz, Ping Chen, Ajay Saxena, Hongxia Lin, Lu Chen, Yan Li, Lu Gaohua, Yiming Cheng

{"title":"Model-informed Drug Development (MIDD) Approach to Support Biopharmaceutical Development of Iberdomide.","authors":"Caroline Sychterz, Ping Chen, Ajay Saxena, Hongxia Lin, Lu Chen, Yan Li, Lu Gaohua, Yiming Cheng","doi":"10.1208/s12248-025-01071-4","DOIUrl":"10.1208/s12248-025-01071-4","url":null,"abstract":"Iberdomide is a BCS III CELMoD™ agent currently under development for treatment of multiple myeloma. Five formulations were used during clinical development, starting with active ingredient in gelatin capsule (AIC), followed by subsequent formulations in gelatin (F1), HPMC capsules (F2 and F3), and finally the intended commercial form (ICF). A food effect study with the Phase I AIC formulation showed no food effect and two relative bioavailability studies bridging from AIC to formulation F1 and F2 showed similar systemic exposure. Modeling and simulation, based on in vitro dissolution, was used to bridge gaps in clinical data to demonstrate lack of a food effect across all formulations including ICF. First, a previously developed population pharmacokinetic (PK) model showed that formulation was not a covariate on iberdomide PK. Then a physiologically-based pharmacokinetic model (PBPK) informed by in vitro biorelevant dissolution was used to mechanistically describe iberdomide absorption. While minor differences between formulations were noted in their in vitro dissolution, PBPK modeling showed lack of a food effect across all five formulations. Sensitivity analysis using the PBPK model demonstrated that iberdomide permeability and total amount of drug released from formulation are the most sensitive parameters in defining the systemic exposure of iberdomide, in agreement with iberdomide's BCS III classification where drug release from drug product, and not solubility, is the rate-limiting step of dissolution. Based on the totality of evidence, which included clinical and in vitro data supplemented by modeling and simulation, no food effect is expected with the ICF.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"85"},"PeriodicalIF":5.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Simultaneous Estimation of fm and F_G Values Directly from Clinical Drug-Drug Interaction Study Data. 直接从临床药物相互作用研究数据同时估计fm和FG值。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-29 DOI: 10.1208/s12248-025-01064-3

Yumi Cleary, Nicolo Milani, Kayode Ogungbenro, Leon Aarons, Aleksandra Galetin, Michael Gertz

{"title":"Simultaneous Estimation of fm and FG Values Directly from Clinical Drug-Drug Interaction Study Data.","authors":"Yumi Cleary, Nicolo Milani, Kayode Ogungbenro, Leon Aarons, Aleksandra Galetin, Michael Gertz","doi":"10.1208/s12248-025-01064-3","DOIUrl":"10.1208/s12248-025-01064-3","url":null,"abstract":"During drug development, the design, interpretation and risk assessment of drug-drug interaction (DDI) are generally performed with physiologically-based pharmacokinetic (PBPK) modelling. Critical parameters are the hepatic metabolic fraction (fm) and intestinal availability (FG) which are commonly informed by clinical data. In this study, two methods for the simultaneous estimation of these parameters are proposed which utilize the distinctive changes in substrate's plasma concentration profiles in response to inhibition of intestinal and hepatic enzymes. The two-dimensional DDI (2D-DDI) method estimates the fm and FG values directly from the ratios of area-under-curve (AUCR) and maximum concentration (CmaxR), while the population PBPK method utilizes the full concentration-time data of a substrate without or with an inhibitor. The utility of both methods was demonstrated for a broad range of > 50,000 virtual and six actual CYP3A substrates. The 2D-DDI method is fast, reliable, and does not require a priori PBPK model development. The population PBPK method can estimate the population parameters and inter-individual variabilities of fm and FG and is applicable to more complex DDIs (e.g., multiple pathways/dynamic inhibitor concentration-time profiles) without the need for IV data. Like other approaches, both methods show an increasing uncertainty for substrates with high hepatic extraction and sensitivity to the assumed degree of enzyme inhibition. While both methods were evaluated for CYP3A substrates, the methodology equally applies to other enzymes. Additionally, this study provides guidance for clinical DDI study design to facilitate robust DDI extrapolation necessary to inform drug labels on concomitant medications in lieu of clinical trials.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"83"},"PeriodicalIF":5.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Realistic Albumin Concentrations in Virtual Subjects Across A Spectrum of Renal Function to Account for Variability in Protein Binding Within PBPK Models. 现实白蛋白浓度在虚拟对象跨越肾功能谱，以解释在PBPK模型中的蛋白质结合变异性。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-26 DOI: 10.1208/s12248-025-01062-5

Yuming Hu, Daniel Scotcher

{"title":"Realistic Albumin Concentrations in Virtual Subjects Across A Spectrum of Renal Function to Account for Variability in Protein Binding Within PBPK Models.","authors":"Yuming Hu, Daniel Scotcher","doi":"10.1208/s12248-025-01062-5","DOIUrl":"10.1208/s12248-025-01062-5","url":null,"abstract":"Use of physiologically-based pharmacokinetic (PBPK) modelling for extrapolation to organ impairment populations requires successful prediction for physiological changes. For drugs bound to human serum albumin (HSA), prediction of albumin concentrations is crucial to predict population differences in fraction unbound in plasma (fu). In this study, a multi-variable model was developed for prediction of HSA concentrations in renal impairment, using easily accessible variables (BMI, eGFR, age, sex, race and ethnicity) as predictors. An increase of eGFR from 15 to 90 mL/min/1.73m2 was predicted to elevate HSA concentration by 0.30-0.32 g/dL regardless of subjects' characteristics. Data from obese patients undergoing mini-gastric bypass surgery was used for external validation (observed BMI from 44.5 to 27.3 kg/m2, leading to predicted HSA concentration change of 0.3 versus 0.1-0.3 g/dL), highlighting the model's potential to enhance PBPK simulations for a broader population. Application of the new albumin model for predicting fu in renal impairment was evaluated with the single binding protein model. Consideration of inter-individual variability predicted by the albumin model could explain some variability in the observed fu data between different drugs and studies (54% observed records within 2.5th-97.5th percentile range of prediction). However, overall underprediction of fold-change in fu between healthy and severe renal impairment (45% observed data exceeded 97.5th percentile of prediction) was noted. Although accounting for changes in binding affinity in predictive models of fu remains a challenge, the newly developed albumin model can support generation of realistic virtual subjects to support PBPK predictions of plasma protein binding.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"82"},"PeriodicalIF":5.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Model-Informed Immunogenicity Assessment of Nivolumab as Monotherapy and in Combination with Ipilimumab. 基于模型的免疫原性评价：Nivolumab单药治疗和与Ipilimumab联合。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-25 DOI: 10.1208/s12248-025-01069-y

Yue Zhao, Li Li, Jessica Ma, Amit Roy, Akintunde Bello, Jennifer Sheng, Lora Hamuro

{"title":"Model-Informed Immunogenicity Assessment of Nivolumab as Monotherapy and in Combination with Ipilimumab.","authors":"Yue Zhao, Li Li, Jessica Ma, Amit Roy, Akintunde Bello, Jennifer Sheng, Lora Hamuro","doi":"10.1208/s12248-025-01069-y","DOIUrl":"10.1208/s12248-025-01069-y","url":null,"abstract":"Immunogenicity to biotherapeutics can lead to antidrug antibodies (ADAs) that have potential to alter pharmacokinetics (PK), efficacy, and safety. Here we provide an extensive model-informed immunogenicity assessments of nivolumab monotherapy and in combination with ipilimumab across multiple clinical trials. ADA was evaluated as both a binary and semiquantitative covariate, incorporating ADA titers to account for intensity over time. Data from 28 clinical trials, including 7,820 subjects with 2,770 ADA titer measurements, were analyzed using population pharmacokinetic (popPK) modeling. Nivolumab ADA incidence rate was higher for combination therapy (~ 32%) compared to monotherapy (~ 16%). ADA increased nivolumab clearance (CL) by 20-80% depending on titer. Nivolumab ADA impact on efficacy and safety was evaluated in melanoma and non-small cell lung cancer (NSCLC) patients. Despite the occurrence of nivolumab ADA being associated with lower nivolumab exposures, objective response rates (ORR) were similar in ADA-positive and negative patients, and ADA titer was not a significant predictor of response. An overall survival (OS) landmark analysis at 3 months suggested similar OS for NSCLC but lower OS for melanoma for ADA-positive vs negative patients mainly due to the imbalanced patient baseline characteristics. Propensity score matching and multivariable Cox Proportional-Hazards analysis indicated no ADA impact on OS. Additionally, there were no associations between ADA and acute hypersensitivities or immune mediated safety events. This model-based approach underscores the importance of accounting for ADA dynamics in clinical development and supports no significant association between ADA presence and clinical efficacy or safety, even with higher ADA incidence in combination therapy.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"79"},"PeriodicalIF":5.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IFN-γ/IL-2 Double-Color FluoroSpot Assay for Monitoring Human Primary T Cell Activation: Validation, Inter-Laboratory Comparison, and Recommendations for Clinical Studies. IFN-γ/IL-2双色荧光点检测用于监测人类原代T细胞活化：验证，实验室间比较，以及临床研究的建议。

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-25 DOI: 10.1208/s12248-025-01072-3

Alexandra Mauthe, Edward Cedrone, Raquel Villar-Hernández, Elisa Rusch, Marco Springer, Martin Schuster, Rosemarie Preyer, Marina A Dobrovolskaia, Matthias Gutekunst

{"title":"IFN-γ/IL-2 Double-Color FluoroSpot Assay for Monitoring Human Primary T Cell Activation: Validation, Inter-Laboratory Comparison, and Recommendations for Clinical Studies.","authors":"Alexandra Mauthe, Edward Cedrone, Raquel Villar-Hernández, Elisa Rusch, Marco Springer, Martin Schuster, Rosemarie Preyer, Marina A Dobrovolskaia, Matthias Gutekunst","doi":"10.1208/s12248-025-01072-3","DOIUrl":"10.1208/s12248-025-01072-3","url":null,"abstract":"The enzyme-linked immunosorbent spot (EliSpot) assay and its fluorescence-based version, FluoroSpot, are sensitive immunoassays commonly used to quantify antigen-specific T and B lymphocytes and other immune cells in peripheral blood or homogenized tissues. Due to their high sensitivity, these assays are popular in clinical trials to evaluate the efficacy of immunotherapy and vaccines, which involve a high level of scrutiny to ensure valid study results. Besides industry consensus white papers and other research publications, there is no formal guidance for the industry on how to validate EliSpot and FluoroSpot assays to ensure their accurate performance for immune monitoring in clinical trials. Herein, we describe a comprehensive in vitro study using healthy human donor peripheral blood mononuclear cells (PBMCs) and model antigens to validate a double-color FluoroSpot assay for monitoring antigen-specific lymphocytes by detecting and quantifying IFN-γ and IL-2-producing lymphocytes. Validation parameters, acceptance criteria set-up, and assay limits-limit of detection (LOD), minimum positive control response, lower and upper limits of quantification (LLOQ and ULOQ)-were determined, and assay performance was demonstrated by assessing precision, specificity, linearity, and robustness. In addition, an inter-laboratory comparison demonstrated concordance between assay results from two laboratories. In summary, this study outlines a robust approach to EliSpot and FluoroSpot validation and demonstrates that the IFN-γ/IL-2 FluoroSpot assay is suitable for the reliable detection of antigen-specific immune responses from PBMC samples across laboratories and meets the current regulatory requirements for bioanalytical method validation.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"81"},"PeriodicalIF":5.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TLR7-Adjuvanted Ionizable Lipid Nanoparticles for mRNA Vaccine Delivery. 用于mRNA疫苗递送的tlr7佐剂可电离脂质纳米颗粒

IF 5 3区医学

AAPS Journal Pub Date : 2025-04-25 DOI: 10.1208/s12248-025-01073-2

Bishal Misra, Krystal A Hughes, William H Pentz, Morgan Surface, Werner J Geldenhuys, Sharan Bobbala

{"title":"TLR7-Adjuvanted Ionizable Lipid Nanoparticles for mRNA Vaccine Delivery.","authors":"Bishal Misra, Krystal A Hughes, William H Pentz, Morgan Surface, Werner J Geldenhuys, Sharan Bobbala","doi":"10.1208/s12248-025-01073-2","DOIUrl":"10.1208/s12248-025-01073-2","url":null,"abstract":"Ionizable lipid nanoparticles (LNPs) are clinically relevant non-viral vectors that allow intracellular delivery of mRNA vaccines to immune cells. To fight against notorious pathogens and cancer, mRNA vaccines necessitate the addition of an adjuvant to induce strong and durable cell-mediated immune responses. Adjuvants that stimulate Toll-like receptor 7 (TLR7) induce the secretion of type I interferons and proinflammatory cytokines, vital for generating strong immune responses. However, the intracellular delivery of TLR7 adjuvants to precisely stimulate the endosomal TLR7 receptor remains a huge challenge. This issue can be addressed by exploiting ionizable LNP platforms, which can encapsulate and carry mRNA vaccines and small molecule hydrophobic adjuvants to immune cells. CL347 is a potent lipid-based adjuvant that selectively stimulates the TLR7 receptor. In this study, we developed ionizable LNPs incorporating SM102 and CL347 adjuvant as the ionizable lipid and TLR7 adjuvant, respectively. CL347-SM102 LNPs exhibited particle sizes of less than 150 nm with spherical morphology and mRNA encapsulation efficiency of greater than 95%. In vivo studies showed a two-fold increase in IFN-γ producing CD4 and CD8 T cells in the lymphoid organs of the mice immunized with adjuvanted LNPs compared to the non-adjuvanted LNPs. Human PBMCs treated with adjuvanted LNPs exhibited significantly higher CD40 expression and pro-inflammatory cytokine (IL-6 and IFN-γ) secretion than non-adjuvanted LNPs. Together, these results suggest the potential of ionizable LNPs as a platform for concurrent delivery of mRNA and adjuvants for prophylactic and therapeutic vaccine applications.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"80"},"PeriodicalIF":5.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiologically Based Modeling of Cefoxitin, Cefazolin, and Piperacillin Pharmacokinetics in Obese and Lean Rats. 肥胖和瘦肉大鼠头孢西丁、头孢唑林和哌拉西林药代动力学的生理建模。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-04-17 DOI: 10.1208/s12248-025-01063-4

Yi-Hua Sheng, Katarzyna Kosicka-Noworzyń, Anna Siemiątkowska, Sijia Yu, Raymond Rosa, Karan Sapra, Marian Awad, Justine Khalil, Thomas Doss, Christine Yohn, Luigi Brunetti, Leonid Kagan

{"title":"Physiologically Based Modeling of Cefoxitin, Cefazolin, and Piperacillin Pharmacokinetics in Obese and Lean Rats.","authors":"Yi-Hua Sheng, Katarzyna Kosicka-Noworzyń, Anna Siemiątkowska, Sijia Yu, Raymond Rosa, Karan Sapra, Marian Awad, Justine Khalil, Thomas Doss, Christine Yohn, Luigi Brunetti, Leonid Kagan","doi":"10.1208/s12248-025-01063-4","DOIUrl":"10.1208/s12248-025-01063-4","url":null,"abstract":"The prevalence of obesity is rapidly increasing worldwide, however there is a notable gap in understanding how obesity affects the pharmacokinetics of drugs and how dosing should be adjusted in obese population. The goals of this work were to evaluate plasma pharmacokinetics and tissue disposition of piperacillin, cefazolin, and cefoxitin in a rat model of diet-induced obesity compared to a lean cohort. Male Long-Evans rats were fed high-fat or control diets for 23 weeks. Various measures of body size and composition were collected. The animals were administered a mixture containing 50 mg/kg cefoxitin, 50 mg/kg cefazolin, and 120 mg/kg piperacillin. Plasma and tissues were collected and analyzed using a validated LC-MS/MS method. Whole-body physiologically-based pharmacokinetic (PBPK) models were develop to capture the biodistribution of these drugs in lean and obese cohorts. Most plasma and tissue concentrations were comparable between lean and obese rats after dosing based on mg/kg of total body weight; however, in some tissues concentration was consistently higher in obese animals. PBPKs successfully captured biodistribution of three drugs and both cohorts; however, cohort-specific (lean or obese) parameters were required for liver (for cefoxitin and cefazolin) and spleen (for all three drugs) for capturing the data.The results support the necessity of using mg/kg dosing for obese rats to achieve drug exposure comparable to that of lean rats. In the future, these models could be extended to predict plasma pharmacokinetics and tissue disposition of cefoxitin, cefazolin, and piperacillin in humans by incorporating interspecies scaling approaches.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"78"},"PeriodicalIF":3.7,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0