CPT: Pharmacometrics & Systems Pharmacology最新文献

A Combined Model-Based Meta-Analysis of Aggregated and Individual FEV1 Data From Randomized COPD Trials. COPD随机试验中总FEV1和个体FEV1数据的基于模型的综合meta分析

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-19 DOI: 10.1002/psp4.70059

Liang Yang, Carolina Llanos-Paez, Shuying Yang, Claire Ambery, Alienor Berges, Maria C Kjellsson, Mats O Karlsson

{"title":"A Combined Model-Based Meta-Analysis of Aggregated and Individual FEV1 Data From Randomized COPD Trials.","authors":"Liang Yang, Carolina Llanos-Paez, Shuying Yang, Claire Ambery, Alienor Berges, Maria C Kjellsson, Mats O Karlsson","doi":"10.1002/psp4.70059","DOIUrl":"https://doi.org/10.1002/psp4.70059","url":null,"abstract":"Model-based meta-analysis allows integration of aggregated-level data (AD) from different clinical trials in one model to assess population efficacy/safety. However, AD is limited in individual-level information, while individual-patient-level data (IPD) are hard to obtain. Combined modeling may take advantage of both sources. Chronic obstructive pulmonary disease (COPD) is a leading cause of poor health and death. This study established a combined ADIPD model of COPD clinical trials with forced expiratory volume in 1 s (FEV1) as an endpoint and explored methods for estimating interstudy variability (ISV), interindividual variability (IIV), and aggregation bias. Stochastic simulation and estimations (SSE) showed the best method in NONMEM to estimate ISV/IIV: using $LEVEL with equal weight of studies; for the AD part, ISVs from the AD model were fixed, estimating IIV with separate ETAs for each arm; the IPD part shared the fixed ISV and estimated IIV. An approximated normal distribution was derived for lognormal IIV to avoid aggregation bias. Covariate correlations were different at aggregated and individual levels, but did not introduce aggregation bias according to SSE. A separate AD model (published) and IPD model were built, then combined to form the ADIPD model. The ADIPD model included FEV1 baseline, disease progression, placebo effect, and Emax/constant dose-responses for 23 compounds. Identified covariate relationships: higher age, female, higher disease severity, non-current smoker related to lower baseline; higher baseline related to faster disease progression and higher drug effects. Covariate coefficients were estimated more precisely in the ADIPD model than the AD model. ADIPD modeling allows more informed clinical trial simulations for study design. Trial Registration: ClinicalTrials.gov identifier: NCT01053988 and NCT01054885.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324621","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

Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling of Dupilumab on Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV₁) in Uncontrolled Moderate-To-Severe Asthma. Dupilumab对未控制的中重度哮喘患者支气管扩张剂前1秒用力呼气量（FEV1）的半机械群体药代动力学/药效学（PK/PD）建模

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-19 DOI: 10.1002/psp4.70057

Li Zhang, John D Davis, Vanaja Kanamaluru, Christine Xu

{"title":"Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling of Dupilumab on Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) in Uncontrolled Moderate-To-Severe Asthma.","authors":"Li Zhang, John D Davis, Vanaja Kanamaluru, Christine Xu","doi":"10.1002/psp4.70057","DOIUrl":"https://doi.org/10.1002/psp4.70057","url":null,"abstract":"In this study, we investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of dupilumab as an add-on therapy in the intent-to-treat (ITT) uncontrolled moderate-to-severe asthma population and identified the factors significantly contributing to variability in forced expiratory volume in 1 second; (FEV1). A semi-mechanistic population PK/PD model was developed using data from two placebo-controlled pivotal studies in 2654 adult and adolescent patients (n = 794 treated with placebo; n = 1860 treated with dupilumab 200 mg [400-mg loading dose] or 300 mg [600-mg loading dose] administered subcutaneously every 2 [Q2W] or 4 weeks [Q4W]). Treatment effect was described using a dupilumab concentration-dependent direct-response Emax model, and placebo effect was described using an empirical time-dependent function. Demographic variables, baseline disease characteristics, type-2 inflammation biomarkers, and immunogenicity were tested as covariates using the stepwise forward selection and backward elimination method. Baseline type-2 inflammation biomarkers (fractional exhaled nitric oxide [FeNO] level and blood eosinophil [EOS] count) were found to be significant covariates for FEV1, with greater efficacy in patients with elevated biomarker levels. None of the other tested covariates, including age (12-87 years), had a significant impact on FEV1. The PK/PD model predicted near-maximum FEV1 response (0.1 L) over a dose of dupilumab. 200-300 mg Q2W in patients with moderate-to-severe asthma.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324622","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

Development and Verification of a Physiologically Based Pharmacokinetic Model of Furmonertinib and Its Main Metabolite for Drug-Drug Interaction Predictions. 基于生理的弗蒙尼尼及其主要代谢物的药代动力学模型的开发和验证，用于药物-药物相互作用预测。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-17 DOI: 10.1002/psp4.70052

Yali Wu, Helena Leonie Hanae Loer, Yifan Zhang, Dafang Zhong, Yong Jiang, Jie Hu, Uwe Fuhr, Thorsten Lehr, Xingxing Diao

{"title":"Development and Verification of a Physiologically Based Pharmacokinetic Model of Furmonertinib and Its Main Metabolite for Drug-Drug Interaction Predictions.","authors":"Yali Wu, Helena Leonie Hanae Loer, Yifan Zhang, Dafang Zhong, Yong Jiang, Jie Hu, Uwe Fuhr, Thorsten Lehr, Xingxing Diao","doi":"10.1002/psp4.70052","DOIUrl":"https://doi.org/10.1002/psp4.70052","url":null,"abstract":"Furmonertinib demonstrated potent efficacy as a newly developed tyrosine kinase inhibitor for the treatment of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. In vitro research showed that furmonertinib is metabolized to its active metabolite AST5902 via the cytochrome P450 (CYP) enzyme CYP3A4. Furmonertinib is a strong CYP3A4 inducer, while the metabolite is a weaker CYP3A4 inducer. In clinical studies, nonlinear pharmacokinetics were observed during chronic dosing. The apparent clearance showed time- and dose-dependent increases. In this evaluation, a combination of in vitro data using radiolabeled compounds, clinical pharmacokinetic data, and drug-drug interaction (DDI) data of furmonertinib in oncology patients and/or in healthy subjects was used to develop a physiologically based pharmacokinetic (PBPK) model. The model was built in PK-Sim Version 11 using a total of 44 concentration-time profiles of furmonertinib and its metabolite AST5902. Suitability of the predictive model performance was demonstrated by both goodness-of-fit plots and statistical evaluation. The model predicted the observed monotherapy concentration profiles of furmonertinib well, with 32/32 predicted AUClast (area under the curve until the last concentration measurement) values and 32/32 maximum plasma concentration (Cmax) ratios being within twofold of the respective observed values. In addition, 8/8 predicted DDI AUClast and Cmax ratios with furmonertinib as a victim of CYP3A4 inhibition or induction were within twofold of their respective observed values. Potential applications of the final model include the prediction of DDIs for chronic administration of CYP3A4 perpetrators along with furmonertinib, considering auto-induction of furmonertinib and its metabolite AST5902.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309625","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

A Quantitative Systems Pharmacology Model That Describes Neurofilament Light Dynamics During Alzheimer's Disease Progression. 描述阿尔茨海默病进展过程中神经丝光动力学的定量系统药理学模型。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-17 DOI: 10.1002/psp4.70062

Polina Maliukova, Tatiana Karelina

{"title":"A Quantitative Systems Pharmacology Model That Describes Neurofilament Light Dynamics During Alzheimer's Disease Progression.","authors":"Polina Maliukova, Tatiana Karelina","doi":"10.1002/psp4.70062","DOIUrl":"https://doi.org/10.1002/psp4.70062","url":null,"abstract":"Neurofilament proteins are important constituents of neuronal cytoskeleton, along with microtubules. An increased concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and plasma is considered a potential biomarker of axonal degeneration, which occurs in various neurodegenerative diseases including Alzheimer's disease (AD). The goal of this study was to develop a QSP model describing the change in the concentration of NfL in the brain, CSF, and plasma during the progression of AD for populations of AD patients manifesting different combinations of biomarkers (amyloid, tau, brain atrophy), to estimate the contributions of different mechanisms to neurodegeneration. The model correctly describes the dynamics of neurofilament proteins during neurodegeneration processes, which depend on cytoskeletal degradation and the release of neurofilament proteins from degenerated axons into cerebrospinal fluid and plasma. These processes are driven by disruptions of neuron homeostasis in AD, such as changes in protein degradation, axonal transport deficits, and the accumulation of pathological amyloid and hyperphosphorylated tau. The model was validated against clinical data and demonstrated correct predictions for anti-tau therapy while showing a tendency to overestimate efficacy of anti-amyloid therapy (lecanemab). This supports the idea that amyloid therapy contribution to neurodegeneration is limited, and that treatment should focus on other mechanisms.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309683","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

Evaluation of Four Semi-Mechanistic Models for Predicting Glycemic Control With a Glucagon Receptor Antagonist in People With Type 2 Diabetes. 预测2型糖尿病患者胰高血糖素受体拮抗剂血糖控制的四种半机制模型的评价

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-17 DOI: 10.1002/psp4.70058

Austin Yue Feng Tan, Karen Schneck, Parag Garhyan, Eric Chun Yong Chan, Lai San Tham

{"title":"Evaluation of Four Semi-Mechanistic Models for Predicting Glycemic Control With a Glucagon Receptor Antagonist in People With Type 2 Diabetes.","authors":"Austin Yue Feng Tan, Karen Schneck, Parag Garhyan, Eric Chun Yong Chan, Lai San Tham","doi":"10.1002/psp4.70058","DOIUrl":"https://doi.org/10.1002/psp4.70058","url":null,"abstract":"Glycated hemoglobin (HbA1c) is the gold standard for measuring long-term glycemic efficacy over at least 3 months in Type 2 diabetes (T2D). Being able to predict HbA1c using glucose response from studies of less than 3 months would be useful. Four semi-mechanistic HbA1c models (ADOPT, FFH, FHH, and IGRH) were evaluated for their predictive performance of longer-term HbA1c at 24 weeks of treatment using glucose and HbA1c data up to 4 weeks of treatment. A novel glucagon receptor antagonist (LY2409021) was evaluated in T2D patients for glycemic control. The models were built using LY2409021 pharmacokinetics, glucose, and HbA1c data from a 4-week Phase 1b study. Predictive performance of the models was assessed based on comparing model-estimated and observed HbA1c values from a 24-week Phase 2b study. Metrics for predictive performance included: (a) mean change from baseline HbA1c (ΔHbA1c) at Week 24 between observed and simulated values; (b) mean prediction error (MPE) for bias; and (c) root mean squared error (RMSE) for precision. Overall, the FHH and IGRH models closely predicted the mean ΔHbA1c at Week 24 within 0.1% difference from the observed values in the Phase 2b study. Both models also had reasonable bias (absolute MPE < 0.1%) and precision (RMSE < 0.3%) estimates. Conversely, the ADOPT and FFH models over-predicted the mean reduction in HbA1c by 0.288% and 0.153%, respectively. The FHH and IGRH models featured transit compartments for modeling long delays between glucose and HbA1c. Thus, these models better represented the physiology and provided superior predictive performance.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316061","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

Tutorial for Modeling Delays in Biological Systems in the NONMEM Software. 在NONMEM软件中建模生物系统中的延迟教程。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-16 DOI: 10.1002/psp4.70046

Robert J Bauer, Wojciech Krzyzanski

{"title":"Tutorial for Modeling Delays in Biological Systems in the NONMEM Software.","authors":"Robert J Bauer, Wojciech Krzyzanski","doi":"10.1002/psp4.70046","DOIUrl":"https://doi.org/10.1002/psp4.70046","url":null,"abstract":"Delays in biological systems are a common phenomenon. The models for delays require specialized mathematical and numerical techniques such as transit compartments, delay differential equations (DDEs), and distributed DDEs (DDDEs). Because of mathematical complexity, DDEs and particularly DDDEs are infrequently used for modeling. DDEs are supported by most pharmacometric programs. Recently, DDDEs have been implemented in NONMEM that greatly improve the applicability of this technique in pharmacokinetic and pharmacodynamic (PKPD) modeling. The objective of this tutorial is to provide examples of PKPD models with delays and demonstrate how to implement them in NONMEM. All examples provide a brief description of the biology and pharmacology underlying model equations, explain how they are coded in the NONMEM control stream, and discuss results of data analysis models were used for. NONMEM codes for all models are presented in supporting information (Data S1). The tutorial concludes with a discussion of the pros and cons of presented delay modeling techniques with guidelines for which one might be preferred given the nature of the delay, available data, and the task to be performed.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309626","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

Viral Dynamic Models During COVID-19: Are We Ready for the Next Pandemic? COVID-19期间的病毒动态模型：我们为下一次大流行做好准备了吗？

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-06-02 DOI: 10.1002/psp4.70055

Aurelien Marc, Joshua T Schiffer, France Mentré, Alan S Perelson, Jérémie Guedj

引用次数: 0

Population Pharmacokinetics and Exposure-Response Relationship of Hemoporfin in Pediatric Patients With Port-Wine Stain. 儿童波特酒染色患者血红蛋白的人群药动学及暴露-反应关系。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-30 DOI: 10.1002/psp4.70050

Rong Chen, Bin Zhang, Jining Tao, Qingyu Yao, Tianyan Zhou, Lin Ma, Zigang Xu

{"title":"Population Pharmacokinetics and Exposure-Response Relationship of Hemoporfin in Pediatric Patients With Port-Wine Stain.","authors":"Rong Chen, Bin Zhang, Jining Tao, Qingyu Yao, Tianyan Zhou, Lin Ma, Zigang Xu","doi":"10.1002/psp4.70050","DOIUrl":"https://doi.org/10.1002/psp4.70050","url":null,"abstract":"Hemoporfin, a porphyrin derivative photosensitizer, has been approved for the treatment of port-wine stain (PWS) in adults. However, its optimal dose for the pediatric population remains unclear. This study aimed to explore appropriate dosing for pediatric patients with PWS through population pharmacokinetics (PopPK) and exposure-response (ER) analysis. Data from a prospective pilot study of hemoporfin photodynamic therapy in pediatric PWS patients, as well as a phase I study in healthy adult volunteers, were utilized for the analysis. The pharmacokinetics of hemoporfin in the pediatric population can be described by a three-compartment model with linear elimination following allometric scaling rules. Simulations indicated that simply scaling down the approved adult dose of 5 mg/kg based on weight for the pediatric population, which is a common practice among clinicians, may lead to reduced drug exposure in pediatric patients. Mean Cmax and AUC0-30min in pediatric patients were 18.7% and 30.5% lower than those in adults, respectively. A positive relationship was identified between AUC0-30min and the probability of investigators or patients giving high ratings for efficacy, suggesting that improved efficacy may be achieved with higher hemoporfin exposure. A series of dosing regimens were explored to match exposure in the pediatric population to that of the adult population. These findings may accelerate the development of pediatric indications for hemoporfin and help address the unmet medical needs of pediatric patients with PWS.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191609","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

Examining the Reliability of Model-Based Meta-Analysis (MBMA) Outcomes: A Simulation Study. 基于模型的meta分析（MBMA）结果的可靠性检验：一项模拟研究。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-29 DOI: 10.1002/psp4.70053

Jiesen Yu, Ting Li, Jieren Luo, Qingshan Zheng, Lujin Li

{"title":"Examining the Reliability of Model-Based Meta-Analysis (MBMA) Outcomes: A Simulation Study.","authors":"Jiesen Yu, Ting Li, Jieren Luo, Qingshan Zheng, Lujin Li","doi":"10.1002/psp4.70053","DOIUrl":"https://doi.org/10.1002/psp4.70053","url":null,"abstract":"Model-based meta-analysis (MBMA) can be utilized to synthesize literature data and predict drug efficacy, particularly suitable for constructing external comparator arms for non-randomized controlled trials (NRCTs). This study evaluated the reliability of MBMA by comparing covariate models generated through MBMA to individual patient data. A pharmacodynamic covariate model, commonly employed in MBMA, was used to set true parameter values and simulate data across various scenarios. The reliability of MBMA models was assessed by comparing estimated to true parameter values and identifying optimal conditions for MBMA use. Linear and nonlinear covariate models were evaluated in 24 scenarios, focusing on the relative deviations of parameter estimates from their true values. Evaluation metrics included minimization successful rate, covariate introduction rate, and the accuracy of parameters such as Emax, ET50, and covariate influences. Both model types showed similar reliability in most scenarios. Notably, model performance significantly improved when the number of included trials was 10 or more, the distribution of covariates exceeded 66.6% of its median, and the covariate impact coefficient was greater than 0.15. The study identified critical factors and thresholds that influence the accuracy of MBMA modeling. Enhanced accuracy in synthetic control analysis using MBMA was achieved under specified conditions, highlighting the effectiveness of MBMA in NRCT applications.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180211","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

A Multiple Imputation Workflow for Handling Missing Covariate Data in Pharmacometrics Modeling 在药物计量学建模中处理缺失协变量数据的多重输入工作流。

IF 3.1 3区医学

CPT: Pharmacometrics & Systems Pharmacology Pub Date : 2025-05-29 DOI: 10.1002/psp4.70039

My-Luong Vuong, Geert Verbeke, Erwin Dreesen

{"title":"A Multiple Imputation Workflow for Handling Missing Covariate Data in Pharmacometrics Modeling","authors":"My-Luong Vuong, Geert Verbeke, Erwin Dreesen","doi":"10.1002/psp4.70039","DOIUrl":"10.1002/psp4.70039","url":null,"abstract":"Covariate missingness is a prevalent issue in pharmacometrics modeling. Incorrect handling of missing covariates can lead to biased parameter estimates, adversely affecting clinical practice and drug development dosing decisions. Single imputation is usually favored by pharmacometricians for its simplicity, but it ignores the uncertainty about imputed values, potentially leading to biased estimates and standard errors. Multiple imputation, in contrast, generates multiple plausible values from a predictive distribution, addressing this uncertainty and thus is a preferable approach over single imputation to handle covariate missingness. Yet, its application in pharmacometrics remains limited due to perceived complexity. To address this, we developed a multiple imputation workflow specifically tailored for pharmacometricians, encouraging wider adoption of this more reliable method in pharmacometrics modeling. We compared single imputation and multiple imputation in estimating covariate effects using a publicly available dataset on warfarin pharmacokinetics in healthy volunteers. A one-compartment population pharmacokinetic model with baseline body weight as the only covariate was used to describe the warfarin pharmacokinetics. We simulated five scenarios in which 6.25%, 12.5%, 25%, 50%, and 75% of the subjects had their body weight missing under a missing at random mechanism conditioned on age and sex. We confirm that multiple imputation better reflects uncertainty estimates than single imputation, regardless of the degree of missingness. This confirms multiple imputation as a superior alternative to single imputation for handling missing covariate data in pharmacometrics.","PeriodicalId":10774,"journal":{"name":"CPT: Pharmacometrics & Systems Pharmacology","volume":"14 6","pages":"991-1005"},"PeriodicalIF":3.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172946","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