AAPS Journal最新文献

{"title":"Challenges in the Quantification of Free TFPI in Human Plasma Following Marstacimab Treatment.","authors":"Katherine Wright, Kerry Kelleher, Parya Nouri, Lindsay King, Hendrik Neubert","doi":"10.1208/s12248-026-01292-1","DOIUrl":"10.1208/s12248-026-01292-1","url":null,"abstract":"<p><p>Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic coagulation pathway. Marstacimab (PF-06741086), a human immunoglobulin G1 monoclonal antibody, binds the TFPI Kunitz-2 domain to improve hemostatic control in individuals with hemophilia. Quantifying the free form of TFPI, i.e., not bound to marstacimab or endogenous binding proteins, is the most direct assessment of target coverage and modulation following treatment. This investigation describes efforts to develop a quantitative assay to measure free TFPI in human plasma to support the marstacimab drug development program. Three protein enrichment methods (competitive antibody capture, binding partner capture, and drug depletion) were assessed in combination with liquid chromatography-tandem mass spectrometry to develop a bioanalytical free target assay. Surface plasmon resonance (SPR) was used to determine the binding affinities of marstacimab and competitive antibody clones to TFPI. SPR analysis demonstrated marstacimab binds TFPI with a nanomolar affinity (equilibrium dissociation constant [K_D], 3.7 nM), whereas antibody clones had picomolar binding affinities. All assay formats over-recovered TFPI, indicating disruption of the marstacimab:TFPI complex during sample handling and release of bound TFPI, under the experimental conditions reported here. As a result, accurate measurement of free TFPI was not feasible. These findings demonstrate that the sample manipulation required for analysis altered the binding equilibrium of the marstacimab:TFPI complex with release of bound TFPI that compromised assay specificity. In conclusion, the accurate measurement of free TFPI from marstacimab-treated human plasma was not achievable with the approaches tested, in part because marstacimab binds TFPI with a low-nanomolar affinity.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026588","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":"Immunogenicity Profile of Lonapegsomatropin During Long-Term Treatment in Children With Growth Hormone Deficiency.","authors":"Per Holse Mygind, Amiee Weiser, Camilla Melin Fürst, Allison S Komirenko, Meng Mao, Aimee D Shu, Vibeke Miller Breinholt","doi":"10.1208/s12248-026-01294-z","DOIUrl":"10.1208/s12248-026-01294-z","url":null,"abstract":"<p><p>Monitoring and evaluation of immunogenicity is important for biological therapeutics due to the potential impact of antibodies on safety and efficacy. A comprehensive immunogenicity assessment was conducted to support clinical development of lonapegsomatropin, a prodrug of somatropin, administered once weekly. Lonapegsomatropin is approved in the United States for pediatric and adult growth hormone deficiency (GHD), and in other countries for pediatric GHD. Lonapegsomatropin consists of somatropin, an inert methoxy polyethylene glycol carrier (mPEG), and a proprietary TransCon^® linker that transiently binds somatropin to the carrier. Four dedicated immunoassays were developed, validated, and applied in a risk-based tiered approach to rigorously assess the immunogenicity of lonapegsomatropin in children with GHD. Samples collected from 298 children with GHD treated with lonapegsomatropin for up to six years were analyzed for anti-drug antibodies (ADAs) against lonapegsomatropin (intact prodrug), released somatropin, and mPEG. Treatment-emergent anti-lonapegsomatropin, anti-somatropin, and anti-mPEG binding antibodies were detected in 4.7%, 5.4%, and 0.7% of treated children, respectively. ADA responses were low titer, transiently detected, and primarily observed within the first year of treatment, and no neutralizing antibodies were detected. These findings support the long-term low immunogenicity of lonapegsomatropin in children with GHD, consistent with somatropin. Importantly, the multi-assay tiered strategy applied here was robust and reproducible, enabling sensitive detection of ADAs against the intact prodrug, mPEG, and released somatropin across trials, and demonstrated its clinical applicability for evaluating a complex long-acting growth hormone like lonapegsomatropin.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018688","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":"Minimum Significant Ratio for Defining Treatment-Boosted ADA Responses Using Signal-to-Noise as an Alternative to Titer.","authors":"Lili Guo, Kenneth Goldberg, Yong Jiang, Christopher Ehlinger","doi":"10.1208/s12248-026-01306-y","DOIUrl":"10.1208/s12248-026-01306-y","url":null,"abstract":"<p><p>Signal-to-noise ratio (S/N) has emerged as a practical alternative to endpoint titer for evaluating anti-drug antibody (ADA) response magnitude. When titration is not performed, a scientifically justified threshold is needed to interpret longitudinal increases in S/N, particularly for identifying treatment-boosted ADA responses in subjects with pre-existing ADA. In conventional titer-based assessments, treatment-boosted responses are typically defined by an increase of two dilution steps relative to the pre-dose titer. In the absence of titer testing, an alternative threshold is needed to determine whether a post-dose/pre-dose increase in S/N exceeds expected analytical variability. This study evaluated minimum significant ratio (MSR) as a project-specific, analytical variability-based threshold for treatment-boosted ADA response classification using S/N. Two MSR calculation approaches were assessed across 11 validated clinical ADA assays representing diverse assay formats, therapeutic modalities, and analytical platforms. MSR_POS was derived from inter-assay precision data using positive controls, whereas MSR_NEG was derived from ADA-negative individual samples and negative-control data generated during assay validation. Retrospective clinical ADA data from two projects were analyzed to compare longitudinal titer ratios with S/N ratios and evaluate treatment-boosted classifications using conventional titer-ratio and MSR-based S/N approaches. Longitudinal titer ratios and S/N ratios were strongly correlated, and MSR-based classifications were broadly consistent with conventional titer-ratio-based classifications. Compared with MSR_POS, MSR_NEG showed higher positive percent agreement while maintaining high negative and overall percent agreement. Overall, these findings support MSR as a practical, project-specific, and statistically justified analytical framework for applying S/N to longitudinal treatment-boosted ADA response characterization.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018653","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":"Benchmarking Automated Mass Photometry against SEC-MALS and AUC for Quantifying Cross-Linked Monoclonal Antibody Aggregates.","authors":"Mingyue Li, Sharon Polleck, Cliff Entrican, Cassandra Larkin, Brenda Watt, Elizabeth McCoy","doi":"10.1208/s12248-026-01307-x","DOIUrl":"10.1208/s12248-026-01307-x","url":null,"abstract":"<p><p>Monoclonal antibodies (mAbs) play pivotal roles in modern biotherapeutics, offering targeted treatments for diseases such as cancers and autoimmune disorders. However, antibody self-association and propensity for aggregation can potentially compromise intended efficacy and pose safety concerns, necessitating robust analytical methods for aggregate detection and quantification. Traditional techniques like Size Exclusion Chromatography with Multi-angle Light Scattering (SEC-MALS) and analytical ultracentrifugation-sedimentation velocity (AUC-SV) are widely used but are limited by long analysis times, large sample requirements, and potential artifacts. Mass photometry (MP), a novel single-molecule technique, measures the interferometric scattering signal arising from molecules binding and unbinding to a glass slide. This study compares automated MP with SEC-MALS and AUC-SV for mAb aggregation analysis, demonstrating that MP equipped with automated sample handling delivers accurate and consistent analysis for the main and subpopulation species comparable to these established methods. Specifically, MP can not only determine the molecular mass distribution but also provide quantitative analysis of the monomer and High Molecular Mass Species (HMMS) generated with chemical cross-linking. When quantifying cross-linked HMMS of an IgG mAb, MP quantitation shows linear correlation with the SEC method, while MP provided superior resolution and dynamic range compared to SEC-MALS. Furthermore, MP and AUC-SV show comparable resolution in differentiating higher order aggregates and exhibit linear correlation for dimer quantitation, the primary form of mAb HMMS. With the capability to differentiate mAb monomers from various oligomeric forms, MP may represent a new approach that offers significant advantages in efficiency and throughput in quantification and characterization of mAb HMMS.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018645","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":"Synonymous Gene Recoding Affects the Accuracy of Protein Quantification Measurements.","authors":"Nayiri M Kaissarian, Nigam Padhiar, Nathan Clement, Wells W Wu, Upendra Katneni, Anton A Komar, Chava Kimchi-Sarfaty","doi":"10.1208/s12248-026-01310-2","DOIUrl":"10.1208/s12248-026-01310-2","url":null,"abstract":"<p><p>Accurate measurement of therapeutic protein concentration is critical for ensuring manufacturing consistency. Synonymous gene recoding is often used to improve protein yield, including for coagulation Factor IX (FIX), used to treat Hemophilia B. Although synonymous recoding does not alter primary amino acid sequence, it can affect protein conformation, potentially influencing the accuracy of protein quantification depending on the method used. In this study, we investigated whether synonymous changes in F9 gene, which encodes FIX, impacted reliability of commonly used protein quantitation methods. HEK293- FlpIn cells were used to generate FIX proteins expressed from seven different synonymous F9 sequences. Purified proteins were initially measured using absorbance at 280 nm, followed by quantification using various colorimetric, and fluorometric protein assays. Relative differences among protein quantification methods were inconsistent between wild-type and synonymous F9 variants. Compared with A280 measurements, mean differences across variants ranged from - 33% to - 8% for Bradford and from 14 to 54% for BCA, whereas wider ranges were observed for OPA (- 23% to 133%), CBQCA (14% to 282%), and Lowry (1% to 185%). Bradford and BCA also exhibited lower intra-assay variability, with standard deviations of 6% and 10%, respectively, compared with 12%, 18%, and 33% for OPA, CBQCA, and Lowry assays. These findings indicate that synonymous codon substitutions influence protein quantification outcomes, with Bradford and BCA producing more consistent results and lowest variability, whereas amine-reactive fluorescence-based assays (OPA and CBQCA) showed greater inconsistencies. In conclusion, protein quantification methods may not produce consistent accuracy among proteins translated from synonymously recoded sequences.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018685","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":"Investigating the Role of Phenolic Acid Coformers in Enhancing the Physicochemical Properties of Enzalutamide Coamorphous Systems.","authors":"Venkata Krishna Rao Balaga, Argyro Chatziadi, Luděk Ridvan, Miroslav Šoóš","doi":"10.1208/s12248-026-01305-z","DOIUrl":"10.1208/s12248-026-01305-z","url":null,"abstract":"<p><p>Coamorphous systems are gaining interest as an effective formulation strategy to improve the solubility and dissolution of poorly water-soluble drugs. This study investigates the role of phenolic acids as coformers in enhancing the physicochemical properties of enzalutamide (ENZ), a poorly soluble anticancer drug. Five phenolic acids-p-coumaric acid (CMA), ferulic acid (FRA), cinnamic acid (CNA), vanillic acid (VNA), and p-hydroxybenzoic acid (HBA)-were selected based on their glass-forming ability and potential for molecular interactions. Coamorphous systems were prepared and characterized using powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR), and Raman spectroscopy. All coformers successfully induced amorphization, evidenced by halo patterns in PXRD and single glass transition temperatures in mDSC. Spectroscopic analysis confirmed the absence of strong intermolecular bonding, indicating homogeneous mixing. The coamorphous systems exhibited improved solubility across physiological pH conditions and maintained supersaturation for at least four hours under non-sink dissolution testing. These results highlight the potential of phenolic acids as coformers in developing stable, high-performing coamorphous drug systems to enhance the bioavailability of poorly soluble APIs like enzalutamide.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002851","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":"Area Under the Curve-Guided Therapeutic Drug Monitoring of Mycophenolic Acid in Lung Transplant Recipients: Volumetric Absorptive Microsampling and Population Pharmacokinetic-Based Limited Sampling Strategies.","authors":"Liang Juan, Manjunath P Pai, Chao-Wen Lu, Ching-Hua Kuo, Hsao-Hsun Hsu, Shu-Wen Lin, Yu-Ju Tseng","doi":"10.1208/s12248-026-01284-1","DOIUrl":"10.1208/s12248-026-01284-1","url":null,"abstract":"<p><p>Mycophenolate mofetil (MMF), a prodrug rapidly converted to mycophenolic acid (MPA), is widely used after lung transplantation, but fixed-dose therapy is complicated by exposure variability, enterohepatic recirculation, drug interactions, and limited routine use of area under the concentration-time curve (AUC)-guided therapeutic drug monitoring (TDM). Volumetric absorptive microsampling (VAMS) may support less invasive sampling, including later sampling windows relevant to enterohepatic recirculation. This prospective exploratory cohort study enrolled Taiwanese lung transplant recipients receiving MMF for more than three days. MPA concentrations were collected using VAMS at eight time points over a 12-hour dosing interval. Full-profile AUC_0-12 was calculated, multiple linear regression was used to develop limited sampling strategies (LSS), and agreement between LSS-predicted and reference AUC values was assessed using Bland-Altman analysis. Exploratory population pharmacokinetic (popPK) modeling was used to characterize exposure variability. Nine patients were enrolled. MPA exposure was highly variable and generally below the commonly cited AUC_0-12 target range of 30-60 mg·h/L (median AUC_0-12: 18.11 mg·h/L; IQR: 14.33). Two- and three-point LSS models demonstrated strong predictive performance, particularly strategies incorporating both early absorption and later enterohepatic recirculation windows (C1 and C8). Leukopenia and infectious complications were common despite low total MPA exposure. Exploratory popPK analysis supported a one-compartment model with dual absorption pathways and identified patient-related factors associated with exposure variability. VAMS-based LSS may provide a practical approach for estimating MPA AUC_0-12 in Taiwanese lung transplant recipients. These findings support simplified AUC-guided MMF TDM, while the exploratory popPK findings require validation in larger cohorts.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002859","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":"Impact of Extraction Recovery and Matrix Effect on qPCR-based Biodistribution Analysis in Gene Therapy: Strategies for Mitigation.","authors":"Ting Jiang, Zhaomeng Feng, Long Yuan","doi":"10.1208/s12248-026-01313-z","DOIUrl":"10.1208/s12248-026-01313-z","url":null,"abstract":"<p><p>In DNA biodistribution studies, genomic DNA (gDNA) is commonly used as a normalizer for quantifying vector DNA (vDNA) to account for multiple variations including tissue type, sample input, DNA extraction efficiency, etc. Typically, the concentrations of both vDNA and gDNA in elution buffer after extraction are interpolated from standard curves prepared in neat solution, and the derived vector genome per diploid genome (vg/dg) ratio is reported to represent the relative amount of delivered vDNA in tissues. However, the accuracy of this interpolated vg/dg relies on the assumption that vDNA and gDNA have equal extraction efficiencies and are similarly affected by the tissue matrix during qPCR quantification. Despite its widespread use operationally, this assumption has yet to be scientifically examined. In this work, we tested this assumption by co-spiking vDNA and gDNA into the same tissue samples, then conducting DNA extraction and qPCR analysis to compare their extraction recovery and matrix effect. Our results revealed that vDNA and gDNA exhibit differential recovery even from the same sample and are affected differently by the tissue matrix. Consequently, this leads to bias in the interpolation of sample vg/dg values. We proposed and developed two strategies to mitigate the impact of recovery and matrix effect on DNA biodistribution studies: (1) using a matching matrix curve that closely resembles the study samples, and (2) optimizing the DNA extraction protocol to minimize the recovery and matrix effect differences. These strategies have been successfully applied to multiple biodistribution studies. We believe these findings provide valuable insights that enhance the accuracy and reliability of DNA biodistribution analysis in gene therapy research.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002845","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":"Artificial Intelligence in Pharmaceutical Regulatory Science: Opportunities, Challenges, and Emerging Frameworks.","authors":"Inês Lucas, João Sousa, Carla Vitorino","doi":"10.1208/s12248-026-01283-2","DOIUrl":"10.1208/s12248-026-01283-2","url":null,"abstract":"<p><p>Digital transformation in pharmaceutical regulatory affairs is accelerating as global submissions grow in complexity and traditional document-based workflows reach their limits. Artificial intelligence (AI), particularly natural language processing (NLP), is increasingly being explored to support regulatory data management, document preparation, and decision support activities. This review examines AI adoption across pharmaceutical regulatory science, including initiatives from major regulatory agencies, AI-supported regulatory workflows, and emerging governance and interoperability frameworks. Current applications include document classification, data extraction, Common Technical Document (CTD) support, pharmacovigilance, and predictive analytics. Key implementation challenges, including explainability, traceability, validation, data quality, interoperability, cybersecurity, and Good Practice (GxP) compliance requirements, are critically discussed. The review further examines emerging regulatory data ecosystems and governance frameworks that may support the responsible integration of AI into regulatory processes. Collectively, these developments highlight the potential of AI to support more structured, interoperable, and efficient regulatory systems while maintaining regulatory oversight and accountability. Current evidence suggests that AI implementation has progressed from conceptual research toward early operational deployment. However, robust evidence demonstrating sustained improvements in regulatory performance and long-term operational impact remains limited.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002842","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":"A Proposal for the Use of an Innovative Two-Stage PK-Clinical Adaptive Trial in Biosimilar Product Development.","authors":"Weijia Mai, Shein-Chung Chow","doi":"10.1208/s12248-026-01279-y","DOIUrl":"10.1208/s12248-026-01279-y","url":null,"abstract":"<p><p>For approval of biosimilar drug products, the United States Food and Drug Administration (FDA) recommends a stepwise approach for obtaining the totality-of-the evidence for demonstration of the biosimilarity between a proposed biosimilar product and its reference (innovative) product. The stepwise approach consists of the assessment of analytical similarity, pharmacokinetics (PK) similarity or pharmacodynamics (PD) similarity, and clinical similarity, which may be conducted either sequentially or at the same time. Although the stepwise totality-of-evidence framework is scientifically rigorous, it may impose substantial time, cost, and operational burden on companies and may prolong the overall development and regulatory review timeline. These challenges can delay patient access to lower-cost biologic therapies. To improve efficiency while maintaining evidentiary rigor, under the Fundamental Biosimilarity Assumption that PK similarity is predictive of clinical similarity, we propose a biosimilar study utilizing an innovative two-stage adaptive trial design by combining a PK study and a clinical study. The proposed two-stage PK-clinical adaptive trial is efficient in the sense that (i) it allows decision-making at end of the first stage, (ii) it can avoid duplicated effort in demonstration of biosimilarity, (iii) it will shorten the development process, and most importantly (iv) it may reduce the development cost and may increase the probability of success in biosimilar drug development. Under the proposed two-stage PK-clinical adaptive trial design, a biosimilarity index based on the concept of reproducibility probability was derived for demonstration of biosimilarity. The biosimilarity index can also be applied for assessment of drug interchangeability under FDA's recommended switching designs.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 6","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002800","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}