AAPS Journal最新文献_第2页

Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich's Ataxia. 非临床弗里德赖希共济失调的药代动力学和药效学研究。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-25 DOI: 10.1208/s12248-025-01093-y

Flavia De Toni, Vanessa Ragaglia, Devin Schecter, Angela S Miller, Eric Gonzalez, Erik J Wagner, Xin Xu, R Mark Payne, Jean-Nicholas Mess, Matthew G Baile, Adrienne Clements-Egan, Gopi Shankar

{"title":"Pharmacokinetics and Pharmacodynamics of Nomlabofusp in Non-clinical Studies of Friedreich's Ataxia.","authors":"Flavia De Toni, Vanessa Ragaglia, Devin Schecter, Angela S Miller, Eric Gonzalez, Erik J Wagner, Xin Xu, R Mark Payne, Jean-Nicholas Mess, Matthew G Baile, Adrienne Clements-Egan, Gopi Shankar","doi":"10.1208/s12248-025-01093-y","DOIUrl":"https://doi.org/10.1208/s12248-025-01093-y","url":null,"abstract":"Nomlabofusp is a cell penetrant peptide-based recombinant fusion protein designed to enter cells and deliver human frataxin into the mitochondria of adults and children with Friedreich's ataxia. In this article we present non-clinical studies evaluating the pharmacology of nomlabofusp, including in a murine striated muscle tissue frataxin knockout model of Friedreich's ataxia. We demonstrate that subcutaneous administration of nomlabofusp distributes in a dose-dependent manner to several organs including the dorsal root ganglion, heart, and skeletal muscle, which are known to be predominantly affected in Friedreich's ataxia, as well as to other tissues, including skin. Plasma nomlabofusp concentrations correlated with levels of human frataxin delivered by nomlabofusp into tissues, and the increases in frataxin were correlated amongst tissues, especially with skin. In the knockout mice, we show that the pharmacokinetics and processing of nomlabofusp were comparable with wild type animals and that treatment with nomlabofusp halts the progression of cardiac dysfunction and significantly increased survival. Together, the findings from these non-clinical studies demonstrate that nomlabofusp exposure increases human frataxin in Friedreich's ataxia-relevant tissues and provide evidence of pharmacologic effects.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"112"},"PeriodicalIF":5.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144499014","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

Correction: Immunogenicity of Atezolizumab: Influence of Testing Method and Sampling Frequency on Reported Anti-drug Antibody Incidence Rates. 更正：Atezolizumab的免疫原性：检测方法和采样频率对报告的抗药物抗体发生率的影响。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-20 DOI: 10.1208/s12248-025-01077-y

Maxime Usdin, Valerie Quarmby, James Zanghi, Coen Bernaards, Laura Liao, Joel Laxamana, Benjamin Wu, Steven Swanson, Yuan Song, Patty Siguenza

引用次数: 0

Effect of Alternative Administrations on P2Y12 Receptor Inhibitors' Pharmacokinetics and Pharmacodynamics: Systematic Review and Meta-Analysis. 不同给药方式对P2Y12受体抑制剂药代动力学和药效学的影响：系统回顾和荟萃分析。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-18 DOI: 10.1208/s12248-025-01095-w

Celine Konecki, Catherine Feliu, Julien Scala-Bertola, Thomas Duflot, Zoubir Djerada

{"title":"Effect of Alternative Administrations on P2Y12 Receptor Inhibitors' Pharmacokinetics and Pharmacodynamics: Systematic Review and Meta-Analysis.","authors":"Celine Konecki, Catherine Feliu, Julien Scala-Bertola, Thomas Duflot, Zoubir Djerada","doi":"10.1208/s12248-025-01095-w","DOIUrl":"10.1208/s12248-025-01095-w","url":null,"abstract":"Alternative administrations methods, such as chewing or crushing tablets, have been proposed to improve P2Y12 receptor inhibitors' absorption in acute and chronic coronary syndromes. This study aimed to evaluate the impact of these alternative strategies on the pharmacokinetics and pharmacodynamics of clopidogrel, ticagrelor, and prasugrel. PubMed, the Cochrane Library, and Web of Science were searched until March 07, 2025 for trials comparing at least one P2Y12 receptor inhibitor alternative administration method to the standard administration (swallowed integral tablets). Drug concentrations, platelet reactivity, and rates of high on-treatment platelet reactivity (HPR) were evaluated by standardized mean differences (SMD) or odds ratios (OR) with 95% confidence interval (CI) using random-effects models. The effects of specific P2Y12 inhibitors and administration methods were assessed using meta-regression. Eleven studies (1,735 patients) were included. Administration of crushed or chewed tablets led to an increase in drug concentrations (SMD at 1 h 0.48, 95% CI 0.001 to 0.95, p < 0.05), resulting in a significant improvement in platelet inhibition (SMD at 1 h -0.53, 95% CI -0.67 to -0.39, p < 0.001) and a reduction in HPR rates (OR 0.29, 95% CI 0.16 to 0.54, p < 0.001) as early as 30 min and during the first 4 h after administration. No differences were found between prasugrel and ticagrelor or between crushed and chewed tablets in the pharmacodynamic outcomes, providing flexibility in clinical practice. Further research is needed to confirm the clinical relevance of these findings.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 5","pages":"110"},"PeriodicalIF":5.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327658","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

Dose Optimization of ClpP Agonists Using an In Vitro Microfluidic Perfusion Platform and In Silico Pharmacokinetic-Pharmacodynamic Modeling. 体外微流控灌注平台优化ClpP激动剂剂量及计算机药动学-药效学建模

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-13 DOI: 10.1208/s12248-025-01088-9

Ronald W Bucher, Lee M Graves, Derek W Bartlett

{"title":"Dose Optimization of ClpP Agonists Using an In Vitro Microfluidic Perfusion Platform and In Silico Pharmacokinetic-Pharmacodynamic Modeling.","authors":"Ronald W Bucher, Lee M Graves, Derek W Bartlett","doi":"10.1208/s12248-025-01088-9","DOIUrl":"10.1208/s12248-025-01088-9","url":null,"abstract":"Small molecule activators of the mitochondrial caseinolytic protease P (ClpP agonists) can disrupt tumor metabolism and deprive tumors of their energy needs. The imipridone, ONC201, is a ClpP agonist currently undergoing clinical evaluation across multiple cancer types, while additional analogs with improved potency and selectivity are in preclinical development. Preclinical studies in mice have demonstrated a unique pharmacokinetic-pharmacodynamic (PK-PD) relationship for ONC201 characterized by prolonged pharmacology following a single dose. This motivated the selection of an initial human dosing regimen of every three weeks, and subsequent dose exploration studies in mice led to dose intensification in human patients. However, a systematic analysis of ClpP agonist PK-PD relationships has not been performed, and the optimal exposure profile for ClpP agonists remains undefined. To address this gap, we combined PK-PD modeling with a microfluidic perfusion platform as an animal-alternative approach for translational PK-PD of ClpP agonists. We demonstrate that the anti-proliferative effect on triple negative breast cancer cells correlates with the magnitude and duration of ClpP agonist exposure above a threshold concentration required for ClpP activation. Moreover, we demonstrate that PK-PD model simulations using parameters derived from microfluidic perfusion datasets can successfully predict the anti-tumor efficacy of a ClpP agonist in a mouse tumor xenograft study. These studies support the translational relevance of the animal-alternative in vitro PK-PD platform and its utility to help guide dose optimization of ClpP agonists as cancer therapeutics.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"109"},"PeriodicalIF":5.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295324","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

Automation of Anti-Drug Antibody Enrichment Using Streptavidin PhyTip® Columns for Sample Pretreatment in an Immunogenicity Assay. 利用链亲和素PhyTip®色谱柱在免疫原性试验中进行样品预处理的抗药物抗体富集自动化。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-06 DOI: 10.1208/s12248-025-01092-z

Michael Luong, Minlei Zhang, Ihor Djura, Ying Wang, Alison Joyce

{"title":"Automation of Anti-Drug Antibody Enrichment Using Streptavidin PhyTip® Columns for Sample Pretreatment in an Immunogenicity Assay.","authors":"Michael Luong, Minlei Zhang, Ihor Djura, Ying Wang, Alison Joyce","doi":"10.1208/s12248-025-01092-z","DOIUrl":"10.1208/s12248-025-01092-z","url":null,"abstract":"The administration of biotherapeutics has the potential to induce potent immune responses, including the induction of anti-drug antibodies (ADA) (1). Detection and characterization of ADA in clinical trials is an important component of a comprehensive immunogenicity program (2). ADA testing is mostly accomplished with ligand-binding assays (LBA). While LBA can be robust and specific, they are susceptible to various sources of interference (3). Of particular concern, interference from residual drug present in patient samples may lead to loss of ADA detection, producing false negative results. To mitigate drug interference, sample pretreatment procedures have been developed to enrich ADA from samples with high drug concentrations (4, 5). The pretreatment procedures can vary considerably but typically involve an initial step to liberate ADA from ADA-drug complexes and a subsequent step to affinity capture ADA and acid elute for detection. While these procedures can be highly effective, they have certain drawbacks when performed manually. First, the procedures are time-consuming and require near constant attention. Second, because of the manual workflow, the procedures can produce variable results between experiments and between different analysts with negative consequences for assay robustness. To address these drawbacks, we developed an automated procedure to enrich ADA by leveraging dual flow chromatography (DFC) and Streptavidin PhyTip® columns on a liquid-handling system (6). The enriched ADA were then tested in an LBA to evaluate the effectiveness of the automated enrichment procedure.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"108"},"PeriodicalIF":5.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250698","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

Factors Impacting the Immunogenicity of Etrolizumab & Clinical Consequences. 影响依曲单抗免疫原性的因素及临床后果。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-06 DOI: 10.1208/s12248-025-01090-1

Gizette Sperinde, Yenny Webb-Vargas, Zicheng Hu, Ashis Saha, Christian Hammer, Richard Erickson, Chris Eden, Deanna Galloway, Rhian Jacob-Moffatt, Ketevan Siradze, Van Nguyen, Saloumeh K Fischer

{"title":"Factors Impacting the Immunogenicity of Etrolizumab & Clinical Consequences.","authors":"Gizette Sperinde, Yenny Webb-Vargas, Zicheng Hu, Ashis Saha, Christian Hammer, Richard Erickson, Chris Eden, Deanna Galloway, Rhian Jacob-Moffatt, Ketevan Siradze, Van Nguyen, Saloumeh K Fischer","doi":"10.1208/s12248-025-01090-1","DOIUrl":"10.1208/s12248-025-01090-1","url":null,"abstract":"Ulcerative colitis (UC) and Crohn's disease (CD), pose a substantial burden, necessitating effective therapies. Etrolizumab, a unique monoclonal antibody targeting integrins, initially showed promise but was terminated due to lack of efficacy in PhIII studies. The immune responses elicited by patients towards etrolizumab make it a compelling subject for further in-depth investigation. This study delves into immunogenic responses to etrolizumab, examining factors contributing to such responses, including anti-drug antibody (ADA) assay format, patient baseline characteristics, immunosuppressive (IS) medication use, human leukocyte antigen (HLA) allelic expression, and the clinical impact of ADA responses on safety and efficacy endpoints. Logistic regression was used to test for association between the presence of ADA & (neutralizing antibody) NAb and HLA alleles with carrier frequencies of at least 2%, alongside age, sex, and IS use. We identified two class-II HLA alleles, HLA-DQB1*06:03 and HLADQA1* 03:03, associated with the development of ADA and NAb. However, there was minimal impact of ADA on clinical parameters, such as pharmacokinetics (PK), safety, and efficacy. The findings enhance our understanding of etrolizumab immunogenicity, in the context of clinical impact, providing insights that may inform future biologic development strategies and patient selection criteria in IBD clinical trials.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"107"},"PeriodicalIF":5.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250699","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

Improving the Therapeutic Selectivity of Trastuzumab Deruxtecan Using 8C2 Fab Fragments. 利用8C2 Fab片段提高曲妥珠单抗德鲁西替康的治疗选择性

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-04 DOI: 10.1208/s12248-025-01087-w

Jue Gong, Brandon M Bordeau, Joseph P Balthasar

{"title":"Improving the Therapeutic Selectivity of Trastuzumab Deruxtecan Using 8C2 Fab Fragments.","authors":"Jue Gong, Brandon M Bordeau, Joseph P Balthasar","doi":"10.1208/s12248-025-01087-w","DOIUrl":"10.1208/s12248-025-01087-w","url":null,"abstract":"DXd, a camptothecin derivative, is employed as the payload molecule for the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd), which is in current clinical use for the treatment of breast and gastric cancer. Despite the clinical success of ADCs for treatment of cancer, exposure to released payload in plasma and extracellular fluids contributes to off-target toxicities, which limit ADC dosage and efficacy. In this study, we evaluated an anti-DXd antibody fragment, 8C2 Fab, for utility in mitigating DXd toxicity in cell culture and for improving the therapeutic index of T-DXd in vivo in mice. 8C2 Fab was produced, purified, and characterized for binding to DXd and T-DXd. In vitro competitive cytotoxicity assays showed that 8C2 Fab blocked the cell-killing effect of DXd, increasing the DXd concentration associated with 50% growth inhibition (IC50) by 50-fold; however, 8C2 did not decrease the cytotoxicity of T-DXd. Co-administration of 8C2 Fab to mice with 600 mg/kg T-DXd significantly decreased the percentage body weight loss at nadir in mice compared to results found with T-DXd alone (12.8 ± 3.66% vs 7.08 ± 4.24%, p = 0.0331). In contrast, co-administration of 8C2 Fab with T-DXd (1 or 10 mg/kg) did not negatively impact the anti-tumor efficacy in mice bearing NCI-N87 xenograft tumors. Our results demonstrate that 8C2 Fab decreases DXd cytotoxicity in vitro, and decreases T-DXd-induced toxicity in vivo, while not inhibiting T-DXd anti-tumor efficacy in vitro or in vivo, supporting utility for improving the therapeutic index of T-DXd.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 4","pages":"106"},"PeriodicalIF":5.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144227411","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

Correction: Nitrosamines Risk Assessment for Biopharmaceutics Classifcation System Class IV Molecule Containing Immediate Release Products: Use of In-Silico Prediction Tools and Physiologically Based Pharmacokinetic Modeling. 修正：生物制药分类系统IV类分子含立即释放产品的亚硝胺风险评估：使用计算机预测工具和基于生理的药代动力学建模。

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-04 DOI: 10.1208/s12248-025-01094-x

Sivacharan Kollipara, Mahendra Chougule, Karthik Parsa, Priyansh Pandya, Tausif Ahmed

引用次数: 0

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

IF 5 3区医学

AAPS Journal Pub Date : 2025-06-04 DOI: 10.1208/s12248-025-01085-y

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

引用次数: 0

The 100^th Monoclonal Antibody Product is Approved in Japan. 第100个单克隆抗体产品在日本获批