Pub Date : 2024-01-24DOI: 10.1208/s12248-024-00888-9
Anas Saadeddin, Vivek Purohit, Yeamin Huh, Mei Wong, Aurelia Maulny, Martin E Dowty, Kazuko Sagawa
Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.
{"title":"Virtual Bioequivalence Assessment of Ritlecitinib Capsules with Incorporation of Observed Clinical Variability Using a Physiologically Based Pharmacokinetic Model.","authors":"Anas Saadeddin, Vivek Purohit, Yeamin Huh, Mei Wong, Aurelia Maulny, Martin E Dowty, Kazuko Sagawa","doi":"10.1208/s12248-024-00888-9","DOIUrl":"10.1208/s12248-024-00888-9","url":null,"abstract":"<p><p>Ritlecitinib, an orally available Janus kinase 3 and tyrosine kinase inhibitor being developed for the treatment of alopecia areata (AA), is highly soluble across the physiological pH range at the therapeutic dose. As such, it is expected to dissolve rapidly in any in vitro dissolution conditions. However, in vitro dissolution data showed slower dissolution for 100-mg capsules, used for the clinical bioequivalence (BE) study, compared with proposed commercial 50-mg capsules. Hence, a biowaiver for the lower 50-mg strength using comparable multimedia dissolution based on the f2 similarity factor was not possible. The in vivo relevance of this observed in vitro dissolution profile was evaluated with a physiologically based pharmacokinetic (PBPK) model. This report describes the development, verification, and application of the ritlecitinib PBPK model to translate observed in vitro dissolution data to an in vivo PK profile for ritlecitinib capsule formulations. Virtual BE (VBE) trials were conducted using the Simcyp VBE module, including the model-predicted within-subject variability or intra-subject coefficient of variation (ICV). The results showed the predicted ICV was predicted to be smaller than observed clinical ICV, resulting in a more optimistic BE risk assessment. Additional VBE assessment was conducted by incorporating clinically observed ICV. The VBE trial results including clinically observed ICV demonstrated that proposed commercial 50-mg capsules vs clinical 100-mg capsules were bioequivalent, with > 90% probability of success. This study demonstrates a PBPK model-based biowaiver for a clinical BE study while introducing a novel method to integrate clinically observed ICV into VBE trials with PBPK models. Trial registration: NCT02309827, NCT02684760, NCT04004663, NCT04390776, NCT05040295, NCT05128058.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547656","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}
Pub Date : 2024-01-24DOI: 10.1208/s12248-024-00889-8
Mahmoud S Hanafy, Zhengrong Cui
Connexin is a transmembrane protein present on the cell membrane of most cell types. Connexins assemble into a hexameric hemichannel known as connexon that pairs with another hemichannel present on a neighboring cell to form gap junction that acts as a channel or pore for the transport of ions and small molecules between the cytoplasm of the two cells. Extracellular vesicles released from connexin-expressing cells could carry connexin hemichannels on their surface and couple with another connexin hemichannel on a distant recipient cell to allow the transfer of the intravesicular content directly into the cytoplasm. Connexin-containing vesicles can be potentially utilized for intracellular drug delivery. In this review, we introduced cell-derived, connexin-containing extracellular vesicles and cell-free connexin-containing liposomes, methods of preparing them, procedures to load cargos in them, factors regulating the connexin hemichannel activity, (potential) applications of connexin-containing vesicles in drug delivery, and finally the challenges and future directions in realizing the promises of this platform delivery system for (intracellular) drug delivery.
{"title":"Connexin-Containing Vesicles for Drug Delivery.","authors":"Mahmoud S Hanafy, Zhengrong Cui","doi":"10.1208/s12248-024-00889-8","DOIUrl":"10.1208/s12248-024-00889-8","url":null,"abstract":"<p><p>Connexin is a transmembrane protein present on the cell membrane of most cell types. Connexins assemble into a hexameric hemichannel known as connexon that pairs with another hemichannel present on a neighboring cell to form gap junction that acts as a channel or pore for the transport of ions and small molecules between the cytoplasm of the two cells. Extracellular vesicles released from connexin-expressing cells could carry connexin hemichannels on their surface and couple with another connexin hemichannel on a distant recipient cell to allow the transfer of the intravesicular content directly into the cytoplasm. Connexin-containing vesicles can be potentially utilized for intracellular drug delivery. In this review, we introduced cell-derived, connexin-containing extracellular vesicles and cell-free connexin-containing liposomes, methods of preparing them, procedures to load cargos in them, factors regulating the connexin hemichannel activity, (potential) applications of connexin-containing vesicles in drug delivery, and finally the challenges and future directions in realizing the promises of this platform delivery system for (intracellular) drug delivery.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547568","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}
This report summarizes the proceedings for Day 1 Session 3 of the 2-day public workshop entitled "Best Practices for Utilizing Modeling Approaches to Support Generic Product Development," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) in the year 2022. The aims of this workshop were to discuss how to modernize approaches for efficiently demonstrating bioequivalence (BE), to establish their role in modern paradigms of generic drug development, and to explore and develop best practices for the use of modeling and simulation approaches in regulatory submissions and approval. The theme of this session is mechanistic modeling approaches supporting BE assessments for oral drug products. As a summary, with more successful cases of PBPK absorption modeling being developed and shared, the general strategies/frameworks on using PBPK for oral products are being formed; this will help further evolvement of this area. In addition, the early communications between the industry and the agency through appropriate pathways (e.g., pre-abbreviated new drug applications (pre-ANDA) meetings) are encouraged, and this will speed up the successful development and utility of PBPK modeling for oral products.
{"title":"Using Mechanistic Modeling Approaches to Support Bioequivalence Assessments for Oral Products.","authors":"Fang Wu, Youssef Mousa, Rebeka Jereb, Hannah Batchelor, Sumon Chakraborty, Tycho Heimbach, Ethan Stier, Filippos Kesisoglou, Sivacharan Kollipara, Lei Zhang, Liang Zhao","doi":"10.1208/s12248-024-00886-x","DOIUrl":"10.1208/s12248-024-00886-x","url":null,"abstract":"<p><p>This report summarizes the proceedings for Day 1 Session 3 of the 2-day public workshop entitled \"Best Practices for Utilizing Modeling Approaches to Support Generic Product Development,\" a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) in the year 2022. The aims of this workshop were to discuss how to modernize approaches for efficiently demonstrating bioequivalence (BE), to establish their role in modern paradigms of generic drug development, and to explore and develop best practices for the use of modeling and simulation approaches in regulatory submissions and approval. The theme of this session is mechanistic modeling approaches supporting BE assessments for oral drug products. As a summary, with more successful cases of PBPK absorption modeling being developed and shared, the general strategies/frameworks on using PBPK for oral products are being formed; this will help further evolvement of this area. In addition, the early communications between the industry and the agency through appropriate pathways (e.g., pre-abbreviated new drug applications (pre-ANDA) meetings) are encouraged, and this will speed up the successful development and utility of PBPK modeling for oral products.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547653","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}
Pub Date : 2024-01-24DOI: 10.1208/s12248-024-00892-z
Veronica Liu, Kelly McGrath, Josh Albert, Andrew P Mayer, Maria Busz, Mary Birchler, Huaping Tang, Yong Jiang
Non-neutralizing anti-idiotype antibodies against a therapeutic monoclonal antibody (mAb) play a crucial role in the creation of total pharmacokinetic (PK) assays and total target engagement (TE) assays during both pre-clinical and clinical development. The development of these anti-idiotype antibodies is challenging. In this study, we utilized a hybridoma platform to produce a variety of anti-idiotype antibodies against GSK2857914, a humanized IgG1 anti-BCMA monoclonal antibody. The candidate clones were evaluated using surface plasmon resonance (SPR) and bio-layer interferometry (BLI) for binding affinity, binding profiling, matrix interference, and antibody pairing determination. We discovered that three anti-idiotype antibodies did not prevent BCMA from binding to GSK2857914. All three candidates demonstrated high binding affinities. One of the three exhibited minimal matrix inference and could pair with the other two candidates. Additionally, one of the three clones was biotinylated as a capture reagent for the total PK assay, and another was labeled with ruthenium as a detection reagent for both the total PK assay and total TE assay. The assay results clearly show that these reagents are genuine non-neutralizing anti-idiotypic antibodies and are suitable for total PK and TE assay development. Based on this and similar studies, we conclude that the hybridoma platform has a high success rate for generating non-neutralizing anti-idiotype antibodies. Our methodology for developing and characterizing non-neutralizing anti-idiotype antibodies to therapeutic antibodies can be generally applied to any antibody-based drug candidate's total PK and total TE assay development.
在临床前和临床开发过程中,针对治疗性单克隆抗体(mAb)的非中和抗同种异体抗体在创建总药代动力学(PK)测定和总靶参与(TE)测定中起着至关重要的作用。这些抗非典型抗体的开发具有挑战性。在本研究中,我们利用杂交瘤平台制备了多种针对 GSK2857914(一种人源化 IgG1 抗 BCMA 单克隆抗体)的抗原型抗体。我们利用表面等离子体共振(SPR)和生物层干涉仪(BLI)对候选克隆进行了评估,以确定其结合亲和力、结合谱、基质干扰和抗体配对。我们发现,三种抗异型抗体并不能阻止 BCMA 与 GSK2857914 结合。所有三种候选抗体都表现出很高的结合亲和力。其中一种抗体表现出最小的基质推断,可与其他两种候选抗体配对。此外,三个克隆中的一个被生物素化,作为总 PK 检测的捕获试剂,另一个被钌标记,作为总 PK 检测和总 TE 检测的检测试剂。检测结果清楚地表明,这些试剂是真正的非中和抗生物素抗体,适合于总 PK 和总 TE 检测的开发。根据这项研究和类似研究,我们得出结论:杂交瘤平台在生成非中和性抗原型抗体方面具有很高的成功率。我们开发和鉴定治疗性抗体的非中和抗原型抗体的方法可普遍应用于任何基于抗体的候选药物的总 PK 和总 TE 检测开发。
{"title":"Screening Non-neutralizing Anti-idiotype Antibodies Against a Drug Candidate for Total Pharmacokinetic and Target Engagement Assay.","authors":"Veronica Liu, Kelly McGrath, Josh Albert, Andrew P Mayer, Maria Busz, Mary Birchler, Huaping Tang, Yong Jiang","doi":"10.1208/s12248-024-00892-z","DOIUrl":"10.1208/s12248-024-00892-z","url":null,"abstract":"<p><p>Non-neutralizing anti-idiotype antibodies against a therapeutic monoclonal antibody (mAb) play a crucial role in the creation of total pharmacokinetic (PK) assays and total target engagement (TE) assays during both pre-clinical and clinical development. The development of these anti-idiotype antibodies is challenging. In this study, we utilized a hybridoma platform to produce a variety of anti-idiotype antibodies against GSK2857914, a humanized IgG1 anti-BCMA monoclonal antibody. The candidate clones were evaluated using surface plasmon resonance (SPR) and bio-layer interferometry (BLI) for binding affinity, binding profiling, matrix interference, and antibody pairing determination. We discovered that three anti-idiotype antibodies did not prevent BCMA from binding to GSK2857914. All three candidates demonstrated high binding affinities. One of the three exhibited minimal matrix inference and could pair with the other two candidates. Additionally, one of the three clones was biotinylated as a capture reagent for the total PK assay, and another was labeled with ruthenium as a detection reagent for both the total PK assay and total TE assay. The assay results clearly show that these reagents are genuine non-neutralizing anti-idiotypic antibodies and are suitable for total PK and TE assay development. Based on this and similar studies, we conclude that the hybridoma platform has a high success rate for generating non-neutralizing anti-idiotype antibodies. Our methodology for developing and characterizing non-neutralizing anti-idiotype antibodies to therapeutic antibodies can be generally applied to any antibody-based drug candidate's total PK and total TE assay development.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547647","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}
Pub Date : 2024-01-24DOI: 10.1208/s12248-024-00885-y
Yuqing Gong, Francis-Xavier Barretto, Yi Tsong, Youssef Mousa, Ke Ren, Darby Kozak, Meiyu Shen, Meng Hu, Liang Zhao
On October 27-28, 2022, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled "Best Practices for Utilizing Modeling Approaches to Support Generic Product Development." This report summarizes the presentations and panel discussions for a session titled "Development of Quantitative Comparative Approaches to Support Complex Generic Drug Development." This session featured speakers and panelists from both the generic industry and the FDA who described applications of advanced quantitative approaches for generic drug development and regulatory assessment within three main topics of interest: (1) API sameness assessment for complex generics, (2) particle size distribution assessment, and (3) dissolution profile similarity comparison. The key takeaways were that the analysis of complex data poses significant challenges to the application of conventional statistical bioequivalence methods, and there are various opportunities for using data analytics approaches for developing and applying suitable equivalence assessment method.
{"title":"Development of Quantitative Comparative Approaches to Support Complex Generic Drug Development.","authors":"Yuqing Gong, Francis-Xavier Barretto, Yi Tsong, Youssef Mousa, Ke Ren, Darby Kozak, Meiyu Shen, Meng Hu, Liang Zhao","doi":"10.1208/s12248-024-00885-y","DOIUrl":"10.1208/s12248-024-00885-y","url":null,"abstract":"<p><p>On October 27-28, 2022, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a virtual public workshop titled \"Best Practices for Utilizing Modeling Approaches to Support Generic Product Development.\" This report summarizes the presentations and panel discussions for a session titled \"Development of Quantitative Comparative Approaches to Support Complex Generic Drug Development.\" This session featured speakers and panelists from both the generic industry and the FDA who described applications of advanced quantitative approaches for generic drug development and regulatory assessment within three main topics of interest: (1) API sameness assessment for complex generics, (2) particle size distribution assessment, and (3) dissolution profile similarity comparison. The key takeaways were that the analysis of complex data poses significant challenges to the application of conventional statistical bioequivalence methods, and there are various opportunities for using data analytics approaches for developing and applying suitable equivalence assessment method.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139547569","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}
Pub Date : 2024-01-10DOI: 10.1208/s12248-023-00884-5
Eleftheria Tsakalozou, Lanyan Fang, Youwei Bi, Michiel van den Heuvel, Tausif Ahmed, Yu Chung Tsang, Robert Lionberger, Amin Rostami-Hodjegan, Liang Zhao
This report summarizes relevant insights and discussions from a 2022 FDA public workshop titled Best Practices for Utilizing Modeling Approaches to Support Generic Product Development which illustrated how model-integrated evidence has been used and can be leveraged further to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA. The workshop attendees discussed that model-integrated evidence (MIE) approaches for generics are being applied in the space of long-acting injectable (LAI) products to develop shorter and more cost-effective alternative study designs for LAI products. Modeling and simulation approaches are utilized to support virtual BE assessments at the site of action for locally acting drug products and to assess the impact of food on BE assessments for oral dosage forms. The factors contributing to the success of the model-informed drug development program under PDUFA VI were discussed. The generic drug industry shared that decisions on formulation candidate/formulation variant selection, on pilot in vivo bioavailability studies, and on alternative study designs for BE assessment are informed by modeling and simulation approaches. There was agreement that interactions between the regulatory agencies and the industry are desirable because they improve the industry's understanding of scientific and other regulatory considerations on implementing modeling and simulation approaches in drug development and regulatory submissions.
本报告总结了 FDA 于 2022 年举办的题为 "利用建模方法支持仿制药产品开发的最佳实践 "的公开研讨会的相关见解和讨论,该研讨会说明了在评估提交给 FDA 的仿制药申请过程中,如何使用并进一步利用模型整合证据为仿制药产品开发和监管决策提供信息。研讨会与会者讨论了仿制药的模型整合证据(MIE)方法在长效注射剂(LAI)产品领域的应用,以便为LAI产品开发时间更短、成本效益更高的替代研究设计。建模和模拟方法用于支持局部作用药物产品作用部位的虚拟 BE 评估,以及评估食物对口服剂型 BE 评估的影响。会议讨论了有助于 PDUFA VI 下的模型信息药物开发计划取得成功的因素。非专利药行业分享了关于候选制剂/制剂变体选择、试验性体内生物利用度研究以及生物利用度评估的替代研究设计的决策都是通过建模和模拟方法进行的。与会者一致认为,监管机构与业界之间的互动是可取的,因为这种互动可以提高业界对在药物开发和监管呈件中实施建模和模拟方法的科学和其他监管考虑因素的理解。
{"title":"Experience Learned and Perspectives on Using Model-Integrated Evidence in the Regulatory Context for Generic Drug Products-a Meeting Report.","authors":"Eleftheria Tsakalozou, Lanyan Fang, Youwei Bi, Michiel van den Heuvel, Tausif Ahmed, Yu Chung Tsang, Robert Lionberger, Amin Rostami-Hodjegan, Liang Zhao","doi":"10.1208/s12248-023-00884-5","DOIUrl":"10.1208/s12248-023-00884-5","url":null,"abstract":"<p><p>This report summarizes relevant insights and discussions from a 2022 FDA public workshop titled Best Practices for Utilizing Modeling Approaches to Support Generic Product Development which illustrated how model-integrated evidence has been used and can be leveraged further to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA. The workshop attendees discussed that model-integrated evidence (MIE) approaches for generics are being applied in the space of long-acting injectable (LAI) products to develop shorter and more cost-effective alternative study designs for LAI products. Modeling and simulation approaches are utilized to support virtual BE assessments at the site of action for locally acting drug products and to assess the impact of food on BE assessments for oral dosage forms. The factors contributing to the success of the model-informed drug development program under PDUFA VI were discussed. The generic drug industry shared that decisions on formulation candidate/formulation variant selection, on pilot in vivo bioavailability studies, and on alternative study designs for BE assessment are informed by modeling and simulation approaches. There was agreement that interactions between the regulatory agencies and the industry are desirable because they improve the industry's understanding of scientific and other regulatory considerations on implementing modeling and simulation approaches in drug development and regulatory submissions.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139418529","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}
Pub Date : 2024-01-05DOI: 10.1208/s12248-023-00882-7
Xiaomin Liang, Megan L Koleske, Jesse Yang, Yurong Lai
To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (Vss). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CLint,active, CLint,passive, and CLint,bile, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized Ki values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates.
{"title":"Building a Predictive PBPK Model for Human OATP Substrates: a Strategic Framework for Early Evaluation of Clinical Pharmacokinetic Variations Using Pitavastatin as an Example.","authors":"Xiaomin Liang, Megan L Koleske, Jesse Yang, Yurong Lai","doi":"10.1208/s12248-023-00882-7","DOIUrl":"10.1208/s12248-023-00882-7","url":null,"abstract":"<p><p>To select a drug candidate for clinical development, accurately and promptly predicting human pharmacokinetic (PK) profiles, assessing drug-drug interactions (DDIs), and anticipating potential PK variations in disease populations are crucial steps in drug discovery. The complexity of predicting human PK significantly increases when hepatic transporters are involved in drug clearance (CL) and volume of distribution (V<sub>ss</sub>). A strategic framework is developed here, utilizing pitavastatin as an example. The framework includes the construction of a monkey physiologically-based PK (PBPK) model, model calibration to obtain scaling factors (SF) of in vitro-in vivo extrapolation (IVIVE) for various clearance parameters, human model development and validation, and assessment of DDIs and PK variations in disease populations. Through incorporating in vitro human parameters and calibrated SFs from the monkey model of 3.45, 0.14, and 1.17 for CL<sub>int,active</sub>, CL<sub>int,passive</sub>, and CL<sub>int,bile</sub>, respectively, and together with the relative fraction transported by individual transporters obtained from in vitro studies and the optimized K<sub>i</sub> values for OATP inhibition, the model reasonably captured observed pitavastatin PK profiles, DDIs and PK variations in human subjects carrying genetic polymorphisms, i.e., AUC within 20%. Lastly, when applying the functional reduction based on measured OATP1B biomarkers, the model adequately predicted PK changes in the hepatic impairment population. The present study presents a strategic framework for early-stage drug development, enabling the prediction of PK profiles and assessment of PK variations in scenarios like DDIs, genetic polymorphism, and hepatic impairment-related disease states, specifically focusing on OATP substrates.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139106886","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}
Pub Date : 2024-01-04DOI: 10.1208/s12248-023-00879-2
Ross L Walenga, Andrew H Babiskin, Sid Bhoopathy, James F Clarke, Jan De Backer, Murray Ducharme, Marc Kelly, Maxime Le Merdy, Miyoung Yoon, Partha Roy
Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.
有证据表明,美国越来越多地使用建模和模拟来支持复杂非专利药品的产品开发和审批,其中包括使用机理建模和模型整合证据(MIE)。美国食品药品管理局 (FDA)、学术界和非专利药产品行业的成员在研讨会上进行了发言和小组讨论,本综述对模型再利用的潜力进行了总结。会上介绍了平台性能评估和 MIE 标准化等概念,分别为与机理模型和 MIE 相关的模型再利用提供了潜在框架。会议探讨了模型捕捉制剂和产品差异的能力,并针对药物产品类别(包括外用、口服吸入、眼科和长效注射药物产品)探讨了模型验证所面临的挑战。会议强调了 FDA 和仿制药行业之间的沟通需求,以继续促进建模和仿真的成熟,从而通过会议和 FDA 发布的指南支持复杂仿制药产品的开发和审批。研讨会简要介绍了复杂仿制药产品建模和仿真的现状,并提供了探讨在多种药物产品中使用此类模型的机会。
{"title":"Use of the Same Model or Modeling Strategy Across Multiple Submissions: Focus on Complex Drug Products.","authors":"Ross L Walenga, Andrew H Babiskin, Sid Bhoopathy, James F Clarke, Jan De Backer, Murray Ducharme, Marc Kelly, Maxime Le Merdy, Miyoung Yoon, Partha Roy","doi":"10.1208/s12248-023-00879-2","DOIUrl":"10.1208/s12248-023-00879-2","url":null,"abstract":"<p><p>Evidence shows that there is an increasing use of modeling and simulation to support product development and approval for complex generic drug products in the USA, which includes the use of mechanistic modeling and model-integrated evidence (MIE). The potential for model reuse was the subject of a workshop session summarized in this review, where the session included presentations and a panel discussion from members of the U.S. Food and Drug Administration (FDA), academia, and the generic drug product industry. Concepts such as platform performance assessment and MIE standardization were introduced to provide potential frameworks for model reuse related to mechanistic models and MIE, respectively. The capability of models to capture formulation and product differences was explored, and challenges with model validation were addressed for drug product classes including topical, orally inhaled, ophthalmic, and long-acting injectable drug products. An emphasis was placed on the need for communication between FDA and the generic drug industry to continue to foster maturation of modeling and simulation that may support complex generic drug product development and approval, via meetings and published guidance from FDA. The workshop session provided a snapshot of the current state of modeling and simulation for complex generic drug products and offered opportunities to explore the use of such models across multiple drug products.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139099070","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}
Pub Date : 2023-12-22DOI: 10.1208/s12248-023-00876-5
Satish G Jadhav, Ryan L Setten, Carlos Medina, Xian-Shu Cui, Steven F Dowdy
RNA therapeutics, including siRNAs, ASOs, and PMOs, have great potential to treat human disease. However, RNA therapeutics are too large, too charged, and/or too hydrophilic to cross the cellular membrane and are instead taken up into cells by endocytosis. Unfortunately, the vast majority of RNA therapeutics remain trapped inside endosomes (≥ 99%), which is the sole reason preventing their use to treat cancer, COVID, and other diseases. In contrast, enveloped viruses, such as influenza, also have an endosomal escape problem, but have evolved a highly efficient endosomal escape mechanism using trimeric hemagglutinin (HA) fusogenic protein. HA contains an outer hydrophilic domain (HA1) that masks an inner hydrophobic fusogenic/endosomal escape domain (HA2). Once inside endosomes, HA1 is shed to expose HA2 that, due to hydrophobicity, buries itself into the endosomal lipid bilayer, driving escape into the cytoplasm in a non-toxic fashion. To begin to address the RNA therapeutics rate-limiting endosomal escape problem, we report here a first step in the design and synthesis of a universal endosomal escape domain (uEED) that biomimics the enveloped virus escape mechanism. uEED contains an outer hydrophilic mask covalently attached to an inner hydrophobic escape domain. In plasma, uEED is inert and highly metabolically stable; however, when placed in endo/lysosomal conditions, uEED is activated by enzymatic removal of the hydrophilic mask, followed by self-immolation of the linker resulting in exposure of the hydrophobic indole ring domain in the absence of any hydrophilic tags. Thus, uEED is a synthetic biomimetic of the highly efficient viral endosomal escape mechanism.
{"title":"Design, Synthesis, and Biochemical Analysis of a Molecule Designed to Enhance Endosomal Escape.","authors":"Satish G Jadhav, Ryan L Setten, Carlos Medina, Xian-Shu Cui, Steven F Dowdy","doi":"10.1208/s12248-023-00876-5","DOIUrl":"10.1208/s12248-023-00876-5","url":null,"abstract":"<p><p>RNA therapeutics, including siRNAs, ASOs, and PMOs, have great potential to treat human disease. However, RNA therapeutics are too large, too charged, and/or too hydrophilic to cross the cellular membrane and are instead taken up into cells by endocytosis. Unfortunately, the vast majority of RNA therapeutics remain trapped inside endosomes (≥ 99%), which is the sole reason preventing their use to treat cancer, COVID, and other diseases. In contrast, enveloped viruses, such as influenza, also have an endosomal escape problem, but have evolved a highly efficient endosomal escape mechanism using trimeric hemagglutinin (HA) fusogenic protein. HA contains an outer hydrophilic domain (HA1) that masks an inner hydrophobic fusogenic/endosomal escape domain (HA2). Once inside endosomes, HA1 is shed to expose HA2 that, due to hydrophobicity, buries itself into the endosomal lipid bilayer, driving escape into the cytoplasm in a non-toxic fashion. To begin to address the RNA therapeutics rate-limiting endosomal escape problem, we report here a first step in the design and synthesis of a universal endosomal escape domain (uEED) that biomimics the enveloped virus escape mechanism. uEED contains an outer hydrophilic mask covalently attached to an inner hydrophobic escape domain. In plasma, uEED is inert and highly metabolically stable; however, when placed in endo/lysosomal conditions, uEED is activated by enzymatic removal of the hydrophilic mask, followed by self-immolation of the linker resulting in exposure of the hydrophobic indole ring domain in the absence of any hydrophilic tags. Thus, uEED is a synthetic biomimetic of the highly efficient viral endosomal escape mechanism.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138832776","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}
Pub Date : 2023-12-19DOI: 10.1208/s12248-023-00877-4
Michelle Stafford, Rachel Linck Dunn, Nirzari Gupta, Raghavi Kakarla, Douglas Kirkpatrick, Daniel Magparangalan, Diem Ngo, Connie Gryniewicz-Ruzicka, Anjanette Smith, Matthew Stark, Wei Ye, Huzeyfe Yilmaz, Jeffrey Woodruff, Mary Manibusan, Neil Stiber, Alex Viehmann
The FDA initiated a cross-sectional, statistically based sampling and testing study to characterize the quality of marketed alcohol-based hand sanitizer (ABHS) by evaluating the alcohol content and impurities present in ABHS products manufactured by establishments that registered with the FDA during March-April 2020. A stratified sampling design divided the population of manufacturers into independent groups based on each establishment's level of experience with FDA oversight and its geographic location. ABHS products were collected and analyzed by spatially offset Raman spectroscopy and gas chromatography with mass spectrometry (GC-MS). The GC-MS results for 310 products, from 196 newly registered domestic manufacturers, showed that 71.6% (± 5.7%) of these manufacturers had violative products. In 104 (33.5%) cases, the alcohol content did not meet label claim assay specifications but still fell within CDC efficacy ranges. Ethanol ABHS products failed more often overall (assay and impurities) (84.3%) and for impurities (84.3%), than isopropanol ABHS products (11.2% and 6.2%, respectively). Differences in test results across active ingredients were statistically significant. Ethanol ABHS products often (63.5% of cases) failed due to the presence of acetal or acetaldehyde, particularly in products with pH ≤ 6. Other impurities were also detected in several ABHS products, suggesting the use of low-grade alcohol in the manufacture of these products. Evidence was insufficient to conclude that having experience manufacturing FDA-regulated products, or lack thereof, influenced product-level violative results. This study highlights the importance of sourcing and testing active pharmaceutical ingredients to produce quality drug products.
{"title":"Quality of New Domestic Hand Sanitizer Drug Product Manufacturers During COVID-19.","authors":"Michelle Stafford, Rachel Linck Dunn, Nirzari Gupta, Raghavi Kakarla, Douglas Kirkpatrick, Daniel Magparangalan, Diem Ngo, Connie Gryniewicz-Ruzicka, Anjanette Smith, Matthew Stark, Wei Ye, Huzeyfe Yilmaz, Jeffrey Woodruff, Mary Manibusan, Neil Stiber, Alex Viehmann","doi":"10.1208/s12248-023-00877-4","DOIUrl":"10.1208/s12248-023-00877-4","url":null,"abstract":"<p><p>The FDA initiated a cross-sectional, statistically based sampling and testing study to characterize the quality of marketed alcohol-based hand sanitizer (ABHS) by evaluating the alcohol content and impurities present in ABHS products manufactured by establishments that registered with the FDA during March-April 2020. A stratified sampling design divided the population of manufacturers into independent groups based on each establishment's level of experience with FDA oversight and its geographic location. ABHS products were collected and analyzed by spatially offset Raman spectroscopy and gas chromatography with mass spectrometry (GC-MS). The GC-MS results for 310 products, from 196 newly registered domestic manufacturers, showed that 71.6% (± 5.7%) of these manufacturers had violative products. In 104 (33.5%) cases, the alcohol content did not meet label claim assay specifications but still fell within CDC efficacy ranges. Ethanol ABHS products failed more often overall (assay and impurities) (84.3%) and for impurities (84.3%), than isopropanol ABHS products (11.2% and 6.2%, respectively). Differences in test results across active ingredients were statistically significant. Ethanol ABHS products often (63.5% of cases) failed due to the presence of acetal or acetaldehyde, particularly in products with pH ≤ 6. Other impurities were also detected in several ABHS products, suggesting the use of low-grade alcohol in the manufacture of these products. Evidence was insufficient to conclude that having experience manufacturing FDA-regulated products, or lack thereof, influenced product-level violative results. This study highlights the importance of sourcing and testing active pharmaceutical ingredients to produce quality drug products.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138813125","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}