AAPS Journal最新文献_第3页

Comparison of RT-qPCR With Branched DNA to Quantify a Lipid Nanoparticle-Encapsulated mRNA Therapeutic in Serum and Liver Tissue Samples From Nonclinical PK Studies.

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-16 DOI: 10.1208/s12248-024-01002-9

Jessica Ortiz, Laura Brunner, Lei Ci, Rena Baek, Darshana Jani, Jean-Claude Marshall, Jason Pennucci

{"title":"Comparison of RT-qPCR With Branched DNA to Quantify a Lipid Nanoparticle-Encapsulated mRNA Therapeutic in Serum and Liver Tissue Samples From Nonclinical PK Studies.","authors":"Jessica Ortiz, Laura Brunner, Lei Ci, Rena Baek, Darshana Jani, Jean-Claude Marshall, Jason Pennucci","doi":"10.1208/s12248-024-01002-9","DOIUrl":"https://doi.org/10.1208/s12248-024-01002-9","url":null,"abstract":"While the branched DNA (bDNA) assay is an established bioanalytical method for measurement of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) pharmacokinetic parameters, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) has been considered as an alternative platform. RT-qPCR and bDNA platforms were compared for sensitivity, specificity, correlation, and overall assay performance using serum and tissue samples from 2 nonclinical mouse studies of a therapeutic mRNA candidate, LNP-PAH-mRNA, which encodes for human phenylalanine hydroxylase enzyme. Pharmacokinetic parameter noncompartmental analysis was completed using Phoenix WinNonlin. The assays were compared using simple linear regression and Bland-Altman analyses. Sensitivity ranged from 0.05 to 6.40 ng/mL for the bDNA assays, from 0.00000761 to 7.61 ng/mL in serum, and from 0.000179 to 179 ng/g in tissue for the RT-qPCR assay. Inter-assay accuracy was within ± 10%, inter-assay precision was ≤ 10%, and the total error for both assays was ≤ 20%. RT-qPCR serum mRNA concentrations were 2- to fourfold lower compared with the bDNA assay, whereas tissue samples were comparable between assays. A linear relationship with - 0.37 to - 0.02 systematic bias demonstrated acceptable concordance. Bland-Altman plots demonstrated close equivalence, with a negative bias of < 0.5, and ≥ 95% of the data points were within the 95% limits of agreement. The comparison of the RT-qPCR with bDNA assay platforms for quantification of pharmacokinetic properties of an mRNA-LNP therapeutic has demonstrated acceptable concordance. This comparison reinforces the use of the RT-qPCR, a widely accessible strategy, as an alternative platform for the quantification of subsequent mRNA-LNP therapeutics.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"27"},"PeriodicalIF":5.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056137","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

Population Pharmacokinetics of Sotorasib in Healthy Subjects and Advanced Solid Tumor Patients Harboring a KRAS^G12C Mutation from Phase 1 and Phase 2 Studies.

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-13 DOI: 10.1208/s12248-024-01013-6

Mario Nagase, Brett Houk, Irene Vuu, Panli Cardona, Sandeep Dutta, Chih-Wei Lin

{"title":"Population Pharmacokinetics of Sotorasib in Healthy Subjects and Advanced Solid Tumor Patients Harboring a KRASG12C Mutation from Phase 1 and Phase 2 Studies.","authors":"Mario Nagase, Brett Houk, Irene Vuu, Panli Cardona, Sandeep Dutta, Chih-Wei Lin","doi":"10.1208/s12248-024-01013-6","DOIUrl":"https://doi.org/10.1208/s12248-024-01013-6","url":null,"abstract":"Sotorasib is a novel KRASG12C inhibitor that has shown robust efficacy, safety, and tolerability in patients with KRASG12C mutation. The objectives of the population pharmacokinetic (PK) analysis were to characterize sotorasib population PK in healthy subjects and patients with advanced solid tumors with KRASG12C mutation from 6 clinical studies, evaluate the effects of intrinsic and extrinsic factors on PK parameters, and perform simulations to further assess the impact of identified covariates on sotorasib exposures. A two-compartment disposition model with three transit compartments for absorption and time-dependent clearance and bioavailability well described sotorasib PK. Sotorasib exposure increased in a less-than-dose proportional manner across the evaluated 180 mg to 960 mg dose range. Disease burden, measured by Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size, were identified as significant covariates on clearance. Lower disease burden was associated with higher clearance (and thus lower sotorasib exposure). Low albumin was found to be associated with lower clearance of sotorasib. Use of PPIs was associated with reduced sotorasib exposures. Although sex, race, and high fat meal were significantly associated with PK parameters, their impact on exposures were not clinically relevant. Other evaluated covariates, including body weight, age, renal impairment (evaluated by chronic kidney disease stage score) and hepatic impairment (evaluated by NCI criteria) were not statistically significant. Greater baseline disease burden and low albumin were associated with lower sotorasib clearance; based on the established efficacy and safety profiles from clinical trials, the estimated magnitude of these effects does not warrant a dose adjustment.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"26"},"PeriodicalIF":5.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056104","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

Meta-Analysis of the Input and Disposition of Various Dosage Forms of Methylprednisolone in Healthy Subjects Utilizing a Physiologically Based Pharmacokinetic Model. 利用基于生理的药代动力学模型对健康受试者中不同剂型甲基强的松龙的输入和处置进行meta分析。

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-09 DOI: 10.1208/s12248-024-01011-8

Ruihong Yu, William J Jusko

{"title":"Meta-Analysis of the Input and Disposition of Various Dosage Forms of Methylprednisolone in Healthy Subjects Utilizing a Physiologically Based Pharmacokinetic Model.","authors":"Ruihong Yu, William J Jusko","doi":"10.1208/s12248-024-01011-8","DOIUrl":"10.1208/s12248-024-01011-8","url":null,"abstract":"The study quantitatively analyzes and compares the pharmacokinetics (PK) of methylprednisolone (MPL) in humans upon administration of various dosage forms. The PK parameters and profiles of MPL in healthy subjects were collected from 22 literature sources. A minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue (lumped liver and kidney, remainder) compartments with nonlinear tissue partitioning was applied to describe MPL disposition. Overall 18 plasma concentration profiles were well captured and 85% of PK parameters reasonably estimated. The clearance (CL) of MPL averaged 336 mL/h/kg and appeared slightly nonlinear across a dosage range of 5 to 800 mg, the distribution volume (Vd) averaged 1.17 L/kg, and the model predicted elimination half-life (t1/2) was 2.6 h. Rapid prodrug conversion was found for intravenous MPL sodium succinate (MPSS) with a t1/2 of 1.7 min, and followed by MPL phosphate (MPPS) 3.8 min, MPL hemisuccinate (MPHS) 16 min, and MPL suleptanate (MPSP) 2.9 h. Their bioavailabilities (F) varied slightly from 60 to 73%. Intramuscular doses showed an absorption rate constant (ka) of 1.5 h-1 for MPSS and 96 h-1 for MPSP. Oral doses of 5 formulations were examined. Medrol exhibited greatest absorption with F of 74% and ka of 2.1 h-1, while one generic product had F of 32.6%. This study demonstrated the utility of a mechanistic mPBPK disposition model for comparing MPL formation from various esters, absorption from several oral dose formulations, and modest variability across numerous PK studies in healthy humans.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"24"},"PeriodicalIF":5.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958403","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

Early and Mid-Term Disposition of α-PVP and its unknown Metabolites in Urine and Oral Fluid Through a Multi-Analytical Hyphenated Approach Following a Single Non-Controlled Administration to Healthy Volunteers. 健康志愿者单次非对照给药后尿液和口服液中α-PVP及其未知代谢物的早期和中期处置

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-09 DOI: 10.1208/s12248-024-01012-7

Annagiulia Di Trana, Nunzia La Maida, Georgina de la Rosa, Alessandro Di Giorgi, Silvia Graziano, Khaled Aldhaehri, Esther Papaseit, Olga Hladun, Magí Farré, Clara Pérez, Simona Pichini

{"title":"Early and Mid-Term Disposition of α-PVP and its unknown Metabolites in Urine and Oral Fluid Through a Multi-Analytical Hyphenated Approach Following a Single Non-Controlled Administration to Healthy Volunteers.","authors":"Annagiulia Di Trana, Nunzia La Maida, Georgina de la Rosa, Alessandro Di Giorgi, Silvia Graziano, Khaled Aldhaehri, Esther Papaseit, Olga Hladun, Magí Farré, Clara Pérez, Simona Pichini","doi":"10.1208/s12248-024-01012-7","DOIUrl":"10.1208/s12248-024-01012-7","url":null,"abstract":"Nowadays, synthetic cathinones (SCs) is the second more representative subclass of New Psychoactive Substances, accounting for 104 analogues in the illegal market. Since its first report in 2011, α-pyrrolidinovalerophenone (α-PVP) gained popularity among drug users, provoking an increased number of intoxications. Nonetheless, pharmacokinetics data is still limited in the literature. An observational non-controlled naturalistic study on 8 healthy volunteers was conducted to assess the α-PVP and β-OH-α-PVP concentrations in OF and urine, after snorting 10 mg or 20 mg of α-PVP. A multi-analytical approach based on GC-EI-MS/MS and LC-HESI-HRMS/MS was developed and fully validated for the analytes quantification, while four untargeted LC-HESI-HRMS/MS methods in full-MS and ddMS2 were set up for unknown metabolites characterization in urine samples assisted by a dedicated data mining software. In OF, α-PVP reached a mean Cmax of 762 ± 323 ng/mL at 1 h after 10 mg administration, while a Cmax of 2,900 ± 1,373 ng/mL at 47 min after 20 mg dose. In urine, a total α-PVP mean amount of 179.2 ± 94.9 µg was accumulated after 10 mg dose, (27.2 ± 9.8 µg between 0-2 h and 152.0 ± 98.2 µg between 2-5 h), while a total amount of 122.9 ± 44.0 µg, of (36.2 ± 16.5 and 86.7 ± 28.3 µg between 0-2 and 2-5 h, respectively) was detected after 20 mg dose. Among the 10 identified metabolites, β-OH-α-PVP was a minor metabolite (total amount: 56.4 ± 27.1 and 69.1 ± 38.1 µg after 10 mg and 20 mg). The N-butanoic acid metabolite was the most abundant, detected also as glucuronide. In conclusion, α-PVP showed a later time peak than non-pyrrolidine SCs, with comparable Cmax. The pyrrolidine ring oxidative opening produced the most abundant urinary metabolite, independently from the dose.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"25"},"PeriodicalIF":5.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958435","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

Simultaneous Quantification of Total Antibody and Conjugated Payload for DS001 in Rat Serum Using a Hybrid Immuno-Capture LC-MS/MS. 利用混合免疫捕获LC-MS/MS同时定量大鼠血清中DS001的总抗体和共轭有效载荷。

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-07 DOI: 10.1208/s12248-024-01007-4

Xiong Yu, Weiqiang Li, Wensi Huang, Bo Xiao, Jing Long, Qi Wang, Guifeng Wang, Chunhe Wang, Mingming Yu, Jinghua Yu, Xingxing Diao

{"title":"Simultaneous Quantification of Total Antibody and Conjugated Payload for DS001 in Rat Serum Using a Hybrid Immuno-Capture LC-MS/MS.","authors":"Xiong Yu, Weiqiang Li, Wensi Huang, Bo Xiao, Jing Long, Qi Wang, Guifeng Wang, Chunhe Wang, Mingming Yu, Jinghua Yu, Xingxing Diao","doi":"10.1208/s12248-024-01007-4","DOIUrl":"https://doi.org/10.1208/s12248-024-01007-4","url":null,"abstract":"Antibody-drug conjugates (ADCs) are intricate compounds that pose significant challenges in bioanalytical characterization. Therefore, multiple bioanalytical methods are required to comprehensively elucidate their pharmacokinetic (PK) profiles. In this study, we investigated DS001, an ADC consisting of a humanized monoclonal antibody (hRS7), a cleavable chemical linker, and the microtubule inhibitor monomethyl auristatin E (MMAE), with a drug-to-antibody ratio (DAR) of 8. This study established a rapid and sensitive hybrid immunoaffinity liquid-chromatography-tandem-mass-spectrometry (LC-MS/MS) approach for the simultaneous quantification of the total antibody and the enzymatically cleavable conjugated payload of DS001. This method is capable of monitoring fluctuations in average DAR values during PK assessments. The sample preparation procedure involved immunocapture, denaturation, trypsin digestion, papain digestion, and termination, all completed within a total processing time of less than 4 h. The method demonstrated linearity for the total antibody in the range of 100 ng/mL (lower-limit-of-quantification, LLOQ) to 100,000 ng/mL, and for the conjugated payload from 3.495 ng/mL (LLOQ) to 3495 ng/mL in rat serum. Both analytes exhibited standard curve correlation coefficients (r) greater than 0.990 within their respective linear ranges. The precision and accuracy of the method were within ± 15% (± 20% for LLOQ). The verified LC-MS/MS approach was successfully employed in the PK analysis following intravenous administration of 0.2 mg/kg DS001 in rats via tail vein injection.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"23"},"PeriodicalIF":5.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958406","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

Innovative Approaches in Regulatory Affairs: Leveraging Artificial Intelligence and Machine Learning for Efficient Compliance and Decision-Making. 监管事务中的创新方法：利用人工智能和机器学习实现高效合规和决策。

IF 5 3区医学

AAPS Journal Pub Date : 2025-01-07 DOI: 10.1208/s12248-024-01006-5

C S Ajmal, Sravani Yerram, V Abishek, V P Muhammed Nizam, Gayatri Aglave, Jayasri Devi Patnam, Rajeev Singh Raghuvanshi, Saurabh Srivastava

{"title":"Innovative Approaches in Regulatory Affairs: Leveraging Artificial Intelligence and Machine Learning for Efficient Compliance and Decision-Making.","authors":"C S Ajmal, Sravani Yerram, V Abishek, V P Muhammed Nizam, Gayatri Aglave, Jayasri Devi Patnam, Rajeev Singh Raghuvanshi, Saurabh Srivastava","doi":"10.1208/s12248-024-01006-5","DOIUrl":"10.1208/s12248-024-01006-5","url":null,"abstract":"Artificial Intelligence (AI) and AI-driven technologies are transforming industries across the board, with the pharmaceutical sector emerging as a frontrunner beneficiary. This article explores the growing impact of AI and Machine Learning (ML) within pharmaceutical Regulatory Affairs, particularly in dossier preparation, compilation, documentation, submission, review, and regulatory compliance. By automating time-intensive tasks, these technologies streamline workflows, accelerate result generation, and shorten the product approval timeline. However, despite their immense potential, AI and ML also introduce new challenges. Issues such as AI software validation, data management security and privacy, potential biases, ethical concerns, and change management requirements must be addressed. This review highlights current AI-based tools actively used by regulatory professionals such as DocShifter, Veeva Vault, RiskWatch, Freyr SubmitPro, Litera Microsystems, cortical.io etc., examines both the benefits and obstacles of integrating these advanced systems into regulatory practices. Given the rapid pace of technological innovation, the article underscores the need for proactive collaboration with regulatory bodies to manage these developments. It also stresses the importance of adapting to evolving regulatory frameworks and embracing new technologies. Although regulatory agencies like the United Sates Food and Drug Administration (USFDA), European Medicines Agency (EMA), and Medicines and Healthcare products Regulatory Agency (MHRA) are working on guidelines for AI and ML adoption, clear, standardized protocols are still in the works. While the journey ahead may be complex, the integration of AI promises to fundamentally reshape regulatory processes and accelerate the approval of safe, effective pharmaceutical products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"22"},"PeriodicalIF":5.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958441","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

Pharmacokinetic-pharmacodynamic Modelling of NH600001 in Healthy Subjects and Patients Undergoing Gastroscopy. NH600001在健康人及胃镜检查患者体内的药代动力学-药效学模型。

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-21 DOI: 10.1208/s12248-024-01004-7

Yaxin Liu, Yun Kuang, Jie Huang, Dan Jiang, Yajie Cao, Qi Gao, Zifeng Li, Wen Ouyang, Saiying Wang, Qi Pei, Guoping Yang

{"title":"Pharmacokinetic-pharmacodynamic Modelling of NH600001 in Healthy Subjects and Patients Undergoing Gastroscopy.","authors":"Yaxin Liu, Yun Kuang, Jie Huang, Dan Jiang, Yajie Cao, Qi Gao, Zifeng Li, Wen Ouyang, Saiying Wang, Qi Pei, Guoping Yang","doi":"10.1208/s12248-024-01004-7","DOIUrl":"https://doi.org/10.1208/s12248-024-01004-7","url":null,"abstract":"NH600001 is a new general anaesthetic drug with a structure similar to etomidate. The objective of this study was to investigate the relationship between concentrations of NH600001 and sedation efficacy based on data from phase I-II studies and factors influencing the pharmacokinetics and pharmacodynamics of NH600001. The dataset consisted of 2 phase I studies in healthy subjects and 1 phase II study in patients undergoing gastroscopy. Nonlinear mixed effects modeling was used in developing the population pharmacokinetics and pharmacodynamics (PopPK/PD) model of NH600001. Three-compartment model was used to describe the PK profile of NH600001. Parameters were used for allometric scaling on body weight, where the exponents were set to 0.75 for clearance and 1 for volumes. Co-administration of alfentanil hydrochloride influenced the distribution volume of the central compartment and clearance. Effect of patients undergoing gastroscopy (compared with healthy subjects) on clearance, the distribution volume of the superficial peripheral compartment and inter-compartmental clearance for deep peripheral compartment and central compartment was included the final PopPK model. The effect compartment model well characterized the PK/PD relationship of NH600001. Simulation results showed that an initial dose of 0.25 mg/kg of NH600001 resulted in rapid sedation, and three additional doses at 5-min intervals could maintain sedation for more than 20 min. A PopPK/PD model was successfully constructed for NH600001 in healthy subjects and in patients undergoing gastroscopy that could inform the dosing regimens of the forthcoming phase III study.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"21"},"PeriodicalIF":5.0,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873153","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

Cell-Based Assays to Detect Innate Immune Response Modulating Impurities: Application to Biosimilar Insulin. 基于细胞的检测先天免疫反应调节杂质的方法：应用于生物类似药胰岛素。

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-20 DOI: 10.1208/s12248-024-00983-x

Cheng Her, Seth Thacker, Joseph Balsamo, Logan Kelley Baker, Derek Dc Ireland, Eric Pang, Daniela Verthelyi

{"title":"Cell-Based Assays to Detect Innate Immune Response Modulating Impurities: Application to Biosimilar Insulin.","authors":"Cheng Her, Seth Thacker, Joseph Balsamo, Logan Kelley Baker, Derek Dc Ireland, Eric Pang, Daniela Verthelyi","doi":"10.1208/s12248-024-00983-x","DOIUrl":"https://doi.org/10.1208/s12248-024-00983-x","url":null,"abstract":"Characterizing and mitigating factors that impact product immunogenicity can aid in risk assessment and/or managing risk following manufacturing changes. For follow-on products that have the same indication, patient population, and active product ingredient, the residual immunogenicity risk resides predominantly on differences in product and process related impurities. Characterizing differences in innate immune modulating impurities (IIRMI), which could act as adjuvants by activating local antigen presenting cells (APCs), can inform the immunogenicity risk assessment potentially reducing the need for clinical trials. To date, assays to detect trace levels of IIRMI are being used to support regulatory decisions by FDA for selected synthetic peptide drug products that refer to reference listed drugs of rDNA origin but not recombinant protein or peptide products where more complex mixtures of trace impurities including host cell proteins are expected. Here we describe an exercise to explore whether or not there are differences in the innate immune response elicited by an insulin glargine (produced in E. coli) and its interchangeable biosimilar insulin (produced in P. pastoris) that could indicate differences in IIRMI. Our results suggest the two products elicit comparable innate immune responses as determined by the expression of 90 immune-related genes, including IL-1α, IL-1β, IL-6, CCL3, CCL2, and CXCL8. The data suggest that these assays can provide useful information when assessing recombinant proteins for the presence of IIRMI.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"20"},"PeriodicalIF":5.0,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873142","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

PK/PD Evaluation of Antibody-Drug Conjugates with Enhanced Immune Effector Functions. 增强免疫效应功能的抗体-药物偶联物的PK/PD评价。

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-19 DOI: 10.1208/s12248-024-00998-4

Hsuan-Ping Chang, Shufang Liu, Dhaval K Shah

{"title":"PK/PD Evaluation of Antibody-Drug Conjugates with Enhanced Immune Effector Functions.","authors":"Hsuan-Ping Chang, Shufang Liu, Dhaval K Shah","doi":"10.1208/s12248-024-00998-4","DOIUrl":"https://doi.org/10.1208/s12248-024-00998-4","url":null,"abstract":"Optimizing the interaction between antibody (mAb)-based therapeutics and immune effector functions (EFs) offers opportunities to improve the therapeutic window of these molecules. However, the role of EFs in antibody-drug conjugate (ADC) efficacy and toxicity remains unknown, with limited studies that have investigated how modulation of EF affects the pharmacology of ADCs. This study aimed to evaluate the effect of EF modulation on ADC efficacy using trastuzumab-vc-MMAE as a model ADC. A series of ADCs with enhanced or eradicated EF were synthesized through Fc engineering of the antibody. Cell-based assays confirmed that the alteration of EFs in ADCs did not change their in vitro potency, and the conjugation of vc-MMAE did not alter the trends in EFs modulation. Pharmacokinetic/pharmacodynamic (PK/PD) studies of Fc engineered ADCs were conducted in a syngeneic mouse system. The enhancement of EFs led to lower systemic exposure, faster clearance, and potentially enhanced tissue distribution and accumulation of ADCs. ADCs with enhanced EFs demonstrated improved efficacy in the syngeneic mouse tumor model, which was quantitatively confirmed by PK/PD modeling. The model indicated that EF enhancement was synergistic for ADC efficacy, whereas the complete removal of EF was less than additive. Our study suggests that developing ADCs with enhanced EF may improve the therapeutic effectiveness of ADCs, although the effect of this modification on ADC safety and extrapolation of our findings to other ADCs necessitates further investigation.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"18"},"PeriodicalIF":5.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866133","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

Quantitative Comparison and Clustering of Circular Dichroism Spectra Using a Symmetrized Weighted Spectral Difference. 利用对称加权谱差对圆二色光谱进行定量比较和聚类。

IF 5 3区医学

AAPS Journal Pub Date : 2024-12-19 DOI: 10.1208/s12248-024-01005-6

Karim Chouchane, Marina Kirkitadze, Rahul Misra, Przemyslaw Kowal, Olivier Dalloz-Bourguignon, Frederic Greco, Sylvie Fayard, Sergio Marco, Didier Clenet

{"title":"Quantitative Comparison and Clustering of Circular Dichroism Spectra Using a Symmetrized Weighted Spectral Difference.","authors":"Karim Chouchane, Marina Kirkitadze, Rahul Misra, Przemyslaw Kowal, Olivier Dalloz-Bourguignon, Frederic Greco, Sylvie Fayard, Sergio Marco, Didier Clenet","doi":"10.1208/s12248-024-01005-6","DOIUrl":"https://doi.org/10.1208/s12248-024-01005-6","url":null,"abstract":"Spectroscopy (UV-visible, circular dichroism, infrared, Raman, fluorescence, etc.) is of fundamental importance to determine the structures of macromolecules and monitor their stability, especially for drug products, based on proteins or nucleic acids. In their 2014 article, Dinh et al. proposed Weighted Spectral Difference (WSD) as a method to quantitatively compute the dissimilarity of a given spectrum to a reference one. Despite the various properties of this method, its lack of symmetry and dependence on the selection of a reference limits the range of possible applications. Here, we propose a reference-free, symmetrized version of WSD (SWSD) that allows the computation of a semi-distance between two spectra. SWSD can be applied to perform group comparisons, track spectral kinetics, or construct a SWSD matrix leading to the hierarchical clustering of spectra. This method was tested on circular dichroism spectra from a split-virus-based (influenza) vaccine and a recombinant spike protein (COVID-19 vaccine). This approach resulted, first, in a perfect clustering of influenza A and B viruses into two distinct clusters, and second, in the detection of the change of secondary structure of the spike protein during a heating experiment, identifying two main temperatures of denaturation (Tm) by SWSD kinetics, in agreement with results obtained by conventional DSC. In summary, we have shown that SWSD is a versatile and efficient tool for quantitative spectral comparison, tracking spectral kinetics and enabling relevant unsupervised classification.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"17"},"PeriodicalIF":5.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866135","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