Journal of Pharmacokinetics and Pharmacodynamics最新文献

Exposure-safety Markov modeling of ocular adverse events in patient populations treated with tisotumab vedotin. 使用维多汀治疗的患者群体眼部不良事件的暴露-安全马尔可夫模型。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-10-03 DOI: 10.1007/s10928-025-10003-w

Summer Feng, Rudy Gunawan, Chaitali Passey, Jenna Voellinger, Daniel Polhamus, Arnout Gerritsen, Christine O'Day, Anne-Sophie Carret, Ibrahima Soumaoro, Manish Gupta, William D Hanley

{"title":"Exposure-safety Markov modeling of ocular adverse events in patient populations treated with tisotumab vedotin.","authors":"Summer Feng, Rudy Gunawan, Chaitali Passey, Jenna Voellinger, Daniel Polhamus, Arnout Gerritsen, Christine O'Day, Anne-Sophie Carret, Ibrahima Soumaoro, Manish Gupta, William D Hanley","doi":"10.1007/s10928-025-10003-w","DOIUrl":"10.1007/s10928-025-10003-w","url":null,"abstract":"Tisotumab vedotin (TV), a tissue factor-directed antibody-drug conjugate (ADC), is approved in the US at 2.0 mg/kg every 3 weeks (Q3W) for adult patients with recurrent or metastatic cervical cancer following disease progression on or after chemotherapy. Previous logistic regression analysis showed a positive association between TV exposure and ocular adverse events (OAEs), which were identified as prespecified AEs of interest in TV clinical studies. To further optimize TV dose from a safety perspective, we developed a discrete-time Markov model (DTMM) to characterize exposure-response (E-R) relationships of exposures of both ADC and the microtubule-disrupting agent monomethyl auristatin E to the incidence, severity, and longitudinal time course of grade ≥ 2 OAEs in patients with advanced solid tumors. A total of 757 patients who received TV as monotherapy or combination (with carboplatin, bevacizumab, or pembrolizumab) across seven clinical studies were included in this analysis. Of multiple covariates modeled, implementation of an eye care plan was the only covariate to significantly reduce risk of grade ≥ 2 OAEs. The DTMM suggested an association between ADC exposure and risk of grade ≥ 2 OAEs. Based on the totality of data from clinical outcomes, pharmacokinetics, and E-R analyses, as well as DTMM modeling results, TV 1.7 mg/kg every 2 weeks may provide higher efficacy with slightly increased risk of OAEs compared with 2.0 mg/kg Q3W, although these OAEs are manageable with an appropriate eye care plan. ClinicalTrials.gov ID (first submission): NCT03485209 (2018-03-08), NCT03657043 (2018-08-22), NCT03438396 (2018-02-08), NCT03786081 (2018-12-13), NCT03913741 (2019-03-29), NCT02001623 (2013-11-14), and NCT02552121 (2015-09-14).","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"52 5","pages":"55"},"PeriodicalIF":2.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225564","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}

引用次数: 0

Impact of covariate model building methods on their clinical relevance evaluation in population pharmacokinetic analyses: comparison of the full model, stepwise covariate model (SCM) and SCM+ approaches - further results based on more conventional practices. 在人群药代动力学分析中，协变量模型构建方法对临床相关性评估的影响：全模型、逐步协变量模型（SCM）和SCM+方法的比较——基于更传统实践的进一步结果

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-09-27 DOI: 10.1007/s10928-025-10002-x

Morgane Philipp, Simon Buatois, Sylvie Retout, France Mentré

{"title":"Impact of covariate model building methods on their clinical relevance evaluation in population pharmacokinetic analyses: comparison of the full model, stepwise covariate model (SCM) and SCM+ approaches - further results based on more conventional practices.","authors":"Morgane Philipp, Simon Buatois, Sylvie Retout, France Mentré","doi":"10.1007/s10928-025-10002-x","DOIUrl":"10.1007/s10928-025-10002-x","url":null,"abstract":"Covariate clinical relevance (CCR) is commonly assessed in population pharmacokinetics using forest plots visualizing parameter changes across covariate values. In our previous work (Philipp et al. 2024), CCR was evaluated using a [0.80-1.20] reference area and a 90% confidence interval for both relevance and significance assessment. However, more conventional thresholds include a broader reference area of [0.80-1.25] and the use of a 5% type I error to assess statistical significance. This commentary extends our previous analysis by evaluating CCR decisions under these more conventional thresholds, in order to assess whether the full model, the stepwise covariate modeling (SCM) and its enhanced version SCM+ remain robust. A comparison with the previous results is also provided. The revised CCR evaluation gave satisfactory results across all three approaches. For covariates with a simulated effect, the full model and SCM/SCM+ provided consistent conclusions with those of the true model. For covariates without a simulated effect, the full model mainly found them non-relevant (NR) non-significant or insufficient information (II) non-significant, while SCM/SCM+ mainly did not select them. These results align with our previous findings. Conclusions for covariates with a simulated effect were almost unchanged. For covariates without a simulated effect, the more conventional threshold allowed the full model to conclude more frequently to their NR instead of II, likely due to the broader reference area and stricter type I error control. Overall, the consistency of our results across different thresholds demonstrates their robustness and supports their generalizability.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"52 5","pages":"54"},"PeriodicalIF":2.8,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181925","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}

引用次数: 0

ADPO: automatic-differentiation-assisted parametric optimization. ADPO：自动微分辅助参数优化。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-09-22 DOI: 10.1007/s10928-025-09997-0

Rong Chen, Mark Sale, Alex Mazur, Michael Tomashevskiy, Shuhua Hu, James Craig, Mike Dunlavey, Robert Leary, Keith Nieforth

{"title":"ADPO: automatic-differentiation-assisted parametric optimization.","authors":"Rong Chen, Mark Sale, Alex Mazur, Michael Tomashevskiy, Shuhua Hu, James Craig, Mike Dunlavey, Robert Leary, Keith Nieforth","doi":"10.1007/s10928-025-09997-0","DOIUrl":"https://doi.org/10.1007/s10928-025-09997-0","url":null,"abstract":"Automatic differentiation (AD), a key method for accurately and efficiently computing derivatives in modern machine learning, is now implemented in Phoenix® NLME™ 8.6 for the first time and applied to the first-order conditional estimation extended least squares (FOCE ELS), Laplacian, and adaptive Gaussian quadrature (AGQ) algorithms. We name the AD implementation as 'automatic-differentiation-assisted parametric optimization' (ADPO), which can be enabled by checking the 'Fast Optimization' option. We present in detail how ADPO is implemented in the frequently used FOCE ELS algorithm, and analyze its performance from the benchmarks based on four PK/PD models. We show both ADPO and traditional FOCE ELS which uses gradients obtained from finite difference (FD) are reasonably accurate and robust, while the main advantage of ADPO being that it considerably reduces computation time no matter what ODE solvers are used: in general ADPO reduces the total run time by around 20% to 50% compared to traditional FOCE ELS. In a case for the realistic voriconazole model using 'auto-detect' ODE solver, 95% reduction in the total run time is observed.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"52 5","pages":"53"},"PeriodicalIF":2.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124932","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}

引用次数: 0

Advancing drug development with "Fit-for-Purpose" modeling informed approaches. 以“符合目的”的建模方法推进药物开发。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-09-15 DOI: 10.1007/s10928-025-09995-2

Jennifer Sheng, Tongli Zhang

{"title":"Advancing drug development with \"Fit-for-Purpose\" modeling informed approaches.","authors":"Jennifer Sheng, Tongli Zhang","doi":"10.1007/s10928-025-09995-2","DOIUrl":"10.1007/s10928-025-09995-2","url":null,"abstract":"Model-informed Drug Development (MIDD) is an essential framework for advancing drug development and supporting regulatory decision-making. The current review presents a strategic blueprint to closely align MIDD tools with key questions of interests (QOI), content of use (COU), and model impact across stages of development -from early discovery to post-market lifecycle management. To demonstrate how the strategy works, we have also provided examples of how the MIDD tools can be applied to enhance the target identification, assist with lead compound optimization, improve preclinical prediction accuracy, facilitate First-in-Human (FIH) studies, optimize clinical trial design including dosage optimization, describe clinical population pharmacokinetics/exposure-response (PPK/ER) characteristics, and support label updates during post-approval stages. Additionally, the roles of some commonly used modeling methodologies, such as quantitative structure-activity relationship (QSAR), physiologically based pharmacokinetic (PBPK), semi-mechanistic pharmacokinetics/pharmacodynamics (PK/PD), PPK/ER, and quantitative systems pharmacology (QSP), are highlighted. What is more, we also explored the evolving role of MIDD in the context of emerging technologies, such as artificial intelligence (AI) and machine learning (ML) approaches. Further, MIDD utilities in development and regulatory evaluation of 505(b) (2) and generic drug products, as well as practical considerations of MIDD in regulatory interactions and asset acquisitions, are briefly discussed. At the end of the review, we briefly addressed the potential challenges faced by MIDD, such as lack of appropriate resources and slow organizational acceptance and alignment, as well as our perspectives on future opportunities of how MIDD could be further expanded.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"52 5","pages":"52"},"PeriodicalIF":2.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145064784","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}

引用次数: 0

Concentration-dependent blood binding: assessing implications through physiologically based Pharmacokinetic modeling of tacrolimus as a case example. 浓度依赖性血液结合：以他克莫司为例，通过基于生理的药代动力学模型评估其影响。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-09-04 DOI: 10.1007/s10928-025-09992-5

Eman El-Khateeb, Deeyen Karsanji, Adam S Darwich, Amin Rostami-Hodjegan

{"title":"Concentration-dependent blood binding: assessing implications through physiologically based Pharmacokinetic modeling of tacrolimus as a case example.","authors":"Eman El-Khateeb, Deeyen Karsanji, Adam S Darwich, Amin Rostami-Hodjegan","doi":"10.1007/s10928-025-09992-5","DOIUrl":"https://doi.org/10.1007/s10928-025-09992-5","url":null,"abstract":"Concentration-dependent binding to red blood cells is a characteristic of several drugs, complicating the understanding of how pathophysiological factors influence drug behavior. This study utilized user-friendly, physiologically-based pharmacokinetic (PBPK) models to compare concentration-dependent and independent blood-to-plasma drug concentration ratios (B/P), using tacrolimus as a case study. Two models were developed and validated for tacrolimus using clinical data from healthy volunteers; Model 1 accounted for saturable blood binding, and Model 2 used a constant B/P level. The differences between the two models based on the two binding assumptions were also studied across clinically relevant hematocrit (HCT) and dose levels. For intravenous (IV) infusions, varying HCT from 15 to 45% resulted in a predicted difference in the area under the concentration-time curve (AUC) of 6-9% for total drug concentration in blood and 37-39% for unbound drug concentration in plasma. Increasing IV doses increased the predicted differences in blood AUC. For oral dosing to steady state, predicted differences in trough concentrations ranged between 50% and 130%, peak concentrations (78-284%), and AUC (up to 125%) according to HCT, dose, and biological medium, e.g., trough differences ranged from 50% (blood, 5 mg) to 130% (plasma, 10 mg). A hypothetical scenario of tacrolimus dose levels increasing above clinically relevant doses revealed a reducing difference in outcomes between the two binding assumptions. Although PBPK models ignoring concentration-dependent binding may adequately fit observed data, they can necessitate compensatory adjustments in disposition parameters, limiting their ability to predict clinical scenarios beyond the model's original development settings.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"52 5","pages":"50"},"PeriodicalIF":2.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000801","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}

引用次数: 0

Computational approaches for toxicology and Pharmacokinetic properties prediction. 毒理学和药代动力学性质预测的计算方法。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-09-04 DOI: 10.1007/s10928-025-09999-y

Navid Kaboudi, Tara Shekari, Ali Shayanfar, Andre Silva Pimentel

引用次数: 0

APOE4 genotypes and the trajectory of biomarkers, neuroimaging, and cognitive measures in Alzheimer's Disease: A mixed-effects disease progression model. APOE4基因型与阿尔茨海默病生物标志物、神经影像学和认知测量的轨迹：一种混合效应疾病进展模型

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-08-30 DOI: 10.1007/s10928-025-09996-1

Carson Essenburg, Murali Ramanathan

{"title":"APOE4 genotypes and the trajectory of biomarkers, neuroimaging, and cognitive measures in Alzheimer's Disease: A mixed-effects disease progression model.","authors":"Carson Essenburg, Murali Ramanathan","doi":"10.1007/s10928-025-09996-1","DOIUrl":"https://doi.org/10.1007/s10928-025-09996-1","url":null,"abstract":"Background: The ε4 allele of the apolipoprotein E gene (APOE4) is a major risk factor for developing sporadic Alzheimer's disease (AD). APOE4 homozygosity has been recently proposed as the defining signature of a genetic form of AD. The goal was to assess the role, if any, of APOE4 in AD progression using a mixed-effects disease progression model-informed approach.Methods: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed for 2092 participants categorized as cognitively normal (CN), subjective memory concerns (SMC), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), or AD. Each included subject had a median of 5.00 (IQR: 3-8) follow-ups; there were n = 13,699 follow-ups. Demographics, APOE4 genotype, cerebrospinal fluid biomarkers, MRI measures, and neuropsychological tests from baseline to 6-years of follow-up visits were analyzed. Linear mixed-effects models were used to evaluate the impact of the APOE4 genotype on disease progression.Results: APOE4 heterozygous and homozygous frequencies were higher in AD vs. CN (p < 0.001). APOE4-positive groups were associated with lower levels of amyloid β1-42, higher levels of Tau and phosphorylated tau-181 proteins, lower hippocampus and entorhinal volumes, and worse AD Assessment Scale Cognitive-11 (ADAS-COG11), ADAS-COG13, and Mini-Mental State Examination neuropsychological test scores. The progression of the biomarkers over time was not associated with APOE4 positivity. The progression of all MRI measures and neuropsychological test scores was associated with APOE4 positivity.Conclusions: APOE4 genotypes adversely influence the levels of biomarkers and the progression of neuroimaging and cognitive outcomes in AD.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"52 5","pages":"49"},"PeriodicalIF":2.8,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958248","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}

引用次数: 0

Sample size determination for cardiodynamic ECG assessment using the Concentration-QTc analysis method. 使用浓度- qtc分析方法确定心电动力学心电图评估的样本量。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-08-28 DOI: 10.1007/s10928-025-09998-z

Hongqi Xue, Georg Ferber, Ellen Freebern, Borje Darpo

{"title":"Sample size determination for cardiodynamic ECG assessment using the Concentration-QTc analysis method.","authors":"Hongqi Xue, Georg Ferber, Ellen Freebern, Borje Darpo","doi":"10.1007/s10928-025-09998-z","DOIUrl":"https://doi.org/10.1007/s10928-025-09998-z","url":null,"abstract":"Concentration-QTc (C-QTc) analysis was accepted to serve as an alternative to the by-time point analysis with intersection-union test (IUT) as the primary basis for decisions to classify the arrhythmogenic risk of a drug by ICH E14 Q&As (R3) in December 2015. Since then, this analysis method has been widely applied by industry as it significantly reduces the sample size to achieve the same power as with IUT. There are many model-based power calculation approaches available for C-QTc through simulation in the literature, however, there is still no standard method with a clear formula to determine the sample size for C-QTc analysis to exclude a small effect on the QTc interval. The current model-based simulation approaches are too complicated to prevent them from being widely used, which is not commensurate with the popular status. We have developed a systematic method based on t-tests to determine the sample size for different study designs using the C-QTc analysis method and applied it to many studies. The results of the sample sizes utilizing this method are consistent with simulation studies and validated by real analyses.","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"52 5","pages":"48"},"PeriodicalIF":2.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958207","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}

引用次数: 0

Dos and don'ts for concentration - QTc analysis as primary analysis for assay sensitivity assessment. 浓度- QTc分析作为测定敏感性评价的主要分析的注意事项。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-08-23 DOI: 10.1007/s10928-025-09994-3

Dalong Huang

引用次数: 0

Pharmacometrics education for all by overcoming language barriers to enhance global collaboration. 全民药物计量学教育，克服语言障碍，加强全球合作。

IF 2.8 4区医学

Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2025-07-30 DOI: 10.1007/s10928-025-09991-6

Sonia Khier, Anna H-X P Chan Kwong, Maud Harnichard, Sihem Ait-Oudhia

引用次数: 0