Pharmaceuticals最新文献

{"title":"Pharmacodynamic Evaluation of Adjuvant Targets: Low Molecular Weight PBP7/8 Effects on β-Lactam Activity Against Carbapenem-Resistant Acinetobacter Baumannii.","authors":"Brian M Ho, Jingxiu Jin, Jacob T Sanborn, Thomas D Nguyen, Navaldeep Singh, Christina Cheng, Nader N Nasief, Ulrike Carlino-MacDonald, Brian T Tsuji, Yanan Zhao, Liang Chen, Bartolome Moya, Thomas A Russo, Nicholas M Smith","doi":"10.3390/ph18060918","DOIUrl":"10.3390/ph18060918","url":null,"abstract":"<p><p><b>Background/Objectives:</b> The increasing occurrence of carbapenem resistance <i>A. baumannii</i> (CRAB) has forced clinicians to seek out alternative options with activity against CRAB. CRAB with inactivated PBP7/8 has been shown to result in an increased outer membrane permeability and could serve as a potential new adjuvant target. <b>Methods</b>: Two isogenic clinical isolates of <i>A. baumannii</i> HUMC1 were utilized (WT and HUMC1 ΔPBP7/8). Static concentration time-kill assays were performed against both isolates with escalating exposures to antibiotics. The resulting data were modeled using the Monolix software suite to capture parameters related to bacterial killing and PBP7/8 synergism. The model results were used to prospectively simulate clinically relevant antibiotic dosing of three antibiotics under physiological conditions and were validated using a hollow-fiber infection model (HFIM). <b>Results</b>: Treatment with monotherapy or combination therapy resulted in concentration-dependent killing for both isolates. Bacterial killing was greater with HUMC1 ΔPBP7/8 for all tested antibiotic concentrations. The mean bacterial population reduction was 4.38 log₁₀ CFU/mL for HUMC1 and 5.38 log₁₀ CFU/mL for HUMC1ΔPBP7/8 knockout isolate. The final mechanism-based model demonstrated improved antibacterial activity with PBP7/8 inhibition through a decline in KC₅₀ values of 59.7% across the beta-lactams in the PBP7/8 knockout. HFIM observations that were retrospectively compared to the simulated model-predicted bacterial concentration time course showed our final model was able to appropriately capture changes in bacterial population within a dynamic HFIM scenario. <b>Conclusions</b>: The quantification of KC₅₀ decline and increase in effectiveness of previously sidelined antimicrobial therapies with PBP7/8 inhibition suggests PBP7/8 is a promising potential target for an antibacterial adjuvant. This lends further support to advance to next-stage studies for identifying compounds that specifically inhibit PBP7/8 activity.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of <i>Periploca chevalieri</i> Browicz on Postprandial Glycemia and Carbohydrate-Hydrolyzing Enzymes.","authors":"Katelene Lima, Maryam Malmir, Shabnam Sabiha, Rui Pinto, Isabel Moreira da Silva, Maria Eduardo Figueira, João Rocha, Maria Paula Duarte, Olga Silva","doi":"10.3390/ph18060913","DOIUrl":"10.3390/ph18060913","url":null,"abstract":"<p><p><b>Background/Objectives:</b><i>Periploca chevalieri</i> Browicz (<i>Apocynaceae</i>), an endemic species of the Cabo Verde archipelago, is commonly used in traditional medicine for the treatment of diabetes. The aim of this study was to characterize the chemical profiles of the aqueous and hydroethanolic (70%) extracts of the <i>P. chevalieri</i> dried aerial parts (PcAE and PcEE) and evaluate their potential to modulate postprandial glycemia and inhibit key carbohydrate-hydrolyzing enzymes. <b>Methods:</b> The chemical characterization was performed by LC/UV-DAD-ESI/MS/MS. An in vivo evaluation of postprandial glycemia modulation was conducted on healthy CD1 mice submitted to an oral sucrose tolerance test. In vitro enzymatic inhibition was performed for the α-amylase, α-glucosidase, and DPP4 enzymes. Additionally, antioxidant and antiglycation activities were also assessed. <b>Results:</b> Phenolic acid derivatives, flavanols, proanthocyanidins, and flavonols were the major classes of secondary metabolites identified. PcEE at 170 mg/kg of body weight significantly (<i>p</i> < 0.05) reduced the postprandial glycemia peak in CD1 mice submitted to sucrose overload. Regarding the enzymatic inhibition, both extracts showed concentration-dependent inhibitory potential against the α-amylase, α-glucosidase, and DPP4 enzymes. Both extracts inhibited α-glucosidase more effectively than acarbose. <b>Conclusions:</b> The obtained results supports the traditional use of <i>P. chevalieri</i> and suggest the potential for further pharmacological investigation.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spontaneous Adverse Drug Reaction Reporting of Congenital Malformations: A Danish National Register Study.","authors":"Ulrik Lausten-Thomsen, Rasmus Huan Olsen, Michael Christiansen, Paula L Hedley, Ida Marie Heerfordt, Jon Trærup Andersen, Christina Gade","doi":"10.3390/ph18060917","DOIUrl":"10.3390/ph18060917","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Maternal use of medication during pregnancy may have teratogenic effects, as seen with drugs like thalidomide, valproate, and phenytoin. Despite rigorous testing, both new and established drugs still pose a risk of teratogenesis, particularly if the teratogenic effects are probabilistic and not deterministic. Public health organizations maintain registers to centralize and evaluate adverse drug reactions (ADR). However, underreporting in these registries can obscure the signals of drug-related congenital malformations. This study aims to evaluate potential ADR-associated congenital malformations in Denmark over the past decade; <b>Methods</b>: An observational cross-sectional study was conducted using data from the national Danish Medicines Agency's pharmacovigilance database, which includes all spontaneous ADR reports submitted to the Danish Medicines Agency from 1 July 2013 to 30 June 2023. Maternal antenatal drug use was identified, and reported ADRs were assessed for congenital malformations; <b>Results</b>: We identified reports of potential ADR-related congenital malformations in 75 children, with 92 diagnoses as classified by ICD-10. Eighty-five different drugs from 58 ATC codes were implicated. Only three diagnoses were reported in five or more children. The reports were generally sporadic, with no new signals detected; <b>Conclusions</b>: Public awareness is crucial when novel threats arise from medications, infections, or technologies, as these may pose risks to unborn children. Ongoing monitoring of potential ADR-related congenital malformations remains a critical component of public health. Given the potential underreporting, we encourage a low threshold for reporting ADRs based on suspicion alone, with final causality assessments made by health authorities.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative Formulation Strategies for Biosimilars: Trends Focused on Buffer-Free Systems, Safety, Regulatory Alignment, and Intellectual Property Challenges.","authors":"Tomas Gabriel Bas","doi":"10.3390/ph18060908","DOIUrl":"10.3390/ph18060908","url":null,"abstract":"<p><p>The formulation of biosimilar products critically determines their stability, safety, immunogenicity, and market accessibility. This article presents a novel integrative framework for biosimilar formulation that balances scientific, regulatory, and intellectual property dimensions, offering a holistic perspective rarely unified in the literature. It highlights the growing trend toward buffer-free, high-concentration systems that leverage protein self-buffering to improve patient comfort and formulation stability. The article also addresses regulatory flexibility from the FDA and EMA, which allows scientifically justified deviations from reference formulations to ensure pharmaceutical equivalence and minimize immunogenicity. A novelty of this article is its comprehensive analysis of how digital innovations, such as Quality-by-Design, Process-Analytical-Technology, and AI-based in silico simulations, are transforming formulation design and bioprocess optimization to reduce immunogenic risks and enhance bioequivalence. Two important key takeaways emerge: (1) strategic innovation in formulation, especially using buffer-free and high concentration systems, improve product stability and patient tolerability while complying with regulatory standards; and (2) intellectual property challenges, including patent thickets, strongly influence formulation decisions, making early legal-strategic alignment essential for market entry. The article confirms that practical recommendations for the selection of recombinant therapeutic protein formulations can effectively guide developers and regulators toward safer, more efficient, and commercially viable biosimilar products.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARP Inhibition in Colorectal Cancer-A Comparison of Potential Predictive Biomarkers for Therapy.","authors":"Abdulaziz Alfahed","doi":"10.3390/ph18060905","DOIUrl":"10.3390/ph18060905","url":null,"abstract":"<p><p><b>Background/Objectives</b>: PARP inhibitors (PARPis) currently play frontline roles in the management of prostate, pancreatic, ovarian and breast cancers, but their roles in colorectal cancer (CRC) management have yet to be clarified. Importantly, the specific predictive biomarkers for PARPis in CRC are still matters of investigations. The aim of this study is to identify the potential predictive biomarkers of PARP inhibition in CRC. <b>Methods</b>: Gene set enrichment analyses (GSEAs) and drug ontology enrichment analyses (DOEAs) of PARPi response gene sets were applied as the surrogates of PARPi response to two CRC cohorts in order to compare the predictive capacities of <i>TP53</i> mutation status, MSI status, as well as <i>PARP1</i> and <i>PARP2</i> expression for PARP inhibition to those of a homologous repair deficiency surrogate, and large-scale state transition (LST). Differential enrichment score (ES) and ontology enrichment (OE) analyses were used to interrogate the differential correlation of the predictive biomarkers with PARPi response, relative to LST. <b>Results</b>: The results demonstrated that LST-low, rather than LST-high, CRC subsets exhibited an enrichment of the PARPi response, in contrast to what has been established for other cancers. Furthermore, CRC subsets with wild-type <i>TP53</i>, positive MSI, as well as high <i>PARP1</i> and <i>PARP2</i> expression exhibited an enrichment of the PARPi response gene sets. Moreover, there was no differential enrichment of the PARPi response between LST and each of the MSI statuses, <i>PARP1</i> expression and <i>PARP2</i> expression. Furthermore, the preliminary differential enrichment observed between the LST-based and <i>TP53</i> mutation status-based PARPi responses could not be validated with further testing. <b>Conclusions</b>: MSI status, <i>TP53</i> mutation status as well as <i>PARP1</i> and <i>PARP2</i> expression may be substitutes for low LST as predictive biomarkers of PARPi response in CRC.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revolutionizing Prostate Cancer Detection: The Role of Approved PSMA-PET Imaging Agents.","authors":"Ute Hennrich, Laurène Wagner, Harun Taş, Luciana Kovacs, Martina Benešová-Schäfer","doi":"10.3390/ph18060906","DOIUrl":"10.3390/ph18060906","url":null,"abstract":"<p><p>Locametz^®/Illuccix^®/Gozellix^TM (Novartis AG (Basel, Switzerland) and Telix Pharmaceuticals, Ltd. (Melbourne, Australia), all three [⁶⁸Ga]Ga-PSMA-11), Pylarify^®/Pylclari^® (Progenics Pharmaceuticals, Inc. (New York, USA) and Curium PET France SA (Paris, France), both [¹⁸F]DCFPyL), Radelumin^® (ABX GmbH (Radeberg, Germany), [¹⁸F]PSMA-1007), and Posluma^® (Blue Earth Diagnostics, Ltd. (Oxford, UK), [¹⁸F]rhPSMA-7.3) are four approved PSMA-PET imaging agents that have significantly advanced the diagnosis and management of prostate cancer. These agents offer a new level of precision and accuracy, enabling clinicians to detect prostate cancer with enhanced sensitivity. As a result, they play a critical role in improving detection, staging, and management, ultimately enhancing clinical outcomes for patients. Their use in routine clinical practice is expected to increase diagnostic precision and provide clearer pathways for personalized therapy. This review offers a comprehensive chemical, pharmaceutical, and medicinal overview, discusses comparative studies, and highlights additional highly relevant candidates for prostate cancer detection.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cold Atmospheric Plasma Improves the Therapeutic Success of Photodynamic Therapy on UV-B-Induced Squamous Cell Carcinoma in Hairless Mice.","authors":"Stephanie Arndt, Petra Unger, Irina Ivanova, Wolfgang Bäumler, Konstantin Drexler, Mark Berneburg, Sigrid Karrer","doi":"10.3390/ph18060907","DOIUrl":"10.3390/ph18060907","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Actinic keratosis (AK) occurs on sun-damaged skin and is considered a precursor to squamous cell carcinoma (SCC). Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) and red light, is a common treatment for AK. However, its clinical efficacy for invasive tumors such as SCC is limited by the poor penetration and distribution of the photosensitizer. Cold atmospheric plasma (CAP), a partially ionized gas, increases skin permeability and exhibits anti-cancer properties through the generation of reactive oxygen species (ROS). In a previous study, CAP showed promising synergistic effects when combined with ALA-PDT for the treatment of SCC cells in vitro. The present study investigated the effects of combining CAP with ALA-PDT on cutaneous AK and SCC induced by ultraviolet B (UV-B) irradiation in SKH1 hairless mice. <b>Methods:</b> We compared various application sequences (CAP-ALA-red light, ALA-red light-CAP, and ALA-CAP-red light) against conventional ALA-PDT using visual, histological, and molecular assessments of the affected skin. <b>Results:</b> The results demonstrated that combined treatments strongly inhibited the growth of UV-B-induced skin lesions. TUNEL staining revealed increased apoptosis following both single and combined therapies, while Ki-67 staining indicated reduced keratinocyte proliferation and diminished DNA damage in treated areas. mRNA expression analysis showed the upregulation of apoptosis-related genes (<i>p16^INK4a</i>, <i>p21^CIP1</i>) alongside enhanced anti-tumor immune responses (<i>IL-6</i>, <i>IL-8</i>) in the affected tissue samples. Notably, the combined treatment enhances the therapeutic effect, whereas the sequence of application does not seem to be relevant for therapeutic efficacy in vivo. <b>Conclusions:</b> Overall, these results suggest that CAP may enhance the anti-tumor effect of conventional ALA-PDT, supporting previous findings on SCC cells.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory Perspectives for AI/ML Implementation in Pharmaceutical GMP Environments.","authors":"Sarfaraz K Niazi","doi":"10.3390/ph18060901","DOIUrl":"10.3390/ph18060901","url":null,"abstract":"<p><p>Integrating artificial intelligence (AI) and machine learning (ML) into pharmaceutical manufacturing processes holds great promise for enhancing efficiency, product quality, and regulatory compliance. However, implementing good manufacturing practices (GMP) in regulated environments introduces complex challenges related to validation, data integrity, risk management, and regulatory oversight. This review article comprehensively analyzes current regulatory frameworks and guidance for AI/ML in pharmaceutical Good Manufacturing Practice (GMP) settings, identifies gaps and uncertainties, and proposes considerations for future policy development. Emphasis is placed on understanding regulatory expectations across various agencies, including the US FDA, EMA, and MHRA. This article examines verified case studies and pilot programs that demonstrate the successful application of AI/ML under regulatory scrutiny, as well as recent developments in regulatory frameworks and implementation strategies. Ultimately, this article emphasizes the importance of a risk-based life cycle approach and the need for advancements in regulatory science to accommodate the dynamic nature of AI/ML technologies.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Brazilian Green Propolis Phytochemicals in the Search for Potential Inhibitors of B-Raf⁶⁰⁰E Enzyme: A Theoretical Approach.","authors":"Garcia Ferreira de Souza, Airis Farias Santana, Fernanda Sanches Kuhl Antunes, Ramon Martins Cogo, Matheus Dornellas Pereira, Daniela Gonçales Galasse Rando, Carolina Passarelli Gonçalves","doi":"10.3390/ph18060902","DOIUrl":"10.3390/ph18060902","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Melanoma is one of the most aggressive forms of skin cancer and is frequently associated with the B-Raf⁶⁰⁰E mutation, which constitutively activates the MAPK signaling pathway. Although selective inhibitors such as Vemurafenib offer clinical benefits, their long-term efficacy is often hindered by resistance mechanisms and adverse effects. In this study, twelve phytochemicals from Brazilian green propolis were evaluated for their potential as selective B-Raf⁶⁰⁰E inhibitors using a computational approach. <b>Methods:</b> Physicochemical, ADME, and electronic properties were assessed, followed by molecular docking using the B-Raf⁶⁰⁰E crystal structure (PDB ID: 3OG7). Redocking validation and 500 ns molecular dynamics simulations were performed to investigate the stability of the ligand-protein complexes, and free energy calculations were then computed. Results: Among the tested compounds, Artepillin C exhibited the strongest binding affinity (-8.17 kcal/mol) in docking and maintained stable interactions with key catalytic residues throughout the simulation, also presenting free energy of binding ΔG of -20.77 kcal/mol. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. <b>Results:</b> Among the tested compounds, Artepillin C exhibited the strongest binding affinity (-8.17 kcal/mol) and maintained stable interactions with key catalytic residues throughout the simulation. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. <b>Conclusions:</b> These findings indicate that Artepillin C is a promising natural compound for further development as a selective B-Raf⁶⁰⁰E inhibitor and suggest its potential utility in melanoma treatment strategies. This study reinforces the value of natural products as scaffolds for targeted drug design and supports continued experimental validation.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the <i>ABCB1</i> Gene Polymorphism and Food Effects on the Avatrombopag Pharmacokinetics in Chinese Individuals: A Population Pharmacokinetic/Pharmacodynamic Analysis.","authors":"Xin Liu, Lulu Chen, Gehang Ju, Chao Li, Bijue Liu, Yunzhou Fei, Xintong Wang, Yang Gao, Qingfeng He, Xiao Zhu, Dongsheng Ouyang","doi":"10.3390/ph18060903","DOIUrl":"10.3390/ph18060903","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Avatrombopag (AVA), a thrombopoietin receptor agonist used to treat thrombocytopenia in patients with chronic liver disease, exhibits significant pharmacokinetic (PK) variability, particularly under fasting conditions. This study investigates the combined influence of food intake and genetic polymorphisms in <i>CYP2C9</i> and <i>ABCB1</i> on the PK and pharmacodynamics (PD) of AVA, with the goal of informing individualized dosing strategies. <b>Methods</b>: A pharmacogenetic analysis was conducted in 92 healthy participants, who received 20 mg of AVA under both fasting and fed conditions. A population PK/PD model was developed to evaluate the covariates effects on the PK variability. Monte Carlo simulations were used to predict AVA exposure and platelet count profiles under diverse dosing scenarios. <b>Results</b>: Food intake significantly reduced PK variability, with approximately 50% reductions in clearance (CL/F) and volume of distribution (Vd/F) compared to fasting conditions. Under fed conditions, <i>CYP2C9</i> intermediate metabolizers showed a 1.70-fold increase in exposure compared to normal metabolizers, but this difference was not observed under fasting conditions. <i>ABCB1</i> polymorphisms showed minimal impact, with the exception of <i>ABCB1</i> (<i>C1236T</i>) heterozygotes, which exhibited 1.37-fold increased exposure. Despite the observed PK variability, simulations demonstrated a consistent platelet count response across dosing regimens. <b>Conclusions</b>: While food intake and genetic polymorphisms in <i>CYP2C9</i> and <i>ABCB1</i> influenced AVA PK, these factors may not require dose adjustments, as platelet count responses remained consistent across genotypes and dosing conditions in the Chinese participants. These findings support simplified dosing strategies without the need for pharmacogenetic testing in Chinese individuals and may contribute to more individualized thrombocytopenia management.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"18 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12196290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144507693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}