CPT: Pharmacometrics & Systems Pharmacology最新文献_第2页

Correction to Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-12-02 DOI: 10.1002/psp4.13289

{"title":"Correction to Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life","authors":"","doi":"10.1002/psp4.13289","DOIUrl":"10.1002/psp4.13289","url":null,"abstract":"Krzyzanski W, Stockard B, Gaedigk A, et al. Developmental pharmacokinetics of indomethacin in preterm neonates: severely decreased drug clearance in the first week of life. CPT Pharmacometrics Syst Pharmacol. 2023;12:110–121. doi:10.1002/psp4.12881In the published version of the above article, the equation reported to convert dried blood spot (DBS) indomethacin concentrations to plasma concentrations is incorrect. Rather than “plasma[IND] = DBS[IND]/(1 – hematocrit) * 1.608,” the equation should be “C(plasma) = 1.837(C(DBS)/(1 – Hct/100)) – 236.6.” There is also an inaccurate statement in the Bioanalytical methods section: “A correction factor (1.608, mean of the ratio of plasma:DBS concentrations) was used to calculate the theoretical plasma concentrations from the hematocrit-corrected DBS concentration,” which does not align with the data analysis that was performed.This author error in reporting does not affect the results or conclusions of the paper as the correct equation (more accurate and appropriate) was used to convert DBS to plasma concentrations for data analysis, and the wrong equation was reported in the manuscript.We apologize for this error.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"13 12","pages":"2210"},"PeriodicalIF":3.1,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767018","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

Isatuximab–dexamethasone–pomalidomide combination effects on serum M protein and PFS in myeloma: Development of a joint model using phase I/II data

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-28 DOI: 10.1002/psp4.13206

Antoine Pitoy, Solène Desmée, François Riglet, Hoai-Thu Thai, Zandra Klippel, Dorothée Semiond, Christine Veyrat-Follet, Julie Bertrand

{"title":"Isatuximab–dexamethasone–pomalidomide combination effects on serum M protein and PFS in myeloma: Development of a joint model using phase I/II data","authors":"Antoine Pitoy, Solène Desmée, François Riglet, Hoai-Thu Thai, Zandra Klippel, Dorothée Semiond, Christine Veyrat-Follet, Julie Bertrand","doi":"10.1002/psp4.13206","DOIUrl":"10.1002/psp4.13206","url":null,"abstract":"This study aimed at leveraging data from phase I/II clinical trials to build a nonlinear joint model of serum M-protein kinetics and progression-free survival (PFS) accounting for the effects of isatuximab (Isa), pomalidomide (Pom), and dexamethasone (Dex) in patients with relapsed and/or refractory multiple myeloma. Serum M-protein levels and PFS data from 203 evaluable patients, included either in a phase I/II study (n = 173) or in a phase I study (n = 30), were used to build the model. First, we independently developed a longitudinal model and a PFS model. Then, we linked them in a nonlinear joint model by selecting the link function that best captured the association between serum M-protein kinetics and PFS. A Claret tumor growth-inhibition model accounting for the additive effects of Isa, with an Emax function, Pom, and Dex on serum M-protein elimination was selected to describe serum M-protein kinetics. PFS was best described with a log-logistic model and associations with baseline beta-2 microglobulin level, age, and coadministration of Dex were identified. The instantaneous change in serum M-protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA-MM phase III pivotal study, and validated it using the same phase III pivotal study data.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"13 12","pages":"2087-2101"},"PeriodicalIF":3.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13206","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749990","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

A computational tool to optimize clinical trial parameter selection in Duchenne muscular dystrophy: A practical guide and case studies. 优化杜氏肌营养不良症临床试验参数选择的计算工具：实用指南和案例研究。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-27 DOI: 10.1002/psp4.13281

Jordan Wilk, Varun Aggarwal, Mike Pauley, Diane Corey, Daniela J Conrado, Karthik Lingineni, Juan Francisco Morales, Deok Yong Yoon, Yi Zhang, Zihan Cui, Jackson Burton, Jane Larkindale, Shu Chin Ma, Collin Hovinga, Terina Martinez, Klaus Romero, Ramona Belfiore-Oshan, Sarah Kim

{"title":"A computational tool to optimize clinical trial parameter selection in Duchenne muscular dystrophy: A practical guide and case studies.","authors":"Jordan Wilk, Varun Aggarwal, Mike Pauley, Diane Corey, Daniela J Conrado, Karthik Lingineni, Juan Francisco Morales, Deok Yong Yoon, Yi Zhang, Zihan Cui, Jackson Burton, Jane Larkindale, Shu Chin Ma, Collin Hovinga, Terina Martinez, Klaus Romero, Ramona Belfiore-Oshan, Sarah Kim","doi":"10.1002/psp4.13281","DOIUrl":"https://doi.org/10.1002/psp4.13281","url":null,"abstract":"Duchenne muscular dystrophy (DMD), a rare pediatric disease, presents numerous challenges when designing clinical trials, mainly due to the scarcity of available trial participants and the heterogeneity of disease progression. A quantitative clinical trial simulator (CTS) has been developed based on previously published five disease progression models describing each of the longitudinal changes in the velocity at which individuals can complete specified timed functional tests, frequently used as clinical trial efficacy endpoints (supine-stand, 4-stair climb, and 10 m walk/run test or 30-foot walk/run test), as well as each of the longitudinal changes in forced vital capacity and North Star Ambulatory Assessment total score. The model-based CTS allows researchers to optimize the selection of numerous trial parameters for designing trials for the five functional measures commonly used as endpoints in DMD clinical trials. This case report serves as a demonstration of the tool's functionality while providing an easy-to-follow guide for users to reference when preparing simulations of their own design. Two case studies, using input selection based on previous DMD clinical trials, provide realistic examples of how the tool can help optimize clinical trial design without the risk of decreasing statistical significance. This optimization allows researchers to mitigate the risk of designing trials that may be longer, larger, or more inclusive/exclusive than necessary.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726674","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

MDMA pharmacokinetics: A population and physiologically based pharmacokinetics model-informed analysis. 摇头丸药物动力学：基于人口和生理的药代动力学模型分析。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-26 DOI: 10.1002/psp4.13282

Marilyn A Huestis, William B Smith, Cathrine Leonowens, Rebecca Blanchard, Aurélien Viaccoz, Erin Spargo, Nicholas B Miner, Berra Yazar-Klosinski

{"title":"MDMA pharmacokinetics: A population and physiologically based pharmacokinetics model-informed analysis.","authors":"Marilyn A Huestis, William B Smith, Cathrine Leonowens, Rebecca Blanchard, Aurélien Viaccoz, Erin Spargo, Nicholas B Miner, Berra Yazar-Klosinski","doi":"10.1002/psp4.13282","DOIUrl":"https://doi.org/10.1002/psp4.13282","url":null,"abstract":"Midomafetamine (3,4-methylenedioxymethamphetamine [MDMA]) is under the U.S. Food and Drug Administration review for treatment of post-traumatic stress disorder in adults. MDMA is metabolized by CYP2D6 and is a strong inhibitor of CYP2D6, as well as a weak inhibitor of renal transporters MATE1, OCT1, and OCT2. A pharmacokinetic phase I study was conducted to evaluate the effects of food on MDMA pharmacokinetics. The results of this study, previously published pharmacokinetic data, and in vitro data were combined to develop and verify MDMA population pharmacokinetic and physiologically based pharmacokinetic models. The food effect study demonstrated that a high-fat/high-calorie meal did not alter MDMA plasma concentrations, but delayed Tmax. The population pharmacokinetic model did not identify any clinically meaningful covariates, including age, weight, sex, race, and fed status. The physiologically based pharmacokinetic model simulated pharmacokinetics for the proposed 120 and 180 mg MDMA HCl clinical doses under single- and split-dose (2 h apart) conditions, indicating minor differences in overall exposure, but lower AUC within the first 4 h and delayed Tmax when administered as a split dose compared to a single dose. The physiologically based pharmacokinetic model also investigated the drug-drug interaction magnitude by varying the fraction metabolized by a representative CYP2D6 substrate (atomoxetine) and evaluated inhibition of renal transporters. The simulations confirm MDMA is a potent CYP2D6 inhibitor, but likely has no meaningful impact on the pharmacokinetics of drugs sensitive to renal transport. This model-informed drug development approach was employed to inform drug-drug interaction potential and predict pharmacokinetics of clinically relevant dosing regimens of MDMA.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726738","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

Vancomycin population pharmacokinetic models: Uncovering pharmacodynamic divergence amid clinicobiological resemblance. 万古霉素群体药代动力学模型：在临床生物学相似性中发现药效学差异

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-26 DOI: 10.1002/psp4.13253

Peggy Gandia, Sahira Chaiben, Nicolas Fabre, Didier Concordet

{"title":"Vancomycin population pharmacokinetic models: Uncovering pharmacodynamic divergence amid clinicobiological resemblance.","authors":"Peggy Gandia, Sahira Chaiben, Nicolas Fabre, Didier Concordet","doi":"10.1002/psp4.13253","DOIUrl":"https://doi.org/10.1002/psp4.13253","url":null,"abstract":"Vancomycin is an antibiotic used for severe infections. To ensure microbiological efficacy, a ratio of AUC/MIC ≥400 is recommended. However, there is significant interindividual variability in its pharmacokinetic parameters, necessitating therapeutic drug monitoring to adjust dosing regimens and ensure efficacy while avoiding toxicity. Population pharmacokinetic (PopPK) models enable dose personalization, but the challenge lies in the choice of the model to use among the multitude of models in the literature. We compared 18 PopPK models created from populations with the same sociodemographic and clinicobiological characteristics. Simulations were performed for a 47 years old man, weighing 70 kg, with an albumin level of 35.5 g/L, a creatinine clearance of 100 mL/min, an eGFR of 106 mL/min/1.73 m2, and receiving an intravenous infusion of 1 g × 2/day of VCM over 1 h for 48 h. Simulations of time-concentration profiles revealed differences, leading us to determine the probability of achieving microbiological efficacy (AUC/MIC ≥ 400) with each model. Depending on some models, a dose of 1 g × 2/day is required to ensure microbiological efficacy in over 90% of the population, while with the same dose other models do not exceed 10% of the population. To ensure that 90% of the patients are correctly exposed, a dose of vancomycin ranging from 0.9 g × 2/day to 2.2 g × 2/day is necessary a priori depending on the chosen model. These differences raise an issue in choosing a model for performing therapeutic drug monitoring using a PopPK model with or without Bayesian approach. Thus, it is fundamental to evaluate the impact of these differences on both efficacy/toxicity.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726740","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

Exploration of the potential impact of batch-to-batch variability on the establishment of pharmacokinetic bioequivalence for inhalation powder drug products. 探讨批次间差异对建立吸入粉末药物产品药代动力学生物等效性的潜在影响。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-22 DOI: 10.1002/psp4.13276

Shuhui Li, Kairui Feng, Jieon Lee, Yuqing Gong, Fang Wu, Bryan Newman, Miyoung Yoon, Lanyan Fang, Liang Zhao, Jogarao V S Gobburu

{"title":"Exploration of the potential impact of batch-to-batch variability on the establishment of pharmacokinetic bioequivalence for inhalation powder drug products.","authors":"Shuhui Li, Kairui Feng, Jieon Lee, Yuqing Gong, Fang Wu, Bryan Newman, Miyoung Yoon, Lanyan Fang, Liang Zhao, Jogarao V S Gobburu","doi":"10.1002/psp4.13276","DOIUrl":"https://doi.org/10.1002/psp4.13276","url":null,"abstract":"Batch-to-batch variability in inhalation powder has been identified as a potential challenge in the development of generic versions. This study explored the impact of batch-to-batch variability on the probability of establishing pharmacokinetic (PK) bioequivalence (BE) in a two-sequence, two-period (2 × 2) crossover study. A model-based parametric simulation approach was employed, incorporating batch-to-batch variability through the relative bioavailability (RBA) ratio. In the absence of batch variability, recruiting a total of 48 subjects in a 2 × 2 crossover study with the reference formulation resulted in a 95% probability of concluding BE. However, this probability decreased to 80% with a 5% batch difference in RBA and further declined to 30% with a 10% batch difference. With a 10% batch difference, the required number of subjects to achieve an 80% probability of concluding BE increased to 84. When considering product differences between the reference and the test formulations, an additional 10% batch difference reduced the study power from 97% to 30% for a T/R bioavailability ratio of 100% in a 2 × 2 crossover study with 48 subjects. As a result, the substantial impact of batch-to-batch variability on the study power and type I error of the PK BE study may pose significant challenges for the development of generic Advair Diskus due to its degree of PK batch-to-batch variability. Therefore, alternative PK BE study designs and guidelines are needed to adequately address the influence of batch-to-batch variability in products like Advair Diskus.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686439","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

Clinical study design strategies to mitigate confounding effects of time-dependent clearance on dose optimization of therapeutic antibodies. 临床研究设计策略，减轻时间依赖性清除率对治疗性抗体剂量优化的干扰效应。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-22 DOI: 10.1002/psp4.13280

Jeffrey R Proctor, Harvey Wong

{"title":"Clinical study design strategies to mitigate confounding effects of time-dependent clearance on dose optimization of therapeutic antibodies.","authors":"Jeffrey R Proctor, Harvey Wong","doi":"10.1002/psp4.13280","DOIUrl":"https://doi.org/10.1002/psp4.13280","url":null,"abstract":"Time-dependent pharmacokinetics (TDPK) is a frequent confounding factor that misleads exposure-response (ER) analysis of therapeutic antibodies, where a decline in clearance results in increased drug exposure over time in patients who respond to therapy, causing a false-positive ER finding. The object of our simulation study was to explore the influence of clinical trial designs on the frequency of false-positive ER findings. Two previously published population PK models representative of slow- (pembrolizumab) and fast-onset (rituximab) TDPK were used to simulate virtual patient cohorts with time-dependent clearance and the frequency of false-positive ER findings. The impact of varying the number of dose groups, dose range, and sample size was evaluated over time. Study designs with a single tested dose level showed a high probability of showing a false-positive ER finding. When TDPK has a slow onset, use of exposure measures from early timepoints in ER analysis significantly reduces the risk of a false-positive, while with fast onset it did not. Randomization of patients to two dose levels greatly reduced the risk, with a threefold or greater dose range offering the greatest benefit. The likelihood of false-positive increases with a larger sample size, where greater care should be taken to identify confounding factors. Clinical trial simulation supports that appropriate clinical study design and analysis with adequate dose exploration can reduce but cannot entirely eliminate the risk of misleading ER findings.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686438","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

Population pharmacokinetics of selexipag for dose selection and confirmation in pediatric patients with pulmonary arterial hypertension 用于肺动脉高压儿科患者剂量选择和确认的 selexipag 群体药代动力学。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-21 DOI: 10.1002/psp4.13231

Lene Nygaard Axelsen, Anne Kümmel, Juan Jose Perez Ruixo, Alberto Russu

{"title":"Population pharmacokinetics of selexipag for dose selection and confirmation in pediatric patients with pulmonary arterial hypertension","authors":"Lene Nygaard Axelsen, Anne Kümmel, Juan Jose Perez Ruixo, Alberto Russu","doi":"10.1002/psp4.13231","DOIUrl":"10.1002/psp4.13231","url":null,"abstract":"Selexipag is an oral selective prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH) in adults. To date, no treatment targeting the prostacyclin pathway is approved for pediatric patients. Our goal is to identify a pediatric dose regimen that results in comparable exposures to selexipag and its active metabolite JNJ-68006861 as those shown to be efficacious in adult PAH patients. Extrapolation from the population pharmacokinetic (PK) model developed in adults (GRIPHON study; NCT01106014) resulted in the definition of three different pediatric body weight groups (≥9 to <25 kg, ≥25 to <50 kg, and ≥50 kg) with corresponding starting doses (100, 150, and 200 μg twice daily) and maximum allowed doses (800, 1200, and 1600 μg twice daily). The proposed pediatric dose regimen was subsequently tested in a clinical study (NCT03492177), including 63 pediatric PAH patients ≥2 to <18 years of age and a body weight range of 9.9–93.5 kg. The body weight-adjusted dose regimen for selexipag resulted in comparable systemic exposures to selexipag and its active metabolite in pediatric patients as previously observed in adult PAH patients. Updating the adult selexipag population PK model provided overall consistent parameters and confirmed that the PK characteristics of selexipag and its active metabolite were comparable between pediatric and adult patients. The presented selexipag dose regimen for pediatric PAH patients is considered appropriate for continuing the clinical evaluation of the safety and efficacy of selexipag in pediatric patients ≥2 years of age.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"13 12","pages":"2185-2195"},"PeriodicalIF":3.1,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686440","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

Exposure-response modeling of liver fat imaging endpoints in non-alcoholic fatty liver disease populations administered ervogastat alone and co-administered with clesacostat. 非酒精性脂肪肝患者单独服用依维莫司他和与氯沙考曲他联合用药时肝脏脂肪成像终点的暴露-反应模型。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-20 DOI: 10.1002/psp4.13275

Jim H Hughes, Neeta B Amin, Jessica Wojciechowski, Manoli Vourvahis

{"title":"Exposure-response modeling of liver fat imaging endpoints in non-alcoholic fatty liver disease populations administered ervogastat alone and co-administered with clesacostat.","authors":"Jim H Hughes, Neeta B Amin, Jessica Wojciechowski, Manoli Vourvahis","doi":"10.1002/psp4.13275","DOIUrl":"https://doi.org/10.1002/psp4.13275","url":null,"abstract":"Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis describe a collection of liver conditions characterized by the accumulation of liver fat. Despite biopsy being the reference standard for determining the severity of disease, non-invasive measures such as magnetic resonance imaging proton density fat fraction (MRI-PDFF) and FibroScan® controlled attenuation parameter (CAP™) can be used to understand longitudinal changes in steatosis. The aim of this work was to describe the exposure-response relationship of ervogastat with or without clesacostat on steatosis, through population pharmacokinetic/pharmacodynamic (PK/PD) modeling of both liver fat measurements simultaneously. Population pharmacokinetic and exposure-response models using individual predictions of average concentrations were used to describe ervogastat/clesacostat PKPD. Due to both liver fat endpoints being continuous-bounded outcomes on different scales, a dynamic transform-both-sides approach was used to link a common latent factor representing liver fat to each endpoint. Simultaneous modeling of both MRI-PDFF and CAP™ was successful with both measurements being adequately described by the model. The clinical trial simulation was able to adequately predict the results of a recent Phase 2 study, where subjects given ervogastat/clesacostat 300/10 mg BID for 6 weeks had a LS means and model-predicted median (95% confidence intervals) percent change from baseline MRI-PDFF of -45.8% and -45.6% (-61.6% to -31.8%), respectively. Simultaneous modeling of both MRI-PDFF and CAP™ was successful with both measurements being adequately described. By describing the underlying changes of steatosis with a latent variable, this model may be extended to describe biopsy results from future studies.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675257","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

Investigation of a fully mechanistic physiologically based pharmacokinetics model of absorption to support predictions of milk concentrations in breastfeeding women and the exposure of infants: A case study for albendazole 研究基于生理学的完全机械化药代动力学吸收模型，以支持母乳喂养妇女乳汁浓度的预测和婴儿的暴露：阿苯达唑案例研究。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2024-11-19 DOI: 10.1002/psp4.13260

Susan Cole, Maria Malamatari, Andrew Butler, Mahnoor Arshad, Essam Kerwash

{"title":"Investigation of a fully mechanistic physiologically based pharmacokinetics model of absorption to support predictions of milk concentrations in breastfeeding women and the exposure of infants: A case study for albendazole","authors":"Susan Cole, Maria Malamatari, Andrew Butler, Mahnoor Arshad, Essam Kerwash","doi":"10.1002/psp4.13260","DOIUrl":"10.1002/psp4.13260","url":null,"abstract":"Due to limited non-clinical and clinical data, European guidance recommends to discontinue breastfeeding when taking albendazole. The aim of this study was to consider the use of PBPK modeling to support the expected exposure in breastfed infants. A fully mechanistic PBPK approach was used to provide quantitative predictions of albendazole and its main active metabolite, albendazole sulfoxide, concentrations in plasma and breast milk of lactating women. The model predicted the exposure in adults and the large food effect, however, it does not predict all the clinical data for the exposure in children. Milk/plasma ratio predictions were also largely over-predicted for this lipophilic compound, but not for the less lipophilic metabolite. Predictions using the observed ratio and a worse-case exposure based on Cmax predictions, suggest doses to children through milk will be low. However, more clinical data are required before full exposure predictions can be made to breastfed infants.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"13 11","pages":"1990-2001"},"PeriodicalIF":3.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.13260","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667218","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