AAPS Journal最新文献

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.

IF 5 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":"https://doi.org/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":5.0,"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.

IF 5 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":"https://doi.org/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":5.0,"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?

IF 5 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":"https://doi.org/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":5.0,"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

Nomlabofusp, a Fusion Protein of Human Frataxin and a Cell Penetrant Peptide, Delivers Mature and Functional Frataxin into Mitochondria.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-26 DOI: 10.1208/s12248-025-01054-5

Matthew G Baile, John Jones, Natasha Sahr, Gopi Shankar

{"title":"Nomlabofusp, a Fusion Protein of Human Frataxin and a Cell Penetrant Peptide, Delivers Mature and Functional Frataxin into Mitochondria.","authors":"Matthew G Baile, John Jones, Natasha Sahr, Gopi Shankar","doi":"10.1208/s12248-025-01054-5","DOIUrl":"https://doi.org/10.1208/s12248-025-01054-5","url":null,"abstract":"Friedreich's ataxia is a rare, progressive, genetic disorder, the root cause of which is a significant deficiency in the mitochondrial protein frataxin. Frataxin is ubiquitously expressed, but its deficiency results in a variety of debilitating symptoms, with disease severity, rate of progression and age of onset inversely correlating with tissue frataxin levels. Nomlabofusp is a novel cell penetrant peptide based recombinant fusion protein designed to enter cells and deliver human FXN into the mitochondria. Using immunofluorescence staining and western blot we show that frataxin delivered by nomlabofusp is detected in the mitochondria of H9c2 and SH-SY5Y cells. Also in these cells, and in C2C12 and HEK293 cells, we demonstrate the presence of mature frataxin after nomlabofusp exposure. Finally, using buccal swab tissue samples taken from study subjects in a Phase 1 clinical trial who received nomlabofusp, we show increases in mature frataxin levels along with marked changes in gene expression post-administration suggesting intracellular pharmacodynamic activity. Together, these results demonstrate that nomlabofusp enters the cell and localizes to the mitochondria, releasing mature frataxin that appears to be biologically active and support the use of nomlabofusp as a potential treatment for patients with Friedreich's ataxia.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"68"},"PeriodicalIF":5.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143722584","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

Lipid Nanoparticles for mRNA Delivery in Cancer Immunotherapy.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-18 DOI: 10.1208/s12248-025-01051-8

Yasir Alshehry, Xiang Liu, Wenhua Li, Qiyan Wang, Janét Cole, Guizhi Zhu

{"title":"Lipid Nanoparticles for mRNA Delivery in Cancer Immunotherapy.","authors":"Yasir Alshehry, Xiang Liu, Wenhua Li, Qiyan Wang, Janét Cole, Guizhi Zhu","doi":"10.1208/s12248-025-01051-8","DOIUrl":"https://doi.org/10.1208/s12248-025-01051-8","url":null,"abstract":"Cancer immunotherapy is poised to be one of the major modalities for cancer treatment. Messenger RNA (mRNA) has emerged as a versatile and promising platform for the development of effective cancer immunotherapy. Delivery systems for mRNA therapeutics are pivotal for their optimal therapeutic efficacy and minimal adverse side effects. Lipid nanoparticles (LNPs) have demonstrated a great success for mRNA delivery. Numerous LNPs have been designed and optimized to enhance mRNA stability, facilitate transfection, and ensure intracellular delivery for subsequent processing. Nevertheless, challenges remain to, for example, improve the efficiency of endosomal escape and passive targeting. This review highlights key advancements in the development of mRNA LNPs for cancer immunotherapy. We delve into the design of LNPs for mRNA delivery, encompassing the chemical structures, characterization, and structure-activity relationships (SAR) of LNP compositions. We discuss the key factors influencing the transfection efficiency, passive targeting, and tropism of mRNA-loaded LNPs. We also review the preclinical and clinical applications of mRNA LNPs in cancer immunotherapy. This review can enhance our understanding in the design and application of LNPs for mRNA delivery in cancer immunotherapy.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 3","pages":"66"},"PeriodicalIF":5.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659693","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 5 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":5.0,"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.

IF 5 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":5.0,"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

A Facile Way to Enhance the Therapeutic Efficacy of Hydrophobic Drugs via Amorphous Solid Dispersions.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01046-5

Ning Tao, Zihui Yan, Xin Wang, Yuhui Wang, Li Ji, Lin Qiu, Pengfei Cui, Jianhao Wang

{"title":"A Facile Way to Enhance the Therapeutic Efficacy of Hydrophobic Drugs via Amorphous Solid Dispersions.","authors":"Ning Tao, Zihui Yan, Xin Wang, Yuhui Wang, Li Ji, Lin Qiu, Pengfei Cui, Jianhao Wang","doi":"10.1208/s12248-025-01046-5","DOIUrl":"10.1208/s12248-025-01046-5","url":null,"abstract":"Approximately 40% of marketed drugs and 75% of invested drugs in the pharmaceutical field are poorly soluble hydrophobic drugs with minimal solubility in water which make them difficult to be absorbed by the body and significantly limiting their applications. Among chemotherapeutic agents, numerous antitumor drugs such as platinum compounds, camptothecin, paclitaxel and others are also restricted in processing and preparation due to solubility issues. Therefore, improving the solubility and enhancing the therapeutic efficacy of drugs have always been significant research topics in current pharmaceutics. Herein, we propose an amorphous solid dispersion system PRTA-DOX, involving the protein drug protamine sulphate and hydrophobic doxorubicin as the model hydrophobic drug. In previous studies, ASD (Amorphous Solid Dispersion) has been demonstrated to enhance the solubility of hydrophobic drugs and result in a storage-stable system. Protamine sulphate as a marketed drug is reliable in safety and conveniently obtained. Doxorubicin, an antitumor drug with a broad antitumor spectrum, is commonly used in the treatment of breast cancer. Typically, doxorubicin is prepared in the form of a hydrochloride salt to increase its solubility. However, the utilization of doxorubicin hydrochloride is reduced due to drug resistance issues in biological cells and it exhibits higher toxicity to the body. In this system, protamine sulphate which is rich in arginine guanidino hydrophobic planes physically mixes with doxorubicin which is a hydrophobic molecule with aromatic rings and they are connected through weak interactions: π-π conjugation. They constitute an amorphous solid dispersion system which increases the solubility of hydrophobic doxorubicin, enhances cellular uptake, mitigate some cellular drug resistance and thereby achieves the purpose of improving therapeutic efficacy.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"63"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634810","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.

IF 5 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":5.0,"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

The Role of Enhanced Analytical Procedure Development in Facilitating Post-Approval Changes Via Established Conditions.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-14 DOI: 10.1208/s12248-025-01037-6

Douglas Kirkpatrick, Nirzari Gupta, Ramesh Gopalaswamy, Rohit Kolhatkar, Morgan Hudson-Davis, David Keire

{"title":"The Role of Enhanced Analytical Procedure Development in Facilitating Post-Approval Changes Via Established Conditions.","authors":"Douglas Kirkpatrick, Nirzari Gupta, Ramesh Gopalaswamy, Rohit Kolhatkar, Morgan Hudson-Davis, David Keire","doi":"10.1208/s12248-025-01037-6","DOIUrl":"10.1208/s12248-025-01037-6","url":null,"abstract":"Enabling greater flexibility for lifecycle management of analytical procedures is one of the primary features of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q12 Lifecycle Management guideline. Rather than rely on a comparatively slower and burdensome post-approval change supplement process, ICH Q12 created a new pathway to facilitate changes to chemistry, manufacturing, and controls. The new framework utilized key concepts such as established conditions (ECs), post-approval change management protocols, and the product lifecycle management document to allow modifications to analytical procedures based upon pre-approved conditions. Shortly after the publication of ICH Q12, the ICH Q14 Analytical Procedure Development guideline provided further guidance on how knowledge gained during analytical procedure development could be incorporated with the ICH Q12 framework to support scientifically sound and risk-based post-approval changes. However, to date, the full potential of ICH Q12 and Q14 remains unrealized, likely due to uncertainty over how analytical procedure development data can be effectively utilized to gain regulatory flexibility for post-approval changes. In this case study, an example of determining, proposing, and justifying analytical procedure ECs, reporting categories, and identification of elements not considered ECs is presented. In addition, how such information could be presented in a regulatory submission is described. Importantly, this case study serves as an example of the application of ICH Q12 and Q14 principles for analytical procedures, but it is not intended to serve as official guidance nor to define the full scope of information required in a regulatory submission.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"61"},"PeriodicalIF":5.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634732","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