AAPS Journal最新文献_第6页

A Tool to Eliminate IgM Immunoassay Interference. 消除IgM免疫测定干扰的工具。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-04-11 DOI: 10.1208/s12248-025-01067-0

Alexander Pöhler, Uwe Wessels, Roland F Staack, Maria Nordgren, Rolf Lood, Kay-Gunnar Stubenrauch

引用次数: 0

Survey and Establishment of Points to Consider for Application of Analytical Techniques to Evaluate Protein Aggregates and Insoluble Particles in Biopharmaceuticals: Experiences in Japan Biopharmaceutical Consortium. 生物制药中蛋白质聚集体和不溶性颗粒分析技术应用的调查和考虑点的建立：日本生物制药协会的经验。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-04-03 DOI: 10.1208/s12248-025-01056-3

Hiroko Shibata, Satoshi Saitoh, Masato Kiyoshi, Yu Hayashi, Kazue Inaba, Shinji Katsura, Maho Sakurai, Yuka Komine, Shinji Okabe, Naomi Ohbayashi, Youko Kita, Hirokazu Kito, Masako Nakano, Kana Miyamoto, Akira Maruyama, Yuya Miyahara, Masanori Noda, Yasuyo Nozawa, Kazutaka Shimbo, Shota Kojima, Shinya Honda, Tetsuo Torisu, Susumu Uchiyama, Akiko Ishii-Watabe

{"title":"Survey and Establishment of Points to Consider for Application of Analytical Techniques to Evaluate Protein Aggregates and Insoluble Particles in Biopharmaceuticals: Experiences in Japan Biopharmaceutical Consortium.","authors":"Hiroko Shibata, Satoshi Saitoh, Masato Kiyoshi, Yu Hayashi, Kazue Inaba, Shinji Katsura, Maho Sakurai, Yuka Komine, Shinji Okabe, Naomi Ohbayashi, Youko Kita, Hirokazu Kito, Masako Nakano, Kana Miyamoto, Akira Maruyama, Yuya Miyahara, Masanori Noda, Yasuyo Nozawa, Kazutaka Shimbo, Shota Kojima, Shinya Honda, Tetsuo Torisu, Susumu Uchiyama, Akiko Ishii-Watabe","doi":"10.1208/s12248-025-01056-3","DOIUrl":"10.1208/s12248-025-01056-3","url":null,"abstract":"Protein aggregates and insoluble particles in biopharmaceutical products are impurities that can elicit immunogenicity. The protein aggregates and insoluble particles form during manufacturing and storage, and should be characterized to optimize the manufacturing process and establish a control strategy. Several issues regarding the evaluation and control of these particles have been concerned, and collaborative studies have been conducted in the Japan Biopharmaceutical Consortium to address them. However, there is still no consensus for utilizing analytical techniques in parallel to establish a control strategy for such protein aggregates and insoluble particles, which range in size from a few nanometers to several hundred micrometers. Therefore, in this study, we surveyed Japanese biopharmaceutical companies through a questionnaire including questions regarding analytical techniques used to establish control strategies for protein aggregates and insoluble particles at various development phases. To summary the survey results, we found that size exclusion chromatography, light obscuration, and visual inspection are consistently used from early development and formulation optimization stage to commercial manufacturing. Apart from the light obscuration method, flow imaging (FI) was the most commonly used technique for subvisible particle characterization; thus, the use of FI to establish a control strategy was documented. The recommendation for establishing a control strategy for protein aggregates and insoluble particles based on life-cycle of drug development are summarized.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"75"},"PeriodicalIF":3.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143781888","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

Virtual Bioequivalence Assessment of Tofacitinib Once Daily Modified Release Dosage Form in Pediatric Subjects. 托法替尼每日一次修正释放剂型在儿科受试者中的虚拟生物等效性评估

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-04-01 DOI: 10.1208/s12248-025-01057-2

Kazuko Sagawa, Vivek Purohit, Vu Le, Hao-Jui Hsu, Martin E Dowty, Susanna Tse, Cheng Chang

{"title":"Virtual Bioequivalence Assessment of Tofacitinib Once Daily Modified Release Dosage Form in Pediatric Subjects.","authors":"Kazuko Sagawa, Vivek Purohit, Vu Le, Hao-Jui Hsu, Martin E Dowty, Susanna Tse, Cheng Chang","doi":"10.1208/s12248-025-01057-2","DOIUrl":"10.1208/s12248-025-01057-2","url":null,"abstract":"Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate release (IR) tablets, modified release (MR) tablets and IR solution. A once daily MR microsphere formulation was developed for pediatric patients. Previously, bioequivalence (BE) between the 10 mg once daily (QD) MR microsphere formulation and 5 mg twice daily (BID) IR solution has been established with PBPK virtual BE trials (VBE) in place of a clinical BE trial in healthy adult population. In this research, the PBPK model based VBE approach was extended to pediatric population. Pediatric PBPK model verification was conducted by first examining predicted vs observed demographic information such as body weight (BWT) and glomerular filtration rate (GFR). After confirming the alignment in demographic background between clinical study participants vs virtual pediatric subjects, multiple ontogeny profiles for CYP3A4 and CYP2C19 were examined. The established model predicted AUC and Cmax within 1.5-fold of observed values for multiple trials, age groups and formulations. Lastly, VBE trials in pediatric subjects were conducted with PBPK model generated pharmacokinetic (PK) parameter values with clinically observed intra-subject coefficient of variation (ICV) in adults. Since ICV in pediatric population is unknown, the sensitivity around ICV was also evaluated to assess the BE risk between IR solution and MR microsphere formulation in pediatric population. The results demonstrated that the IR oral solution BID and MR microsphere formulation QD are BE in pediatric population.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"71"},"PeriodicalIF":3.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765814","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

Effect of FcRn Binding on Monoclonal Antibody Disposition in the Brain. FcRn 结合对脑部单克隆抗体处置的影响

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-04-01 DOI: 10.1208/s12248-025-01060-7

Hsien Wei Huang, Shengjia Wu, Shufang Liu, Dhaval K Shah

{"title":"Effect of FcRn Binding on Monoclonal Antibody Disposition in the Brain.","authors":"Hsien Wei Huang, Shengjia Wu, Shufang Liu, Dhaval K Shah","doi":"10.1208/s12248-025-01060-7","DOIUrl":"10.1208/s12248-025-01060-7","url":null,"abstract":"This study investigates the role of FcRn in brain disposition of monoclonal antibodies. Human FcRn (hFcRn) expressing mice and different FcRn binding variants of a non-target binding antibody trastuzumab (WT) were used for the investigation. The FcRn binding mutations were: YTE, YPY, YQAY, and IHH. YQAY and YPY mutants have enhanced FcRn binding at both neutral and acidic pH (7+/6+). YTE mutant has enhanced FcRn binding at only acidic pH (7-/6+), and IHH mutant has no FcRn binding (7-/6-). The pharmacokinetics (PK) of these mutants in plasma, brain interstitial fluid (ISF), and brain homogenate were measured following intravenous administration. The area under the concentration-time curve (AUC) for all PK profiles and ratios of brain and plasma AUCs were calculated for comparison. Results showed that WT antibody had brain:plasma AUC ratio of 0.70% and ISF:plasma AUC ratio of 0.59%. Among all mutants, YPY exhibited the highest AUC ratio for brain (3.86%) and ISF (3.49%). YQAY had relatively high AUC ratios of 1.49% in the brain and 0.81% in ISF. YTE showed a similar AUC ratio in the brain (0.60%) and ISF (0.62%) compared to WT, while IHH exhibited similar AUC ratio in the brain (0.52%) but higher AUC ratio in ISF (2.48%). The results suggest that binding to FcRn at neutral and acidic pH facilitates transcytosis of antibody into the brain. Just increasing the binding to FcRn at acidic pH does not impact the disposition of antibody in the brain. Complete removal of FcRn binding might lead to prolonged retention of antibody in ISF. Together, these data demonstrate that FcRn significantly affects brain disposition of antibody, and engineering of Fc domain to alter the binding of antibody to FcRn may be exploited to achieve better exposure of antibodies in the brain.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"72"},"PeriodicalIF":3.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765810","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

Leveraging Buprenorphine and Halofantrine as Tool Molecules to Develop a Novel Semi-Physiologically based Pharmacokinetic Model Accounting for Gastro-Intestinal Lymphatic Absorption and Enabling Cross-Species Translation. 利用丁丙诺啡和卤啡碱作为工具分子，开发一种新的半生理的药代动力学模型，用于胃肠道淋巴吸收和跨物种翻译。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-03-26 DOI: 10.1208/s12248-025-01053-6

Xun Tao, Shraddha Sadekar, Douglas Leipold, Gregory Z Ferl, Eric Gary Stefanich, Amrita V Kamath

{"title":"Leveraging Buprenorphine and Halofantrine as Tool Molecules to Develop a Novel Semi-Physiologically based Pharmacokinetic Model Accounting for Gastro-Intestinal Lymphatic Absorption and Enabling Cross-Species Translation.","authors":"Xun Tao, Shraddha Sadekar, Douglas Leipold, Gregory Z Ferl, Eric Gary Stefanich, Amrita V Kamath","doi":"10.1208/s12248-025-01053-6","DOIUrl":"10.1208/s12248-025-01053-6","url":null,"abstract":"Intestinal lymphatic absorption is a crucial alternative to portal uptake for highly lipophilic drugs (log P > 5), bypassing first-pass metabolism. Unlike the portal-hepatic pathway, lymphatic uptake is rarely considered in physiologically based pharmacokinetic (PBPK) models for oral delivery. Our study developed an innovative Gastro-Intestinal (GI)-lymph-PBPK model that includes GI absorption, chylomicron extraction (CE) to rescue drugs from gut extraction (GE), and bypass hepatic extraction (HE). This model introduces CE clearance (CLCE), competing with GE clearance, to estimate the drug proportion subjected to CE versus GE. PBPK analysis for Buprenorphine revealed extensive GE (0.87) and HE (0.58), explaining the low bioavailability (F%) of 5.28% in rats. Buprenorphine prodrugs activated CLCE, leading to CE ranging from 0.37 to 0.79, boosting oral F% to 39.9%-79.9% in rats. To translate from rat to human, our model considered species differences in GI transit time, formulation, food-dependent drug dissolution, allometric scaling in CLCE, and between species variability in gut metabolism. Using Halofantrine, we established an allometric scaling factor for CLCE at 1.1. Accounting for six times faster human gut metabolism, our model predicted an extremely low oral F% of 0.382% for Buprenorphine in humans. Incorporating the allometric scaled CLCE competing with the extensive gut metabolism, our model predicted Buprenorphine prodrugs remains effective in enabling substantial absorption boosts, with oral F% estimates ranging from 15.8% to 56.7% in humans. This study highlights the significant potential of GI-lymph-PBPK modeling in predicting intestinal lymphatic absorption and facilitating cross-species translation.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"67"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722583","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

Establishing a Platform Method for Physical Appearance Assessment of New Parenteral Pharmaceuticals. 新型注射用药物外观评价平台方法的建立。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-03-26 DOI: 10.1208/s12248-025-01049-2

Ying Wan, Walter Wasylaschuk, Joseph Straub, Wei Xu, Nicole Lepo, Patricia M Egan, Jillian Acevedo-Skrip, Elizabeth Thoryk, Megan Mackey

{"title":"Establishing a Platform Method for Physical Appearance Assessment of New Parenteral Pharmaceuticals.","authors":"Ying Wan, Walter Wasylaschuk, Joseph Straub, Wei Xu, Nicole Lepo, Patricia M Egan, Jillian Acevedo-Skrip, Elizabeth Thoryk, Megan Mackey","doi":"10.1208/s12248-025-01049-2","DOIUrl":"10.1208/s12248-025-01049-2","url":null,"abstract":"Physical appearance (PA) is an attribute indicating the quality of parenteral pharmaceuticals. It is routinely evaluated during release and stability testing and included in regulatory filings. PA assessment of liquids involves three tests: visible particulates, clarity, and color. For each test, compendial general method chapters are available requiring minimal modification. This allows for a platform PA method approach, streamlining method readiness for new test articles. However, selecting the appropriate method is challenging, as no method suits all test articles, and pharmacopeias do not specify suitable condition(s) for each method. Improper method selection can lead to inappropriate specification setting and unreliable results. The need for guidance is especially urgent for vaccines, which often exhibit a wide range of PA attributes due to complex delivery systems and adjuvants that boost immunogenicity. This manuscript addresses this challenge by explaining method suitability and presenting a decision table for PA method selection based on the appearance properties of pharmaceuticals. A case study involving a yellow-turbid vaccine adjuvant is presented to demonstrate the practical application of the decision table. When color and turbidity make visual comparison to reference liquids difficult, instrumental clarity and visual qualitative methods are suitable options. The manuscript provides valuable insights on PA method selection and setting specifications for new parenteral pharmaceuticals. Furthermore, the decision table enables platform methods for test articles sharing similar appearance properties, eliminating the need for individual methods, reducing document preparation time for method and verification protocol, and enhancing the consistency and efficiency of GMP testing for PA.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"69"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722582","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

The Drug Titration Paradox in the Presence of Intra-Individual Variation: Can we Estimate the True Concentration-Effect Relationship? 存在个体内变异的药物滴定悖论：我们能估计真正的浓度-效应关系吗？

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-03-26 DOI: 10.1208/s12248-025-01055-4

Sebastiaan C Goulooze, Elke H J Krekels, Catherijne A J Knibbe, Martijn van Noort

{"title":"The Drug Titration Paradox in the Presence of Intra-Individual Variation: Can we Estimate the True Concentration-Effect Relationship?","authors":"Sebastiaan C Goulooze, Elke H J Krekels, Catherijne A J Knibbe, Martijn van Noort","doi":"10.1208/s12248-025-01055-4","DOIUrl":"10.1208/s12248-025-01055-4","url":null,"abstract":"The drug titration paradox arises when higher drug concentrations are paradoxically associated with poorer efficacy outcomes, due to the titration of an individual's drug dose to achieve a desired effect. In cases with substantial intraindividual variability of the disease state, the drug titration paradox can also occur on the individual level (resulting in a higher dose when the individual has a worse disease state) and it has been suggested that it may not be possible to estimate the true exposure-response (ER) relationship in such situations. We simulated a titration study with strong intra-individual variability of disease state (causing the drug titration paradox at the individual level) and investigated the performance of four PKPD modelling methods in obtaining an unbiased estimate of the ER relationship. Strong bias in the estimated ER relationship was observed with two commonly used modelling methods: the model which only estimated inter-individual variability (IIV) and the model that included IIV and inter-occasion variability (IOV) on disease severity. In contrast, inclusion of stochastic differential equations (SDE) or accounting for the autocorrelation of the residual error between observations did yield successful estimation of the ER relationship without bias. The success of these methods can be understood from the principles of causal inference: confounding is avoided by controlling for the previous observations which drive the drug titration. Our results underline the importance of adequately characterizing intra-individual variability to avoid bias in PKPD modelling, especially for clinical areas where titration designs are common, such as analgesia.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"70"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722585","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

Enhancing Efavirenz Bioavailability Via Polymer-Based Buccal Administration: Optimization and Characterization of Nanocrystal-Loaded Dissolving Microneedle Delivery Systems. 通过基于聚合物的口腔给药提高依非韦伦的生物利用度：纳米晶体负载溶解微针给药系统的优化与表征。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01047-4

Khairiyah Khairiyah, Muh Bisfain Asaf, Nur Afni Annisa Achmad, Rachmatya W Tuna, Irfan Kurniawan, Anugerah Yaumil Ramadhani Aziz, Maria Mir, Juan Domínguez-Robles, Mónica Millán-Jiménez, Ilyas Essadki-Aittaji, Ana B Cobo-González, Muhammad Aswad, Latifah Rahman, Marianti A Manggau, Aliyah Aliyah, Eyman Mohamed Eltayib, Andi Dian Permana

{"title":"Enhancing Efavirenz Bioavailability Via Polymer-Based Buccal Administration: Optimization and Characterization of Nanocrystal-Loaded Dissolving Microneedle Delivery Systems.","authors":"Khairiyah Khairiyah, Muh Bisfain Asaf, Nur Afni Annisa Achmad, Rachmatya W Tuna, Irfan Kurniawan, Anugerah Yaumil Ramadhani Aziz, Maria Mir, Juan Domínguez-Robles, Mónica Millán-Jiménez, Ilyas Essadki-Aittaji, Ana B Cobo-González, Muhammad Aswad, Latifah Rahman, Marianti A Manggau, Aliyah Aliyah, Eyman Mohamed Eltayib, Andi Dian Permana","doi":"10.1208/s12248-025-01047-4","DOIUrl":"10.1208/s12248-025-01047-4","url":null,"abstract":"Efavirenz (EFV) is a widely utilized antiretroviral agent in HIV/AIDS therapy that is known for its efficacy but is also associated with various side effects. For improved drug delivery, buccal administration offers a promising alternative by allowing the drug to enter the systemic circulation directly through the oral mucosa, bypassing the gastrointestinal tract and first-pass metabolism. This study explored the interaction between EFV and different polymers through molecular docking, revealing a strong binding affinity to Pluronic®F-127 (-2.1 kcal/mol). EFV was formulated into nanocrystals (EFV-NC) using Pluronic®F-127 as the stabilizer, characterized by an average particle size of 174.83 ± 15.21 nm, a narrow size distribution (PDI of 0.15 ± 0.013), and good stability (zeta potential of -22.27 ± 1.12 mV). FTIR and XRD analyses revealed polymer-induced alterations in the crystalline structure of the EFV. The EFV-NC formulation enhanced the solubility (up to 400 µg/mL) and achieved 89.58 ± 4.01% drug release within 24 h, following the Higuchi model kinetics for controlled release. EFV-NC-loaded dissolving microneedles (EFV-NC-DMN) demonstrated robust mechanical properties, efficient tissue penetration, and minimal moisture absorption. Ex vivo and in vivo studies revealed that compared with oral EFV, EFV-NC-DMN provided a relative bioavailability of 137.40%, with higher plasma concentrations and prolonged release, highlighting its potential for superior HIV/AIDS management via buccal administration and improved therapeutic outcomes.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"64"},"PeriodicalIF":3.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634813","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

Therapeutic Drug Monitoring of Biologics: Current Practice, Challenges and Opportunities - a Workshop Report. 生物制剂治疗药物监测：当前实践，挑战和机遇-研讨会报告。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01050-9

Sophie Shubow, Michele Gunsior, Amy Rosenberg, Yow-Ming Wang, Tara Altepeter, Daphne Guinn, Mohsen Rajabiabhari, Joseph Kotarek, Diane R Mould, Honghui Zhou, Adam S Cheifetz, Sandra Garces, Rachel Chevalier, Sean Gavan, Mark R Trusheim, Theo Rispens, Kurtis Bray, Michael A Partridge

{"title":"Therapeutic Drug Monitoring of Biologics: Current Practice, Challenges and Opportunities - a Workshop Report.","authors":"Sophie Shubow, Michele Gunsior, Amy Rosenberg, Yow-Ming Wang, Tara Altepeter, Daphne Guinn, Mohsen Rajabiabhari, Joseph Kotarek, Diane R Mould, Honghui Zhou, Adam S Cheifetz, Sandra Garces, Rachel Chevalier, Sean Gavan, Mark R Trusheim, Theo Rispens, Kurtis Bray, Michael A Partridge","doi":"10.1208/s12248-025-01050-9","DOIUrl":"10.1208/s12248-025-01050-9","url":null,"abstract":"Therapeutic drug monitoring (TDM) for dose modification of biologics has the potential to improve patient outcomes. The US Food and Drug Administration (FDA) and the American Association of Pharmaceutical Scientists (AAPS) hosted the first US-based public workshop on TDM of biologics with contributions from a broad array of interested parties including healthcare providers, clinical pharmacologists, test developers, bioanalysis and immunogenicity scientists, health economics and outcomes research (HEOR) experts and regulators. The key insight was that despite a body of evidence to support TDM in certain therapeutic areas, there remain substantial challenges to widespread clinical implementation. There is a lack of consensus regarding the integration of TDM in clinical guidelines, and a lack of consensus on the cost-effectiveness of TDM; both factors contribute to the difficulty that healthcare providers face in obtaining reimbursement for TDM (both coverage of testing itself, and coverage of potential dosing modifications). The HEOR experts outlined alternative routes to obtaining reimbursement and suggested advocating for changes in coverage policies to promote TDM use in the clinic. Reaching alignment across policy makers, patients and advocacy groups, payers, and healthcare providers, on specific treatment settings where TDM will be clearly beneficial, was identified as an important step to advancing TDM implementation for the benefit of patients.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"62"},"PeriodicalIF":3.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634734","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

Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Using Human and Rat Liver Fractions. 用人和大鼠肝脏组织表征酮酯及其代谢产物的肝脏代谢途径。

IF 3.7 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01044-7

N Panse, P M Gerk

{"title":"Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Using Human and Rat Liver Fractions.","authors":"N Panse, P M Gerk","doi":"10.1208/s12248-025-01044-7","DOIUrl":"10.1208/s12248-025-01044-7","url":null,"abstract":"Although exogenous ketogenic dietary supplements continue to grow in popularity, their pharmacokinetic properties have not been adequately studied, thus hindering their optimal use and benefits. Here, the metabolic characteristics of one such supplement (Veech ketone mono-ester ((R)-3-hydroxybutyl(R)-3-hydroxybutyrate) (KE)) were studied along with its metabolite- (R)-1,3-butanediol ((R)-1,3-BD), both of which are precursors and undergo metabolic conversion to (R)-beta-hydroxybutyrate (BHB). The metabolism of aldol (an aldehyde intermediate between the conversion of (R)-1,3-BD to (R)-BHB was also evaluated, as it is frequently not considered in any scientific discussion. The metabolic parameters were calculated using pooled human (mixed gender) and pooled rat (male and female) liver fractions. These were later used to estimate the hepatic extraction ratio and the hepatic clearance of these molecules. KE showed rapid and non-saturable clearance in human and rat liver fractions, even at concentrations as high as 15,000 μM. In the case of (R)-1,3-BD, there was saturable metabolism in rats and humans with Km and Vmax values of 8,000 μM and 27.1 nmol/min/mg of protein (humans), 19,300 μM and 113.5 nmol/min/mg of protein (male rats), and 11,910 μM and 75.8 nmol/min/mg of protein (female rats). The metabolism of aldol showed rapid and non-saturable hepatic clearance in human liver fractions.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"65"},"PeriodicalIF":3.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634812","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