AAPS Journal最新文献

{"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":"<p><p>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.</p>","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}

{"title":"Bioanalytical Method Comparison Strategy for Clinical Anti-drug Antibody Immunoassays.","authors":"R J Elliott, T Pourmohamad, Y Webb-Vargas, W Yan, I Nijem, P Siguenza, Y Song","doi":"10.1208/s12248-024-00999-3","DOIUrl":"https://doi.org/10.1208/s12248-024-00999-3","url":null,"abstract":"<p><p>Per FDA guidance, method comparability should be established if an anti-drug antibody (ADA) assay is run by two or more independent laboratories during a study. Genentech, Inc. is evaluating an immunogenicity risk-based comparability approach consisting of both technical and clinical aspects. Technical comparability of the relative sensitivity (RS) is assessed using the Two One-Sided T-tests (TOST) statistical analysis which evaluates if the difference (in absolute value) of the RS means of the two laboratories is less than a pre-specified level of comparability, the practically significant difference (PSD). Clinical comparability is based on the molecule's immunogenicity risk. A basic and in-depth assessment for low and high-risk molecules are used, respectively. An alternative strategy for molecules with limited incurred sample availability is to be used. In the basic assessment, samples are either unfortified or fortified with surrogate ADA positive control at method appropriate concentrations in a representative biological matrix. Acceptable comparability requires in both methods i) at least 80% of the unfortified samples screen and confirm negative, ii) at least 90% of the low concentration samples screen and confirm positive; and iii) 100% of the high concentration samples screen and confirm positive. The in-depth assessment uses at least 100 incurred samples from 30 or more ADA-positive and ADA-negative patients. The results are evaluated using a 2 by 2-confusion matrix and Cohen's Kappa score where 1 indicates perfect agreement. Acceptable comparability requires a Cohen's Kappa score of greater than 0.40. This strategy allows for a robust technical and clinical method comparability assessment.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"19"},"PeriodicalIF":5.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866171","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":"Regulatory Considerations for Stability Studies of Co-Processed Active Pharmaceutical Ingredient.","authors":"Robert K Orr, Thimma Rawalpally, Lindsey Saunders Gorka, Llorente R Bonaga, Luke Schenck, Stacy Osborne, Deniz Erdemir, Robert J Timpano, Haitao Zhang","doi":"10.1208/s12248-024-00995-7","DOIUrl":"https://doi.org/10.1208/s12248-024-00995-7","url":null,"abstract":"<p><p>A co-processed active pharmaceutical ingredient (CP API) is the combination of an active pharmaceutical ingredient (API) with non-active component(s). This technology has been demonstrated to offer numerous benefits, including but not limited to improved API properties and stability. The infrastructure requirements are such that the manufacture of a CP API is typically best suited for an API facility. CP API has been regulated as either an API or as a drug product intermediate (DPI). This variability in the designation has led to ambiguities on the regulatory CMC expectations in the CP API including the stability of CP API and CP API containing products which, in turn has hampered the broader application of this technology in the pharmaceutical industry. This difference in designation also resulted in challenges to the lifecycle management of the regulatory documentation for the CMC information of the CP API.This white paper represents the proposals for the regulatory requirements on stability studies related to CP API and to drug product containing CP API by the CP API Working Group (WG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). Additionally, considerations and the WG's recommendations on the stability studies of CP API from different manufacturing sites or processes and post-approval changes for product containing CP API are described.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"16"},"PeriodicalIF":5.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848379","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":"Evaluation of Incurred Subject Period Re-analysis (ISPR) as a Tool to Distinguish Fraudulent Pharmacokinetic Profile Pairs from Non-fraudulent Pairs.","authors":"Anders Fuglsang, Anshul Dogra, Naveen Sharma","doi":"10.1208/s12248-024-01000-x","DOIUrl":"https://doi.org/10.1208/s12248-024-01000-x","url":null,"abstract":"<p><p>Duplicate pharmacokinetic profiles in bioequivalence trials is an issue which has caused hundreds of retracted marketing authorizations. No formal test for profile duplication exists in spite of the existence of profile comparison algorithms, so defining a threshold that distinguishes a naturally occurring pair from a duplication remains difficult. An idea called ISPR (incurred subject period analysis) was aired in 2023 and is evaluated in this paper along with three new profile comparison methods. ISPR involves analysis of entire PK-profiles within a study. It is shown that when ISPR is combined with appropriate PK-profile comparison methods, the duplicate pairs display a lower score (better similarity) than pair that do not arise out of duplication. Therefore, ISPR may help establish a threshold that distinguishes fraudulent profile pairs from non-fraudulent profile pairs. ISPR therefore may be used as QA tool, serves as a method by which a CRO can -to some extent- show that their studies do not contain duplicates in the primary analysis, and thus also may be a means by which sponsor can argue that their studies are trustworthy, in case the suspicion about duplication arises. This paper does not introduce a formal test for this type of fraud; rather the authors see it as a first moderate step in that direction. Hopefully, if or when ISPR data is submitted to authorities as part of general dossier submission, data will accumulate to the extent that they may be able to develop models that allow formal testing for profile duplication.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"15"},"PeriodicalIF":5.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840191","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":"Rejoinder to the 'Letter to the Editor' on \"Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies\".","authors":"Helmut Schütz, Divan A Burger, Erik Cobo, David Dubins, Tibor Farkás, Detlew Labes, Benjamin Lang, Jordi Ocaña, Arne Ring, Anastasia Shitova, Volodymyr Stus, Michael Tomashevskiy","doi":"10.1208/s12248-024-01008-3","DOIUrl":"https://doi.org/10.1208/s12248-024-01008-3","url":null,"abstract":"","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"14"},"PeriodicalIF":5.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142840192","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":"Reformation of a Clinical Anti-Drug Antibody Assay to Enable the Immunogenicity Assessment of a Bispecific Antibody Biotherapeutic.","authors":"Wenyu Liu, Jie Yang, Weili Yan, Kun Peng","doi":"10.1208/s12248-024-00996-6","DOIUrl":"https://doi.org/10.1208/s12248-024-00996-6","url":null,"abstract":"<p><p>An enzyme-linked immunosorbent assay (ELISA) based anti-drug antibody (ADA) assay was developed to support the clinical development of a bispecific antibody biotherapeutic anti-A/B. This anti-A/B clinical ADA Version 1 (V1) assay was successfully validated initially using commercial samples from the target indication. However, applying the validation cut point factors (CPFs) led to a high untreated ADA positive rate in the Phase 1 study baseline sample analysis. While implementing the in-study CPFs was effective to mitigate the high baseline prevalence, this led to unfavorable assay sensitivity with no drug tolerance, which necessitated an assay re-optimization. The re-optimized Version 2 assay (V2) was able to mitigate the matrix interference observed in the clinical sample testing using the V1 assay, proven to be a more suitable method. The V2 assay optimization work was discussed, and the performance of the V1 and V2 assays during validation and clinical sample analysis was compared. Preliminary sample testing results generated using the two versions of the assay were compared and the ADA clinical impact was discussed. Our experience insinuates that a successfully validated method does not guarantee to be appropriate for sample testing. Adjustments of the method may be required to ensure that it performs as expected during sample testing and throughout the assay's lifecycle. This work highlights the importance of verifying the assay suitability during clinical sample testing and making appropriate adjustments as needed, especially in the first clinical study and the first study for a new indication.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"12"},"PeriodicalIF":5.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814995","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":"Prediction of Drug-Drug Interactions for Highly Plasma Protein Bound Compounds.","authors":"David Tess, Makayla Harrison, Jian Lin, Rui Li, Li Di","doi":"10.1208/s12248-024-00987-7","DOIUrl":"https://doi.org/10.1208/s12248-024-00987-7","url":null,"abstract":"<p><p>Accurate prediction of drug-drug interactions (DDI) from in vitro data is important, as it provides insights on clinical DDI risk and study design. Historically, the lower limit of plasma fraction unbound (f_u,p) is set at 1% for DDI prediction of highly bound compounds by the regulatory agencies due to the uncertainty of the f_u,p measurements. This leads to high false positive DDI predictions for highly bound compounds. The recently published ICH M12 DDI guideline allows the use of experimental f_u,p for DDI prediction of highly bound compounds. To further build confidence in DDI prediction of highly bound compounds using experimental f_u,p values, we evaluated a set of drugs with f_u,p < 1% and clinical DDI > 20% using both basic and mechanistic static models. All the compounds evaluated were flagged for DDI risk with the mechanistic model using experimental f_u,p values. There was no false negative DDI prediction. Similarly, using the basic model, the DDI risk of all the compounds was identified except for CYP2D6 inhibition of almorexant. The totality of the data demonstrates that the DDI potential of highly bound compounds can be predicted accurately when actual protein binding numbers are measured.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"13"},"PeriodicalIF":5.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814994","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":"Challenging the Standard Immunogenicity Assessment Approach: 1-Tiered ADA Testing Strategy in Clinical Trials.","authors":"Ching-Ha Lai, Mu Chen, Sasha Fraser, Jessica Wang, Sean McAfee, Emma Speaks, Nicholas Simeone, Jacqueline Rodriguez, Colin Stefan, Lisa DeStefano, Chinnasamy Elango, Matthew D Andisik, Giane Sumner, An Zhao, Susan C Irvin, Albert Torri, Michael A Partridge","doi":"10.1208/s12248-024-00993-9","DOIUrl":"https://doi.org/10.1208/s12248-024-00993-9","url":null,"abstract":"<p><p>The ADA testing strategy for protein therapeutics was established almost two decades ago when assay methodologies were rudimentary, and serious immunogenicity-related safety issues had recently been observed with some biotherapeutics. The current testing paradigm employs multiple tiers and stringent cut points to minimize false negatives, reflecting a conservative stance towards ADA analysis. The development of highly sensitive ADA assay platforms and technologies such as humanized or fully human monoclonal antibody (mAb) drugs has put the traditional, resource-intensive 3-tiered testing approach under scrutiny. ADA data from clinical studies for three different mAb programs were re-assessed to explore the feasibility of a simplified 1-tiered ADA testing strategy with a 1% false positive cut point versus the traditional 3-tiered approach. The analysis demonstrated moderate to strong correlations between screening results (signal-to-noise, S/N) and those of confirmation and titer results, with the vast majority of samples (~ 97%) across all studies having the same ADA positive/negative classification with either testing approach. Furthermore, at the subject level, over 92% had the same ADA category (pre-existing, treatment-emergent, treatment-boosted) under both testing approaches. The re-categorized subjects had low titer ADA responses with no observed clinical implications on pharmacokinetics, efficacy, or safety. Finally, the treatment-emergent ADA incidences were comparable between the 1-tiered and 3-tiered approaches. The results demonstrate that the 1-tiered testing strategy is suitable for ADA assessment in these programs and is likely more widely applicable. Additionally, the 1-tiered approach could expedite data delivery and reduce resource needs in clinical development without compromising data quality or clinical interpretation.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"11"},"PeriodicalIF":5.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814993","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":"Interference of Plasticizers on Plasma Protein Binding Measurements.","authors":"Makayla Harrison, Samantha Jordan, Li Di","doi":"10.1208/s12248-024-00988-6","DOIUrl":"https://doi.org/10.1208/s12248-024-00988-6","url":null,"abstract":"<p><p>Accurate measurement of plasma protein binding (PPB) is of critical importance in drug discovery. Methodologies for PPB measurement continue to evolve to address the challenges of highly bound compounds. In order to generate high quality PPB data, it is crucial to not only apply state-of-the-art methods and highly sensitive and selective detectors, but also use high-quality plasma. In this study, we found that plasticizers, leaching from polyvinyl chloride (PVC) plasma storage bags, interfered with drug binding to both human α1-acid glycoprotein (AAG) and human serum albumin (HSA). Several AAG and HSA binding drugs were used to probe the differences in PPB using blood/plasma collected and stored in PVC bags or glass tubes through vacutainers. The results showed that plasma collected using vacutainers into the glass tubes has lower plasma fraction unbound (f_u,p) values than those from the PVC bags. The f_u,p differences can be as high as 32-fold. Hence, it is recommended to use vacutainers and glass tubes rather than PVC bags, for blood collection and plasma storage. Plasma from animal species collected using polypropylene syringes into polyethylene tubes showed no differences in f_u,p from plasma collected using vacutainers into glass tubes. Not all compounds are sensitive to plasticizer interference for PPB. It is therefore important to select appropriate positive controls for f_u,p measurement, such as warfarin for HSA and imatinib for AAG, to monitor the quality of plasma and minimize the interference from plasticizers.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"10"},"PeriodicalIF":5.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808063","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":"Quantitative Analysis of Physical Stability Mechanisms of Amorphous Solid Dispersions by Molecular Dynamic Simulation.","authors":"Hao Zhong, Tianshu Lu, Ruifeng Wang, Defang Ouyang","doi":"10.1208/s12248-024-01001-w","DOIUrl":"10.1208/s12248-024-01001-w","url":null,"abstract":"<p><p>Amorphous solid dispersions (ASDs) represent a promising strategy for enhancing the solubility of poorly soluble drugs. However, the mechanisms underlying the physical stability of ASDs remain insufficiently understood. This study aims to investigate these mechanisms and propose quantitative thresholds to predict the maximum stable drug loading using molecular dynamics simulations. Poly(vinylpyrrolidone) (PVP) and poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA64) are selected as polymeric carriers, while naproxen and acetaminophen serve as model drugs, resulting in the formulation of 18 distinct ASDs across four types for comparison with experimental results. Our findings indicate that the molecular mobility of active pharmaceutical ingredients (APIs) is the primary determinant of solid dispersion stability. High polymer concentrations limit drug molecular mobility through spatial structural constraints and ASD viscosity. As drug loading increases, the polymer concentration reaches a critical threshold (C*), beyond which drug-rich regions form, leading to potential aggregation, rearrangement, and recrystallization of drug molecules into more energetically stable forms. Notably, both the interaction energy and diffusion coefficient show sharp fluctuations at the maximum stable drug loading, which can serve as predictive indicators for ASD stability. Additionally, a search strategy is used to identify potential pre-crystalline sites. By integrating kinetic, thermodynamic, and pre-crystalline analyses through molecular dynamics simulations, this study provides a foundation for more accurate predictions of ASD stability, significantly aiding future formulation development.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"27 1","pages":"9"},"PeriodicalIF":5.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787742","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}