Journal of Pharmacokinetics and Pharmacodynamics最新文献

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General quasi-equilibrium multivalent binding model to study diverse and complex drug-receptor interactions of biologics. 通用准平衡多价结合模型,用于研究生物制剂的各种复杂的药物-受体相互作用。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-08-17 DOI: 10.1007/s10928-024-09936-5
Chee M Ng, Robert J Bauer
{"title":"General quasi-equilibrium multivalent binding model to study diverse and complex drug-receptor interactions of biologics.","authors":"Chee M Ng, Robert J Bauer","doi":"10.1007/s10928-024-09936-5","DOIUrl":"10.1007/s10928-024-09936-5","url":null,"abstract":"<p><p>Pharmacokinetics and pharmacodynamics of many biologics are influenced by their complex binding to biological receptors. Biologics consist of diverse groups of molecules with different binding kinetics to its receptors including IgG with simple one-to-one drug receptor bindings, bispecific antibody (BsAb) that binds to two different receptors, and antibodies that can bind to six or more identical receptors. As the binding process is typically much faster than elimination (or internalization) and distribution processes, quasi-equilibrium (QE) binding models are commonly used to describe drug-receptor binding kinetics of biologics. However, no general QE modeling framework is available to describe complex binding kinetics for diverse classes of biologics. In this paper, we describe novel approaches of using differential algebraic equations (DAE) to solve three QE multivalent drug-receptor binding (QEMB) models. The first example describes the binding kinetics of three-body equilibria of BsAb that binds to 2 different receptors for trimer formation. The second example models an engineered IgG variant (Multabody) that can bind to 24 identical target receptors. The third example describes an IgG with modified neonatal Fc receptor (FcRn) binding affinity that competes for the same FcRn receptor as endogenous IgG. The model parameter estimates were obtained by fitting the model to all data simultaneously. The models allowed us to study potential roles of cooperative binding on bell-shaped drug exposure-response relationships of BsAb, and concentration-depended distribution of different drug-receptor complexes for Multabody. This DAE-based QEMB model platform can serve as an important tool to better understand complex binding kinetics of diverse classes of biologics.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"841-857"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995945","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
Generation of realistic virtual adult populations using a model-based copula approach. 利用基于模型的共轭方法生成逼真的虚拟成人种群。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-06-06 DOI: 10.1007/s10928-024-09929-4
Yuchen Guo, Tingjie Guo, Catherijne A J Knibbe, Laura B Zwep, J G Coen van Hasselt
{"title":"Generation of realistic virtual adult populations using a model-based copula approach.","authors":"Yuchen Guo, Tingjie Guo, Catherijne A J Knibbe, Laura B Zwep, J G Coen van Hasselt","doi":"10.1007/s10928-024-09929-4","DOIUrl":"10.1007/s10928-024-09929-4","url":null,"abstract":"<p><p>Incorporating realistic sets of patient-associated covariates, i.e., virtual populations, in pharmacometric simulation workflows is essential to obtain realistic model predictions. Current covariate simulation strategies often omit or simplify dependency structures between covariates. Copula models are multivariate distribution functions suitable to capture dependency structures between covariates with improved performance compared to standard approaches. We aimed to develop and evaluate a copula model for generation of adult virtual populations for 12 patient-associated covariates commonly used in pharmacometric simulations, using the publicly available NHANES database, including sex, race-ethnicity, body weight, albumin, and several biochemical variables related to organ function. A multivariate (vine) copula was constructed from bivariate relationships in a stepwise fashion. Covariate distributions were well captured for the overall and subgroup populations. Based on the developed copula model, a web application was developed. The developed copula model and associated web application can be used to generate realistic adult virtual populations, ultimately to support model-based clinical trial design or dose optimization strategies.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"735-746"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283910","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
Likelihood comparisons in bounded outcome score analysis must be internally consistent. 有界结果得分分析中的可能性比较必须具有内部一致性。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-07-05 DOI: 10.1007/s10928-024-09933-8
Chuanpu Hu
{"title":"Likelihood comparisons in bounded outcome score analysis must be internally consistent.","authors":"Chuanpu Hu","doi":"10.1007/s10928-024-09933-8","DOIUrl":"10.1007/s10928-024-09933-8","url":null,"abstract":"<p><p>Clinical trial endpoints are often bounded outcome scores (BOS), which are variables having restricted values within finite intervals. Common analysis approaches may treat the data as continuous, categorical, or a mixture of both. The appearance of BOS data being simultaneously continuous and categorical easily leads to confusions in pharmacometrics regarding the appropriate domain for model evaluation and the circumstances under which data likelihoods can be compared. This commentary aims to clarify these fundamental issues and facilitate appropriate pharmacometric analyses.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"577-579"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534586","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
A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema. 遗传性血管性水肿中血浆激肽-激肽系统失调的定量系统药理学模型。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-05-11 DOI: 10.1007/s10928-024-09919-6
Dan Sexton, Hoa Q Nguyen, Salomé Juethner, Haobin Luo, Zhiwei Zhang, Paul Jasper, Andy Z X Zhu
{"title":"A quantitative systems pharmacology model of plasma kallikrein-kinin system dysregulation in hereditary angioedema.","authors":"Dan Sexton, Hoa Q Nguyen, Salomé Juethner, Haobin Luo, Zhiwei Zhang, Paul Jasper, Andy Z X Zhu","doi":"10.1007/s10928-024-09919-6","DOIUrl":"10.1007/s10928-024-09919-6","url":null,"abstract":"<p><p>Hereditary angioedema (HAE) due to C1-inhibitor deficiency is a rare, debilitating, genetic disorder characterized by recurrent, unpredictable, attacks of edema. The clinical symptoms of HAE arise from excess bradykinin generation due to dysregulation of the plasma kallikrein-kinin system (KKS). A quantitative systems pharmacology (QSP) model that mechanistically describes the KKS and its role in HAE pathophysiology was developed based on HAE attacks being triggered by autoactivation of factor XII (FXII) to activated FXII (FXIIa), resulting in kallikrein production from prekallikrein. A base pharmacodynamic model was constructed and parameterized from literature data and ex vivo assays measuring inhibition of kallikrein activity in plasma of HAE patients or healthy volunteers who received lanadelumab. HAE attacks were simulated using a virtual patient population, with attacks recorded when systemic bradykinin levels exceeded 20 pM. The model was validated by comparing the simulations to observations from lanadelumab and plasma-derived C1-inhibitor clinical trials. The model was then applied to analyze the impact of nonadherence to a daily oral preventive therapy; simulations showed a correlation between the number of missed doses per month and reduced drug effectiveness. The impact of reducing lanadelumab dosing frequency from 300 mg every 2 weeks (Q2W) to every 4 weeks (Q4W) was also examined and showed that while attack rates with Q4W dosing were substantially reduced, the extent of reduction was greater with Q2W dosing. Overall, the QSP model showed good agreement with clinical data and could be used for hypothesis testing and outcome predictions.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"721-734"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908115","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
Population pharmacokinetic analyses of pozelimab in patients with CD55-deficient protein-losing enteropathy (CHAPLE disease). 波珠单抗在 CD55 缺乏性蛋白失代偿性肠病(CHAPLE 病)患者中的群体药代动力学分析。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-09-30 DOI: 10.1007/s10928-024-09941-8
Kuan-Ju Lin, Jeanne Mendell, John D Davis, Lutz O Harnisch
{"title":"Population pharmacokinetic analyses of pozelimab in patients with CD55-deficient protein-losing enteropathy (CHAPLE disease).","authors":"Kuan-Ju Lin, Jeanne Mendell, John D Davis, Lutz O Harnisch","doi":"10.1007/s10928-024-09941-8","DOIUrl":"10.1007/s10928-024-09941-8","url":null,"abstract":"<p><p>Pozelimab, a monoclonal antibody directed against C5, is the first and only treatment for adult and pediatric patients (≥ 1 year) with CD55-deficient protein-losing enteropathy (CHAPLE) disease. A target-mediated drug disposition (TMDD) population pharmacokinetic (PopPK) model was developed using pooled data from four phase 1-3 studies to characterize the pharmacokinetics (PK) of total pozelimab and total C5, and to simulate free pozelimab and free C5 to support the dose regimen in patients with CHAPLE disease. A TMDD PopPK model was developed using total pozelimab and total C5 concentration-time data from 106 participants (82 healthy volunteers; 24 patients with paroxysmal nocturnal hemoglobinuria [PNH]). This model was refined and updated to include PK data from 10 patients with CHAPLE disease from a phase 2/3 study. Stochastic simulations predicted concentration-time profiles for total pozelimab, free pozelimab, and free C5, to obtain pozelimab exposure metrics for patients with CHAPLE disease. A two-compartment TMDD model with two binding sites based on the quasi-equilibrium approximation adequately described the concentration-time profiles of total pozelimab and total C5. Body weight was identified as the most important source of pozelimab PK variability; therefore, the dose was adjusted based on body weight for the predominantly pediatric patients with CHAPLE disease. A robust TMDD PopPK model was developed to describe the PK of total pozelimab and total C5 following pozelimab administration. Reliable predictions for individual exposures of total pozelimab and free C5 were possible and supported the 10 mg/kg weight-based dose regimen in patients with CHAPLE disease.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"905-917"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348912","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
Generative models for synthetic data generation: application to pharmacokinetic/pharmacodynamic data. 合成数据生成模型:应用于药代动力学/药效学数据。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-08-27 DOI: 10.1007/s10928-024-09935-6
Yulun Jiang, Alberto García-Durán, Idris Bachali Losada, Pascal Girard, Nadia Terranova
{"title":"Generative models for synthetic data generation: application to pharmacokinetic/pharmacodynamic data.","authors":"Yulun Jiang, Alberto García-Durán, Idris Bachali Losada, Pascal Girard, Nadia Terranova","doi":"10.1007/s10928-024-09935-6","DOIUrl":"10.1007/s10928-024-09935-6","url":null,"abstract":"<p><p>The generation of synthetic patient data that reflect the statistical properties of real data plays a fundamental role in today's world because of its potential to (i) be enable proprietary data access for statistical and research purposes and (ii) increase available data (e.g., in low-density regions-i.e., for patients with under-represented characteristics). Generative methods employ a family of solutions for generating synthetic data. The objective of this research is to benchmark numerous state-of-the-art deep-learning generative methods across different scenarios and clinical datasets comprising patient covariates and several pharmacokinetic/pharmacodynamic endpoints. We did this by implementing various probabilistic models aimed at generating synthetic data, such as the Multi-layer Perceptron Conditioning Generative Adversarial Neural Network (MLP cGAN), Time-series Generative Adversarial Networks (TimeGAN), and a more traditional approach like Probabilistic Autoregressive (PAR). We evaluated their performance by calculating discriminative and predictive scores. Furthermore, we conducted comparisons between the distributions of real and synthetic data using Kolmogorov-Smirnov and Chi-square statistical tests, focusing respectively on covariate and output variables of the models. Lastly, we employed pharmacometrics-related metric to enhance interpretation of our results specific to our investigated scenarios. Results indicate that multi-layer perceptron-based conditional generative adversarial networks (MLP cGAN) exhibit the best overall performance for most of the considered metrics. This work highlights the opportunities to employ synthetic data generation in the field of clinical pharmacology for augmentation and sharing of proprietary data across institutions.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"877-885"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080627","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
Visual predictive check of longitudinal models and dropout. 纵向模型和辍学的可视化预测检查。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-08-18 DOI: 10.1007/s10928-024-09937-4
Chuanpu Hu, Anna G Kondic, Amit Roy
{"title":"Visual predictive check of longitudinal models and dropout.","authors":"Chuanpu Hu, Anna G Kondic, Amit Roy","doi":"10.1007/s10928-024-09937-4","DOIUrl":"10.1007/s10928-024-09937-4","url":null,"abstract":"<p><p>Visual predictive checks (VPC) are commonly used to evaluate pharmacometrics models. However their performance may be hampered if patients with worse outcomes drop out earlier, as often occurs in clinical trials, especially in oncology. While methods accounting for dropouts have appeared in literature, they vary in assumptions, flexibility, and performance, and the differences between them are not widely understood. This manuscript aims to elucidate which methods can be used to handle VPC with dropout and when, along with a more informative VPC approach using confidence intervals. Additionally, we propose constructing the confidence interval based on the observed data instead of the simulated data. The theoretical framework for incorporating dropout in VPCs is developed and applied to propose two approaches: full and conditional. The full approach is implemented using a parametric time-to-event model, while the conditional approach is implemented using both parametric and Cox proportional-hazard (CPH) models. The practical performances of these approaches are illustrated with an application to the tumor growth dynamics (TGD) modeling of data from two cancer clinical trials of nivolumab and docetaxel, where patients were followed until disease progression. The dataset consisted of 3504 tumor size measurements from 855 subjects, which were described by a TGD model. The dropout of subjects was described by a Weibull or CPH model. Simulated datasets were also used to further illustrate the properties of the VPC methods. The results showed that the more familiar full approach might not provide meaningful improvement for TGD model evaluation over the naive approach of not adjusting for dropout, and could be outperformed by the conditional approach using either the Weibull model or the Cox proportional hazard model. Overall, including confidence intervals in VPC should improve interpretation, the conditional approach was shown to be more generally applicable when dropout occurs, and the nonparametric approach could provide additional robustness.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"859-875"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995946","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
Population pharmacokinetics and exposure-response relationships of maribavir in transplant recipients with cytomegalovirus infection. 感染巨细胞病毒的移植受者体内马利巴韦的群体药代动力学和暴露-反应关系。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-12-01 Epub Date: 2024-09-27 DOI: 10.1007/s10928-024-09939-2
Ivy H Song, Grace Chen, Siobhan Hayes, Colm Farrell, Claudia Jomphe, Nathalie H Gosselin, Kefeng Sun
{"title":"Population pharmacokinetics and exposure-response relationships of maribavir in transplant recipients with cytomegalovirus infection.","authors":"Ivy H Song, Grace Chen, Siobhan Hayes, Colm Farrell, Claudia Jomphe, Nathalie H Gosselin, Kefeng Sun","doi":"10.1007/s10928-024-09939-2","DOIUrl":"10.1007/s10928-024-09939-2","url":null,"abstract":"<p><p>Maribavir is approved for management of post-transplant cytomegalovirus (CMV) infections refractory and/or resistant to CMV therapies at a dose of 400 mg twice daily (BID). Population pharmacokinetic (PopPK) and exposure-response analyses were conducted to support the appropriateness of 400 mg BID dosing. A PopPK model was developed using non-linear mixed-effects modeling with pooled maribavir plasma concentration-time data from phase 1 and 2 studies (from 100 mg up to 1200 mg as single or repeated doses) and the phase 3 SOLSTICE study (400 mg BID). Exposure-response analyses were performed for efficacy, safety, and viral resistance based on data collected in the SOLSTICE study. Maribavir PK after oral administration was adequately described by a two-compartment model with first-order elimination, first-order absorption, and an absorption lag-time. There was no evidence that maribavir PK was affected by age, sex, race, diarrhea, vomiting, disease characteristics, or concomitant use of histamine H<sub>2</sub> blockers, or proton pump inhibitors. In the SOLSTICE study, higher maribavir exposure was not associated with increased probability of achieving CMV DNA viremia clearance, nor with reduced probability of treatment-emergent maribavir-resistant CMV mutations. A statistically significant association with maribavir exposure was identified for taste disturbance, fatigue, and treatment-emergent serious adverse events, while transplant type, enrollment region, CMV DNA level at baseline, and/or CMV resistance at baseline were identified as additional risk factors for these safety outcomes. In conclusion, the findings of these PopPK and exposure-response analyses provide further support for the recommended maribavir dose of 400 mg BID.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"887-904"},"PeriodicalIF":2.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348913","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
Prospective approaches to gene therapy computational modeling - spotlight on viral gene therapy. 基因治疗计算建模的前瞻性方法——病毒基因治疗的焦点。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-10-01 Epub Date: 2023-10-17 DOI: 10.1007/s10928-023-09889-1
Mary P Choules, Peter L Bonate, Nakyo Heo, Jared Weddell
{"title":"Prospective approaches to gene therapy computational modeling - spotlight on viral gene therapy.","authors":"Mary P Choules, Peter L Bonate, Nakyo Heo, Jared Weddell","doi":"10.1007/s10928-023-09889-1","DOIUrl":"10.1007/s10928-023-09889-1","url":null,"abstract":"<p><p>Clinical studies have found there still exists a lack of gene therapy dose-toxicity and dose-efficacy data that causes gene therapy dose selection to remain elusive. Model informed drug development (MIDD) has become a standard tool implemented throughout the discovery, development, and approval of pharmaceutical therapies, and has the potential to inform dose-toxicity and dose-efficacy relationships to support gene therapy dose selection. Despite this potential, MIDD approaches for gene therapy remain immature and require standardization to be useful for gene therapy clinical programs. With the goal to advance MIDD approaches for gene therapy, in this review we first provide an overview of gene therapy types and how they differ from a bioanalytical, formulation, route of administration, and regulatory standpoint. With this biological and regulatory background, we propose how MIDD can be advanced for AAV-based gene therapies by utilizing physiological based pharmacokinetic modeling and quantitative systems pharmacology to holistically inform AAV and target protein dynamics following dosing. We discuss how this proposed model, allowing for in-depth exploration of AAV pharmacology, could be the key the field needs to treat these unmet disease populations.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"399-416"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41236281","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
A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics. 研究抗体大小、电荷以及与 FcRn/抗原的结合亲和力对抗体药代动力学的综合影响的基于生理学的最小药代动力学模型。
IF 2.2 4区 医学
Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-10-01 Epub Date: 2024-02-24 DOI: 10.1007/s10928-023-09899-z
Krutika Patidar, Nikhil Pillai, Saroj Dhakal, Lindsay B Avery, Panteleimon D Mavroudis
{"title":"A minimal physiologically based pharmacokinetic model to study the combined effect of antibody size, charge, and binding affinity to FcRn/antigen on antibody pharmacokinetics.","authors":"Krutika Patidar, Nikhil Pillai, Saroj Dhakal, Lindsay B Avery, Panteleimon D Mavroudis","doi":"10.1007/s10928-023-09899-z","DOIUrl":"10.1007/s10928-023-09899-z","url":null,"abstract":"<p><p>Protein therapeutics have revolutionized the treatment of a wide range of diseases. While they have distinct physicochemical characteristics that influence their absorption, distribution, metabolism, and excretion (ADME) properties, the relationship between the physicochemical properties and PK is still largely unknown. In this work we present a minimal physiologically-based pharmacokinetic (mPBPK) model that incorporates a multivariate quantitative relation between a therapeutic's physicochemical parameters and its corresponding ADME properties. The model's compound-specific input includes molecular weight, molecular size (Stoke's radius), molecular charge, binding affinity to FcRn, and specific antigen affinity. Through derived and fitted empirical relationships, the model demonstrates the effect of these compound-specific properties on antibody disposition in both plasma and peripheral tissues using observed PK data in mice and humans. The mPBPK model applies the two-pore hypothesis to predict size-based clearance and exposure of full-length antibodies (150 kDa) and antibody fragments (50-100 kDa) within a onefold error. We quantitatively relate antibody charge and PK parameters like uptake rate, non-specific binding affinity, and volume of distribution to capture the relatively faster clearance of positively charged mAb as compared to negatively charged mAb. The model predicts the terminal plasma clearance of slightly positively and negatively charged antibody in humans within a onefold error. The mPBPK model presented in this work can be used to predict the target-mediated disposition of a drug when compound-specific and target-specific properties are known. To our knowledge, a combined effect of antibody weight, size, charge, FcRn, and antigen has not been incorporated and studied in a single mPBPK model previously. By conclusively incorporating and relating a multitude of protein's physicochemical properties to observed PK, our mPBPK model aims to contribute as a platform approach in the early stages of drug development where many of these properties can be optimized to improve a molecule's PK and ultimately its efficacy.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"477-492"},"PeriodicalIF":2.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139944235","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
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