AAPS Journal最新文献_第2页

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

PBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic Variability.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-12 DOI: 10.1208/s12248-025-01042-9

Xuexin Ye, Feiyan Liu, Zeneng Cheng, Feifan Xie

{"title":"PBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic Variability.","authors":"Xuexin Ye, Feiyan Liu, Zeneng Cheng, Feifan Xie","doi":"10.1208/s12248-025-01042-9","DOIUrl":"10.1208/s12248-025-01042-9","url":null,"abstract":"Nevirapine, primarily metabolized by CYP2B6 and CYP3A4, exhibits enzyme auto-induction and significant ethnic variability in its pharmacokinetics (PK). These complexities are further exacerbated in HIV-TB co-infected patients, where nevirapine is often co-administered with rifampicin/isoniazid-based anti-tuberculosis (TB) therapies. Rifampicin, a strong CYP3A4 inducer and moderate CYP2B6 inducer, and isoniazid, a moderate CYP3A4 inhibitor, create intricate drug interactions that challenge optimal nevirapine dosing strategies, leading to clinical uncertainty and debate. We developed a physiologically based pharmacokinetic (PBPK) model for nevirapine that integrates auto-induction, drug interactions, and ethnic variability. The model successfully captured the time-dependent PK of nevirapine across Caucasian, African, and Asian populations, with and without rifampicin/isoniazid co-administration. Simulations revealed that the standard nevirapine regimen (200 mg QD lead-in, 200 mg BID maintenance) was appropriate for Caucasian and African HIV patients but required adjustment to 150 mg QD lead-in and 150 mg BID maintenance for Asians to minimize toxicity. In HIV-TB co-infected patients, nevirapine co-administration with rifampicin/isoniazid was unsuitable for Caucasians due to sub-therapeutic levels. For Africans, an increased regimen (200 mg QD lead-in, 300 mg BID maintenance) was recommended, while drug interactions did not alter the reduced dosing recommendation of nevirapine for Asians. Our findings underscore the necessity of incorporating ethnic variability and drug interaction profiles into nevirapine dosing strategies to optimize therapeutic efficacy and safety in HIV and HIV-TB co-infected patients.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"59"},"PeriodicalIF":5.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617774","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

Uniform Spray Dried Loxapine Microparticles Potentially for Nasal Delivery: Exploring Discriminatory In Vitro Release Evaluation Methods.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-12 DOI: 10.1208/s12248-025-01045-6

Mengyuan Li, Ziwei Nie, Shen Yan, Shengyu Zhang, Xiao Dong Chen, Winston Duo Wu

{"title":"Uniform Spray Dried Loxapine Microparticles Potentially for Nasal Delivery: Exploring Discriminatory In Vitro Release Evaluation Methods.","authors":"Mengyuan Li, Ziwei Nie, Shen Yan, Shengyu Zhang, Xiao Dong Chen, Winston Duo Wu","doi":"10.1208/s12248-025-01045-6","DOIUrl":"10.1208/s12248-025-01045-6","url":null,"abstract":"This study aimed to develop suitable in vitro evaluation methods for the release behavior of nasal powders (NPs). We synthesized a range of standardized microparticles with adjustable size and morphology by co-spray-drying loxapine succinate (LOX) and gelatin (GEL) using an ethanol/water solvent mixture in a self-designed micro-fluidic jet spray dryer (MFJSD). The influence of the LOX/GEL mass ratio and solvent composition on particle characteristics, including size, morphology, and crystalline properties, was systematically investigated. In vitro release profiles of NPs were thoroughly assessed across different release medium, apparatus, and membranes. The modified Transwell® system, utilizing simulated nasal electrolyte solution (SNES) as the release medium, was identified as the most effective in distinguishing the performance of microparticles with diverse attributes. Furthermore, the impact of particle size, morphology, and crystalline properties on in vitro release profiles was discussed. This research presents a robust methodology for the in vitro evaluation of NPs release profiles and provides a practical approach for the rational fabrication of high-quality NPs products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"60"},"PeriodicalIF":5.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617775","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

Best Practices and Recommendations for Non-Liquid Matrices Bioanalysis.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-11 DOI: 10.1208/s12248-025-01033-w

Faye Vazvaei-Smith, Wenkui Li, Omar S Barnaby, Sanjeev Bhardwaj, Juyao Dong, Carolyne Dumont, Carmen Fernández-Metzler, Brian Geist, Mohamed Hassanein, Amanda Hays, Anna Ilinskaya, Eugene P Kadar, Kris King, Nadia Kulagina, Murali K Matta, Krishna Midde, Rina Pan, Divya Pathania, Thomas Tarnowski, Eric Tewalt, Eric Thomas, Enaksha Wickremsinhe, Deqing Xiao

{"title":"Best Practices and Recommendations for Non-Liquid Matrices Bioanalysis.","authors":"Faye Vazvaei-Smith, Wenkui Li, Omar S Barnaby, Sanjeev Bhardwaj, Juyao Dong, Carolyne Dumont, Carmen Fernández-Metzler, Brian Geist, Mohamed Hassanein, Amanda Hays, Anna Ilinskaya, Eugene P Kadar, Kris King, Nadia Kulagina, Murali K Matta, Krishna Midde, Rina Pan, Divya Pathania, Thomas Tarnowski, Eric Tewalt, Eric Thomas, Enaksha Wickremsinhe, Deqing Xiao","doi":"10.1208/s12248-025-01033-w","DOIUrl":"10.1208/s12248-025-01033-w","url":null,"abstract":"The analysis of Non-Liquid Matrices (NLMs) can provide key information on many aspects in drug discovery and development. These include but are not limited to drug uptake and distribution, engagement and modulation, and target exposure. A thorough understanding of these aspects is fundamental to the progression of drug development. In many cases, such an understanding can only be achieved through quantitative analysis of NLMs. Such dependence can lead to bottlenecks in the drug development process-as the practices and regulations that govern bioanalysis of conventional liquid matrices typically cannot be directly applied to NLMs. This paper strives to fill this crucial gap. To this end, subject matter experts from across the industry, through the auspices of the AAPS Bioanalytical Community, have combined their collective best practices for NLM bioanalysis in this paper. Certainly, this endeavor came with challenges, the most prominent of which also serves as the impetus for this project, the lack of literature on NLM bioanalysis dealing with different types of NLM, analysis rigor, and best practices to draw from. This paper aims to serve as a comprehensive set of best practices drawn from the experiences of leading scientists across the industry-for NLM bioanalysis in drug development.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"57"},"PeriodicalIF":5.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607060","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

Functional Activity and Binding Specificity of Small Ankyrin Repeat Proteins Called Ankyrons Against SARS-CoV-2 Variants.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-11 DOI: 10.1208/s12248-025-01043-8

Yun-Jong Park, Wojciech Jankowski, Nicholas C Hurst, Jeremy W Fry, Nikolai F Schwabe, Linda C C Tan, Zuben E Sauna

{"title":"Functional Activity and Binding Specificity of Small Ankyrin Repeat Proteins Called Ankyrons Against SARS-CoV-2 Variants.","authors":"Yun-Jong Park, Wojciech Jankowski, Nicholas C Hurst, Jeremy W Fry, Nikolai F Schwabe, Linda C C Tan, Zuben E Sauna","doi":"10.1208/s12248-025-01043-8","DOIUrl":"10.1208/s12248-025-01043-8","url":null,"abstract":"Effective management of COVID-19 requires clinical tools to treat the disease in addition to preventive vaccines. Several recombinant mAbs and their cocktails have been developed to treat COVID-19 but these have limitations. Here, we evaluate small ankyrin repeat proteins called Ankyrons that were generated to bind with high affinity to the SARS-CoV-2 virus. Ankyrons are ankyrin repeat proteins comprised of repetitions a structural module. Each module consists of a β-turn followed by two antiparallel α-helices. The Ankyrons™ are directly selected in vitro from a highly diverse library of around a trillion clones in ribosome display and like antibodies can bind with high affinity to almost any target. We assessed Ankyrons that were generated against the wild-type SARS-CoV-2 and the Delta (B.1.617.2) and Omicron (BA.1) variants in a binding assay. We determined that all Ankyrons were specific in that they did not bind to MERS. While all Ankyrons bound with high affinity to the variant they were generated against, some also showed cross-reactivity to all three SARS-CoV-2 variants. Binding assays are useful for screening analytes but do not provide information about clinical effectiveness. Therefore, we used a pseudovirus-based neutralization assay to show that five of the Ankyrons evaluated neutralized all three strains of SARS-CoV-2. We have provided a workflow for the evaluation of novel Ankyrons against a viral target. This suggests that Ankyrons could be useful for rapidly developing new research tools for studying other emerging infectious diseases rapidly with the optional further potential for developing Ankyrons into diagnostic and even therapeutic applications.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"58"},"PeriodicalIF":5.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607072","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 Phase-Appropriate Risk Assessment Strategy in Support of the Safety of Peptide and Oligonucleotide-Related Impurities.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-06 DOI: 10.1208/s12248-025-01023-y

Brian W Pack, Robert W Siegel, Paul D Cornwell, Andrea Ferrante, Douglas A Roepke, Michael E Hodsdon, Laurent Malherbe, Mark A Carfagna

{"title":"A Phase-Appropriate Risk Assessment Strategy in Support of the Safety of Peptide and Oligonucleotide-Related Impurities.","authors":"Brian W Pack, Robert W Siegel, Paul D Cornwell, Andrea Ferrante, Douglas A Roepke, Michael E Hodsdon, Laurent Malherbe, Mark A Carfagna","doi":"10.1208/s12248-025-01023-y","DOIUrl":"10.1208/s12248-025-01023-y","url":null,"abstract":"There is limited regulatory guidance that outlines the globally acceptable level of individual and total impurities present in peptide and oligonucleotide drug substances that can be supported and accepted during clinical testing. In early clinical development, there is uncertainty regarding the potential toxicological and immunogenicity risk of these impurities relative to the active pharmaceutical ingredient; however, as pharmaceutical development companies move closer to marketing applications, this uncertainty lessens through knowledge gained by clinical and toxicology studies. While these peptide and oligonucleotide related impurities are predicted to be under process control and to have the same safety profile as the parent drug substance, they do not offer any inherent advantages to the patient. Thus, the safety and specification control of these impurities is frequently challenged by regulatory agencies. In support of phase-appropriate control strategies, this manuscript presents a risk-based approach to evaluate the safety of peptide and oligonucleotide impurities from a toxicology and immunogenicity perspective. In many cases, the proposed safety threshold is higher than what is accepted by regulatory bodies, but still is expected to be safe based upon sound toxicological principles which should be the focus for clinical studies. The risk assessment strategies presented here consider the stage of development, indication, potential impact of unintended cross reactivity with endogenous proteins, dose, and frequency of dosing throughout development to inform chemistry manufacturing and control of inherent safety risks associated with API-related impurities. Importantly, for the first time, this manuscript establishes a threshold of immunogenicity concern along with an experimental mitigation plan specifically for peptide impurities as a function of the development phase.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"56"},"PeriodicalIF":5.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574594","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

Cellular Kinetics and Biodistribution of Adoptive T Cell Therapies: from Biological Principles to Effects on Patient Outcomes.

IF 5 3区医学

AAPS Journal Pub Date : 2025-03-03 DOI: 10.1208/s12248-025-01017-w

Ran Li, Abigail K Grosskopf, Louis R Joslyn, Eric Gary Stefanich, Vittal Shivva

{"title":"Cellular Kinetics and Biodistribution of Adoptive T Cell Therapies: from Biological Principles to Effects on Patient Outcomes.","authors":"Ran Li, Abigail K Grosskopf, Louis R Joslyn, Eric Gary Stefanich, Vittal Shivva","doi":"10.1208/s12248-025-01017-w","DOIUrl":"10.1208/s12248-025-01017-w","url":null,"abstract":"Cell-based immunotherapy has revolutionized cancer treatment in recent years and is rapidly expanding as one of the major therapeutic options in immuno-oncology. So far ten adoptive T cell therapies (TCTs) have been approved by the health authorities for cancer treatment, and they have shown remarkable anti-tumor efficacy with potent and durable responses. While adoptive T cell therapies have shown success in treating hematological malignancies, they are lagging behind in establishing promising efficacy in treating solid tumors, partially due to our incomplete understanding of the cellular kinetics (CK) and biodistribution (including tumoral penetration) of cell therapy products. Indeed, recent clinical studies have provided ample evidence that CK of TCTs can influence clinical outcomes in both hematological malignancies and solid tumors. In this review, we will discuss the current knowledge on the CK and biodistribution of anti-tumor TCTs. We will first describe the typical CK and biodistribution characteristics of these \"living\" drugs, and the biological factors that influence these characteristics. We will then review the relationships between CK and pharmacological responses of TCT, and potential strategies in enhancing the persistence and tumoral penetration of TCTs in the clinic. Finally, we will also summarize bioanalytical methods, preclinical in vitro and in vivo tools, and in silico modeling approaches used to assess the CK and biodistribution of TCTs.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"55"},"PeriodicalIF":5.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143543660","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

Considerations in K_p,uu,brain-based Strategy for Selecting CNS-targeted Drug Candidates with Sufficient Target Coverage and Substantial Pharmacodynamic Effect.

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-28 DOI: 10.1208/s12248-025-01035-8

Ling Zou, Huan-Chieh Chien, Devendra Pade, Yanfei Li, Minhkhoi Nguyen, Ravi Kanth Bhamidipati, Zhe Wang, Osatohanmwen Jessica Enogieru, Jan Wahlstrom

{"title":"Considerations in Kp,uu,brain-based Strategy for Selecting CNS-targeted Drug Candidates with Sufficient Target Coverage and Substantial Pharmacodynamic Effect.","authors":"Ling Zou, Huan-Chieh Chien, Devendra Pade, Yanfei Li, Minhkhoi Nguyen, Ravi Kanth Bhamidipati, Zhe Wang, Osatohanmwen Jessica Enogieru, Jan Wahlstrom","doi":"10.1208/s12248-025-01035-8","DOIUrl":"10.1208/s12248-025-01035-8","url":null,"abstract":"Kp,uu,brain is a critical parameter for evaluating the brain penetration of CNS-targeted compounds, reflecting the ratio of unbound drug concentration in the brain to that in the plasma. While Kp,uu,brain is widely used in the pharmaceutical industry to assess brain exposure, the fidelity of translating Kp,uu,brain to target coverage and pharmacodynamic (PD) effect remains uncertain. This study explores the effectiveness of Kp,uu,brain-based strategies in identifying drug candidates with sufficient target coverage and substantial PD effect. By analyzing reported Kp,uu,brain, unbound drug concentrations in the brain and IC50 values against pharmacological targets for 17 drugs including anticonvulsants, antidepressants, antipsychotics, and antimicrobials, our study demonstrated that while in vitro and in vivo models work well for rank ordering compounds with high Kp,uu,brain, this parameter does not necessarily translate into adequate target coverage (Cu/IC50). In addition, by leveraging PK and PD profiles of 18 drugs measured from human glioblastoma tumors, our study showed that target coverage (glioblastoma Cu/5xIC50) generally correlates well with PD effect. Additionally, Kp,uu,brain tumor is a better indicator for glioblastoma PD effect than Kp,uu,brain, suggesting that intact BBB model may not adequately reflect the barrier heterogeneity in brain tumors such as glioblastoma. In conclusion, while Kp,uu,brain provides an insight on the extent of brain penetration, our study highlighted the need for integrative approaches combining Kp,uu,brain data with comprehensive PK/PD analysis to prioritize CNS-targeted drug candidates with sufficient target coverage and substantial PD effect.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"52"},"PeriodicalIF":5.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532148","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

Estimation of Ganciclovir Exposure in Adults Transplant Patients by Machine Learning.

IF 5 3区医学

AAPS Journal Pub Date : 2025-02-28 DOI: 10.1208/s12248-025-01034-9

Hamza Sayadi, Yeleen Fromage, Marc Labriffe, Pierre-André Billat, Cyrielle Codde, Selim Arraki Zava, Pierre Marquet, Jean-Baptiste Woillard

{"title":"Estimation of Ganciclovir Exposure in Adults Transplant Patients by Machine Learning.","authors":"Hamza Sayadi, Yeleen Fromage, Marc Labriffe, Pierre-André Billat, Cyrielle Codde, Selim Arraki Zava, Pierre Marquet, Jean-Baptiste Woillard","doi":"10.1208/s12248-025-01034-9","DOIUrl":"10.1208/s12248-025-01034-9","url":null,"abstract":"Introduction: Valganciclovir, a prodrug of ganciclovir (GCV), is used to prevent cytomegalovirus infection after transplantation, with doses adjusted based on creatinine clearance (CrCL) to target GCV AUC0-24 h of 40-60 mg*h/L. This sometimes leads to overexposure or underexposure. This study aimed to train, test and validate machine learning (ML) algorithms for accurate GCV AUC0-24 h estimation in solid organ transplantation.Methods: We simulated patients for different dosing regimen (900 mg/24 h, 450 mg/24 h, 450 mg/48 h, 450 mg/72 h) using two literature population pharmacokinetic models, allocating 75% for training and 25% for testing. Simulations from two other literature models and real patients provided validation datasets. Three independent sets of ML algorithms were created for each regimen, incorporating CrCL and 2 or 3 concentrations. We evaluated their performance on testing and validation datasets and compared them with MAP-BE.Results: XGBoost using 3 concentrations generated the most accurate predictions. In testing dataset, they exhibited a relative bias of -0.02 to 1.5% and a relative RMSE of 2.6 to 8.5%. In the validation dataset, a relative bias of 1.5 to 5.8% and 8.9 to 16.5%, and a relative RMSE of 8.5 to 9.6% and 10.7% to 19.7% were observed depending on the model used. XGBoost algorithms outperformed or matched MAP-BE, showing enhanced generalization and robustness in their estimates. When applied to real patients' data, algorithms using 2 concentrations showed relative bias of 1.26% and relative RMSE of 12.68%.Conclusions: XGBoost ML models accurately estimated GCV AUC0-24 h from limited samples and CrCL, providing a strategy for optimized therapeutic drug monitoring.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 2","pages":"53"},"PeriodicalIF":5.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532149","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