Pharmaceutical Research最新文献

{"title":"Raman Spectroscopy for Characterizing Monoclonal Antibody Reduction: A Process Analytical Technology Approach for Antibody-Drug Conjugation Process Development.","authors":"David Pople, Zhenshu Wang, Anton Kozyryev, Bhumit Patel, Emmanuel Appiah-Amponsah, Hanzhou Feng","doi":"10.1007/s11095-026-04154-9","DOIUrl":"10.1007/s11095-026-04154-9","url":null,"abstract":"<p><strong>Background: </strong>Controlled disulfide bond reduction is critical in antibody-drug conjugate (ADC) manufacturing, enabling site-specific conjugation and desired drug-to-antibody ratios. Current characterization relies on time-consuming offline capillary electrophoresis, creating bottlenecks in process development where multiple conditions must be rapidly screened. This study evaluates Raman spectroscopy as a process analytical technology (PAT) to elucidate reduction kinetics and accelerate optimization for ADC development.</p><p><strong>Methods: </strong>A Design of Experiments approach investigated TCEP-mediated reduction of an IgG1 antibody under varying TCEP/mAb ratios (5-15) and pH conditions (5.5-7.5). Raman spectra were collected throughout reduction reactions. Principal component analysis (PCA) characterized reduction kinetics, while partial least squares (PLS) regression quantified fragment formation against non-reduced capillary electrophoresis sodium dodecyl sulfate (nrCE-SDS) measurements.</p><p><strong>Results: </strong>PCA effectively captured reduction kinetics, with PC1 trajectories correlating strongly with heavy chain (HC) formation measured by nrCE-SDS. The analysis revealed pH-dependent TCEP saturation effects: higher pH showed convergent kinetics at elevated ratios while lower pH maintained ratio-dependent rates. PLS models successfully predicted HC formation, demonstrating potential for endpoint detection despite the interchain disulfide bonds representing only ~ 0.2% of total protein mass.</p><p><strong>Conclusions: </strong>Raman spectroscopy with chemometric analysis provides valuable insights for ADC process development. PCA enables rapid screening of reduction conditions without nrCE-SDS confirmation, reducing analytical burden during early development. Unlike offline nrCE-SDS, Raman offers potential for real-time online PAT implementation. Future work focusing on narrower operating ranges could enhance model performance for manufacturing applications.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3299-3315"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448677","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}

{"title":"Comprehensive Analytical Characterization of mRNA Influenza Vaccine Under Stress Conditions: Implications for Stability and Quality Control.","authors":"Jiyoun Kim, Jiyoung Sim, Seulgi Park, Jiyoung Ma, Jihoon Kim, Yunji Kum, Hyewon Lee, Inyoung Huh, Jaeseung Lee, Yeon-Jung Kim, Byoungju Lee, Jeungwoon Hong, Min-Duk Seo","doi":"10.1007/s11095-026-04175-4","DOIUrl":"10.1007/s11095-026-04175-4","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to characterize the physicochemical stability of mRNA-lipid nanoparticle (LNP) influenza vaccine candidates under various environmental stressors using forced degradation studies (FDSs) and to correlate these changes with in vitro protein expression.</p><p><strong>Methods: </strong>FDSs were conducted to evaluate the effects of temperature, oxidation, hydrolysis, and agitation on mRNA-LNP formulations. Comprehensive analytical techniques were employed to monitor the purity and integrity of mRNA, mRNA encapsulation efficiency, in vitro expression, LNP components, and particle characteristics.</p><p><strong>Results: </strong>The study revealed hydrolysis-induced degradation of distearoylphosphatidylcholine (DSPC), a key LNP component, and rapid oxidation-induced mRNA degradation within the LNPs. Agitation was found to increase LNP size, decrease mRNA encapsulation efficiency, and subsequently reduce in vitro protein expression.</p><p><strong>Conclusions: </strong>We established robust analytical methods to monitor the quality and stability of mRNA-LNP products. These findings provide a critical foundation for integrated analytical strategies to enhance the stability of mRNA-LNP therapeutics and vaccines during storage, transport, and clinical application.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3273-3286"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796669","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}

{"title":"Discovering the Differences of the Individual Batches of API and its Polymorphs Using Hansen Solubility Parameters.","authors":"Matúš Švichký, Ondřej Sauer, Eva Petříková, Jan Patera","doi":"10.1007/s11095-026-04157-6","DOIUrl":"10.1007/s11095-026-04157-6","url":null,"abstract":"<p><strong>Purpose: </strong>Physicochemical stability of drug products depends on excipient-API (active pharmaceutical ingredient) compatibility, where interfacial interactions at the particle surface can initiate degradation pathways and solid-state transformations. Conventional compatibility approaches often emphasise bulk properties and may under-represent surface effects.</p><p><strong>Methods: </strong>A methodology based on Hansen solubility parameters (HSPs) determined by inverse gas chromatography (IGC) was applied to characterise API surface properties. Three model compounds (ramipril, sertraline hydrochloride, agomelatine) were analysed to compare polymorphic forms and production batches. Measurements were performed at infinite dilution using multiple molecular probes at several temperatures.</p><p><strong>Results: </strong>The HSP profiles showed pronounced differences between polymorphs and, importantly, between batches sharing the same polymorphic form. The data indicate that molecular packing, stereochemistry and processing history can measurably alter surface energetics, with direct implications for excipient compatibility and formulation robustness.</p><p><strong>Conclusion: </strong>IGC-derived HSP analysis provides complementary, surface-sensitive information that can support excipient selection during early formulation development and help manage risks related to polymorphic variability and supplier-to-supplier differences. Further work should link HSP profiles to formulation performance metrics such as processability, compatibility and stability.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3349-3362"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148550026","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}

{"title":"Physiologically Based Pharmacokinetic Modeling for Mechanistic Analysis of Food Effects: A Case Study with Radotinib.","authors":"Minseo Kang, Na Yun Kim, Jae Soo Shin, Min Soo Park, Eunjin Hong, Jangik I Lee","doi":"10.1007/s11095-026-04179-0","DOIUrl":"10.1007/s11095-026-04179-0","url":null,"abstract":"<p><strong>Purpose: </strong>Physiologically based pharmacokinetic (PBPK) modeling has emerged as a promising tool for food effect assessment, yet its utility for poorly soluble and poorly permeable compounds has not been fully established. This study aimed to develop a PBPK model for radotinib, a second-generation tyrosine kinase inhibitor, to predict the food effect.</p><p><strong>Methods: </strong>The model was verified against plasma concentration-time (Cp-time) data obtained from a clinical trial conducted in healthy volunteers who received an oral dose of 400 mg under fasted and fed conditions. Sensitivity analyses were subsequently performed to identify the absorption-related parameters that influence the prediction of food effect.</p><p><strong>Results: </strong>All simulated-to-observed ratios for maximum Cp (C_max), and area under the Cp-time curve from time zero to infinity (AUC_inf) fell within two-fold acceptance criterion under fasted and fed conditions. Simulated geometric mean ratios for the food effect on C_max and AUC_inf were 2.65 and 3.47, which closely recapitulated the observed ratios of 2.65 and 3.49, respectively. Intrinsic solubility and the logarithm of the bile micelle-to-water partition coefficient for neutral species were identified as the primary determinants of food effect prediction.</p><p><strong>Conclusions: </strong>These findings demonstrate the utility of PBPK modeling for prediction of food effect on radotinib pharmacokinetics.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3159-3171"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796713","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":"Generic Long-Acting Injectable Product Availability and Approval Standards.","authors":"Krista Anim Anno, Doortje Esther Lubberts, Lei Zhang, Sarah Ibrahim, Jessica T Smith, Kevin Blake, Arno Nolting, Carolien Versantvoort, Wenlei Jiang","doi":"10.1007/s11095-026-04159-4","DOIUrl":"10.1007/s11095-026-04159-4","url":null,"abstract":"<p><strong>Purpose: </strong>Long-acting injectables (LAIs) offer substantial clinical and economic advantages, including improved patient adherence, enhanced safety and efficacy, and reduced overall healthcare costs. Despite these benefits, the availability of generic LAIs remains limited, largely due to the complexity of formulation development and regulatory assessment. This study aimed to characterize the landscape of LAI product availability, regulatory frameworks, and approval standards in the United States and Europe, and to identify opportunities to support generic LAI development.</p><p><strong>Methods: </strong>A comparative analysis was conducted of LAI product approvals through December 2025, along with regulatory guidance documents issued by the U.S. Food and Drug Administration (FDA) through February 2026, the European Medicines Agency (EMA) through December 2025, and European national agencies through July 2023.</p><p><strong>Results: </strong>The FDA approved 64 distinct new LAIs via the 505(b)(1) and 505(b)(2) pathways and 13 generic LAIs via the 505(j) pathway. In contrast, new and generic LAIs covering 26 and 15 active pharmaceutical ingredients (API), respectively, were approved by the EMA and European national agencies. The FDA issued 48 product-specific guidances (PSGs) for LAIs, whereas the EMA published five PSGs in addition to general modified-release guidance documents. Both agencies issued PSGs for five shared LAI products: exenatide, lanreotide, octreotide, and paliperidone palmitate (1-month and 3-month formulations). Comparative review of these PSGs revealed both alignment and differences in bioequivalence recommendations. Global collaborative efforts to promote generic LAI development were highlighted.</p><p><strong>Conclusions: </strong>These findings provide a foundation for harmonizing generic LAI approval standards, which may improve resource allocation, promote generic competition, and enhance patient access to LAI therapies.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3083-3104"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866497","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":"Spray-Dried Formulations of Relaxin-H2 for Inhalation.","authors":"Danforth P Miller, Nani P Kadrichu, Thomas E Tarara, Philip J Kuehl, John S Patton, Jeffry G Weers","doi":"10.1007/s11095-026-04156-7","DOIUrl":"10.1007/s11095-026-04156-7","url":null,"abstract":"<p><strong>Purpose: </strong>To develop an inhaled formulation of relaxin-H2 that achieves sustained concentrations of protein above 10 ng/mL in serum and epithelial lining fluid over 24 h, thereby enabling chronic administration of the medicine at home.</p><p><strong>Methods: </strong>Dry powder formulations of relaxin-H2 were prepared by spray drying an aqueous feedstock comprising protein in sodium acetate buffer. The physicochemical properties and aerosol performance of the powder were assessed using standard methods for inhaled dry powders. The pharmacokinetics of relaxin-H2 was assessed in rats following intratracheal administration and in dogs following administration by oral inhalation.</p><p><strong>Results: </strong>The spray dried powder was comprised of fine corrugated particles. The amorphous dry powder was stable for a period of at least two years at room temperature, with low formation of iso-Asp and oligomers on storage. Process optimization enabled a high total lung dose (> 90% w/w) to be achieved following administration with a portable dry powder inhaler. Following intratracheal administration of a 500 μg/kg dose of relaxin-H2 to rats or inhaled administration of the same dose to dogs, the relaxin-H2 serum and bronchoalveolar lavage fluid concentrations were maintained above 10 ng/ml over 18-24 h, with a high absolute bioavailability.</p><p><strong>Conclusions: </strong>Dry powder formulations of relaxin-H2 may provide a noninvasive delivery technology enabling chronic administration of the pleiotropic hormone for both local lung and systemic applications.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3377-3391"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148448689","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}

{"title":"Dual C20 Fatty Acid-Conjugated Insulin Analog LPJT-026: Enhanced HSA Binding, Prolonged PK/PD Profiles, and Reduced Hypoglycemia Risk for Biweekly Diabetes Therapy.","authors":"Yiwei Tou, Jihong Luo, Jiuyi Sun, Pai Liu, Qishen Huang, Yun-Hong Zhang","doi":"10.1007/s11095-026-04166-5","DOIUrl":"10.1007/s11095-026-04166-5","url":null,"abstract":"<p><strong>Purpose: </strong>This research aimed to develop a next-generation ultra-long-acting insulin analog with dual long-chain fatty acid conjugation, addressing unmet needs of frequent injections and hypoglycemia risk in diabetes therapy.</p><p><strong>Methods: </strong>LPJT-026, a dual C20 fatty acid-modified insulin (LysA22 and LysB29), was designed, synthesized and characterized. Head-to-head comparisons with marketed insulin icodec (Awiqli®) were performed via in vitro binding assays (HSA/INSR/IGF-1R) and in vivo PK/PD evaluations in STZ-induced type 1 diabetic (T1D) rats and Beagle dogs. Long-term efficacy (HbA1c reduction) and safety (hypoglycemia-related mortality) were assessed in 8-week repeated-dose studies.</p><p><strong>Results: </strong>LPJT-026 (purity ≥ 98%) bears C20 fatty acid chains at LysA22 and LysB29, exhibiting significantly higher human serum albumin (HSA) binding affinity (KD = 139 nM vs. 510 nM for Insulin Icodec) and favorable insulin receptor binding (KD = 134 nM). Animal studies demonstrated superior PK/PD profiles: LPJT-026 sustained glucose-lowering effects for 96 h (vs. 72 h for Insulin Icodec) with significantly lower hypoglycemia-related mortality (10% vs. 40%, p < 0.05) in T1D rats, dose-proportional PK profiles in Beagle dogs (AUC_0-∞ = 75,851-301,529 h·ng/mL at 0.1-0.4 mg/kg concentration with subcutaneous administration) and cross-species plasma stability (t_1/2 > 373 min) supporting translational potential.</p><p><strong>Conclusions: </strong>Dual fatty acid conjugation enables LPJT-026 to form a stable HSA-binding reservoir, achieving biweekly dosing potential, superior glycemic control, and improved safety. LPJT-026 represents a promising next-generation therapy for insulin-dependent diabetes.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3105-3123"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866502","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}

{"title":"Engineering Diffusion-Controlled Drug Delivery Systems to Achieve a Desired Drug Release Profile: Mathematical Modelling and Optimisation.","authors":"Daniele Peri, Elliot J Carr, Giuseppe Pontrelli, Sean McGinty","doi":"10.1007/s11095-026-04149-6","DOIUrl":"10.1007/s11095-026-04149-6","url":null,"abstract":"<p><strong>Objective: </strong>Drug delivery devices offer a promising strategy for the localized treatment of disease while minimising systemic side effects. However, designing diffusion-controlled systems to achieve a prescribed drug release profile remains a major challenge due to their inherently time-varying release rates. This study aims to develop a mathematical framework to enable the rational design of such systems to achieve desired therapeutic release profiles.</p><p><strong>Methods: </strong>We develop a continuum-scale mathematical model describing diffusion-controlled drug release from a spherical microcapsule composed of a functionally graded polymer with spatially varying diffusivity and non-uniform initial drug distribution. These spatial design variables are parameterised using Bézier curves and identified via an inverse optimisation procedure based on a hybrid imperialist competitive algorithm. The framework is applied to two inverse design problems: (i) achieving near constant (zero-order) drug release over a specified time window, and (ii) reproducing prescribed release profiles defined by target checkpoints.</p><p><strong>Results: </strong>The results show that a constant release rate can be achieved by tailoring the initial drug distribution while selecting an appropriate constant diffusivity. In contrast, more general release profiles require simultaneous optimisation of both spatially varying diffusivity and initial drug loading.</p><p><strong>Conclusions: </strong>The proposed framework demonstrates how mathematical modelling and optimisation can enable the rational design of diffusion-controlled drug delivery systems capable of producing tailored therapeutic release behaviours.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3221-3232"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669595","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":"Surfactant Regulation of the Solution-Mediated Phase Transformation of Nitrofurantoin Anhydrate to Monohydrate.","authors":"Zhuangzhuang Chen, Xiyan Wang, An Chen, Lin Li, Zhongting Zhuang, Minshan Guo, Ting Cai","doi":"10.1007/s11095-026-04169-2","DOIUrl":"10.1007/s11095-026-04169-2","url":null,"abstract":"<p><strong>Purpose: </strong>Hydration of metastable anhydrates during dissolution can eliminate their supersaturation advantage and compromise formulation performance. This study used nitrofurantoin as a model system to clarify how surfactant molecular structure regulates solution-mediated phase transformation (SMPT) from anhydrate to monohydrate and supersaturation maintenance.</p><p><strong>Methods: </strong>Six surfactants, including SDS, DTAB, CTAB, STAB, Tween 20, and Tween 80, were evaluated by dissolution testing, solid-state characterization, crystallization kinetics, and molecular dynamics simulations.</p><p><strong>Results: </strong>Surfactants inhibited SMPT in a structure-dependent manner, following the order Tween 80 > STAB > Tween 20 > CTAB > DTAB > SDS ≈ plain buffer. Longer hydrophobic chains more effectively delayed monohydrate nucleation and reduced crystal growth, whereas differences in head-group characteristics further modulated surface adsorption and inhibition among surfactants with comparable chain lengths. Molecular dynamics simulations suggested that stronger adsorption on monohydrate surfaces was associated with greater blockage of growth sites.</p><p><strong>Conclusions: </strong>This study provides mechanistic insight into surfactant-regulated nitrofurantoin hydration, highlighting hydrophobic chain length and head-group characteristics as key structural factors governing surfactant adsorption and stabilization of the anhydrate during dissolution.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3363-3376"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148669549","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}

{"title":"Integrating Clinical Evidence with PBPK Modeling to Assess PPI-Clopidogrel-CYP2C19 Interactions in Chinese ACS Patients.","authors":"Ya-Xin Liu, Yun Kuang, Jun-Long Ma, Jin-Long Liu, Nuo Xu, Qi Pei, Li-Ying Gong, Guo-Ping Yang","doi":"10.1007/s11095-026-04158-5","DOIUrl":"10.1007/s11095-026-04158-5","url":null,"abstract":"<p><strong>Purpose: </strong>The interaction between proton pump inhibitors (PPIs) and clopidogrel in acute coronary syndrome (ACS) patients is mediated by CYP2C19 genetic variants. This study quantitatively assessed their CYP2C19 genotype-dependent impact on clopidogrel pharmacokinetics and pharmacodynamics using clinical data and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling.</p><p><strong>Methods: </strong>A total of 409 ACS patients from a prospective clinical study were genotyped for CYP2C19 (*1, 2, and 3 alleles) and evaluated for platelet reactivity index (PRI) following clopidogrel therapy, with or without concomitant pantoprazole or lansoprazole use. A PBPK model was developed in PK-Sim, incorporating CYP2C19-specific metabolic pathways, and linked with a pharmacodynamic model of P2Y12 receptor inhibition to simulate the effects of genotypes and PPIs on platelet inhibition.</p><p><strong>Results: </strong>In extensive metabolizer individuals, PPI coadministration modestly increased platelet reactivity, while no significant change occurred in poor metabolizers. The PBPK simulations accurately predicted pharmacokinetic parameters, with over 90% of C_max and AUC values within 0.5-twofold of clinical data. The integrated drug-drug-gene interaction-pharmacodynamic framework effectively captured the active metabolite's exposure and platelet inhibition dynamics.</p><p><strong>Conclusions: </strong>These results provide a quantitative understanding of the genotype- and PPI-dependent effects on clopidogrel's pharmacodynamics, offering a tool to personalize therapy in ACS patients.</p>","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":"3145-3157"},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148550069","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}