The AAPS Journal最新文献

{"title":"Effect of Food Composition on the PK of Isoniazid Quantitatively Explained Using Physiologically Based Biopharmaceutics Modeling.","authors":"Xavier Pepin, Sandra Suarez-Sharp","doi":"10.1208/s12248-024-00923-9","DOIUrl":"https://doi.org/10.1208/s12248-024-00923-9","url":null,"abstract":"This work shows the utilization of a physiologically based biopharmaceutics model (PBBM) to mechanistically explain the impact of diverse food types on the pharmacokinetics (PK) of isoniazid (INH) and acetyl-isoniazid (Ac-INH). The model was established and validated using published PK profiles for INH along with a combination of measured and predicted values for the physico-chemical and biopharmaceutical propertied of INH and Ac-INH. A dedicated ontogeny model was developed for N-acetyltransferase 2 (NAT2) in human integrating Michaelis Menten parameters for this enzyme in the physiologically based pharmacokinetic (PBPK) model tissues and in the gut, to explain the pre-systemic and systemic metabolism of INH across different acetylator types. Additionally, a novel equation was proposed to calculate the luminal drug degradation related to the presence of reducing sugars, using individual sugar molar concentrations in the meal. By incorporating luminal degradation into the model, adjusting bile salt concentrations and gastric emptying according to food type and quantity, the PBBM was able to accurately predict the negative effect of carbohydrate-rich diets on the PK of INH.","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":"26 10","pages":"54"},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140661847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Advanced Modeling Approaches Supporting Generic Product Development Under GDUFA for Fiscal Year 2023.","authors":"E. Tsakalozou, Yuqing Gong, A. Babiskin, Meng Hu, Youssef M. Mousa, Ross Walenga, Fang Wu, Miyoung Yoon, Sam G Raney, James E. Polli, A. Schwendeman, Vishalakshi Krishnan, Lanyan Fang, Liang Zhao","doi":"10.1208/s12248-024-00924-8","DOIUrl":"https://doi.org/10.1208/s12248-024-00924-8","url":null,"abstract":"","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":"30 18","pages":"55"},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140659960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Third Generation Solid Dispersion-Based Formulation of Novel Anti-Tubercular Agent Exhibited Improvement in Solubility, Dissolution and Biological Activity.","authors":"Gourav Paudwal, Rigzin Dolkar, Summaya Perveen, Rashmi Sharma, Parvinder Pal Singh, Prem N Gupta","doi":"10.1208/s12248-024-00922-w","DOIUrl":"https://doi.org/10.1208/s12248-024-00922-w","url":null,"abstract":"The long treatment period and development of drug resistance in tuberculosis (TB) necessitates the discovery of new anti-tubercular agents. The drug discovery program of the institute leads to the development of an anti-tubercular lead (IIIM-019), which is an analogue of nitrodihydroimidazooxazole and exhibited promising anti-tubercular action. However, IIIM-019 displays poor aqueous solubility (1.2 µg/mL), which demands suitable dosage form for its efficient oral administration. In the present study, third generation solid dispersion-based formulation was developed to increase the solubility and dissolution of IIIM-019. The solubility profile of IIIM-019 using various polymeric carriers was determined and subsequently, PVP K-30 and P-407 were selected for preparation of binary and ternary solid dispersion. The third-generation ternary solid dispersion comprising PVP K-30 and P-407 revealed a remarkable enhancement in the aqueous solubility of IIIM-019. Physicochemical characterization of the developed formulations was done by employing FTIR spectroscopy, scanning electron microscopy, X-ray diffraction analysis, differential scanning calorimetry, and dynamic light scattering analysis. The dissolution study indicated an impressive release profile with the optimized formulation. The optimized formulation was further examined for cytotoxicity, cellular uptake, and hemolytic activity. The results indicated that the formulation had no apparent cytotoxicity on Caco-2 cells and was non-hemolytic in nature. Moreover, the optimized formulation showed significantly improved anti-tubercular activity compared to the native molecule. These findings showed that the developed third generation ternary solid dispersion could be a promising option for the oral delivery of investigated anti-tubercular molecule.","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":"42 16","pages":"52"},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140672596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in Drug Delivery.","authors":"A. Salem","doi":"10.1208/s12248-024-00920-y","DOIUrl":"https://doi.org/10.1208/s12248-024-00920-y","url":null,"abstract":"","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":"47 4","pages":"49"},"PeriodicalIF":0.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140698958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Cell-Based Therapies Formulations: Unintended Components.","authors":"Fouad Atouf","doi":"10.1208/s12248-022-00747-5","DOIUrl":"https://doi.org/10.1208/s12248-022-00747-5","url":null,"abstract":"","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":" ","pages":"95"},"PeriodicalIF":4.5,"publicationDate":"2022-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40371951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines.","authors":"David A Keire, Robert Bream, Uwe Wollein, Schmaler-Ripcke, Annette Burchardt, Massimiliano Conti, Adam Zmysłowski, Peter Keizers, Justin Morin, Jalene Poh, Mark George, Michael Wierer","doi":"10.1208/s12248-022-00734-w","DOIUrl":"https://doi.org/10.1208/s12248-022-00734-w","url":null,"abstract":"","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":" ","pages":"84"},"PeriodicalIF":4.5,"publicationDate":"2022-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40614256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Process Analytical Technology (PAT) Implementation for Membrane Operations in Continuous Manufacturing of mAbs: Model-Based Control of Single-Pass Tangential Flow Ultrafiltration.","authors":"Garima Thakur,&nbsp;Vishnu Masampally,&nbsp;Amey Kulkarni,&nbsp;Anurag S Rathore","doi":"10.1208/s12248-022-00731-z","DOIUrl":"https://doi.org/10.1208/s12248-022-00731-z","url":null,"abstract":"<p><p>Control of single pass tangential flow ultrafiltration (SPTFF) is crucial for continuous manufacturing of monoclonal antibodies (mAbs). Integrating SPTFF technology into continuous manufacturing trains requires successful resolution of several challenges that arise due to the complexity of mass transfer interactions across multi-membrane configurations, the significant effect of feed material attributes and process variability on flux, and the need for advanced scheduling. In this paper, we propose a real-time, automated monitoring and control strategy for SPTFF in continuous processing of mAbs. The approach leverages a previously developed model for predicting the VCF across an SPTFF module based on the gel polarization model of protein ultrafiltration. A distributed control system (DCS) architecture was created for integrating the monitoring sensors and control elements, including NIRS sensors for concentration monitoring, as well as weighing balances, pressure sensors, pumps, and valves. Two different SPTFF control strategies were developed, firstly for final formulation of the drug product into the drug substance (ultrafiltration and diafiltration), and secondly for in-line concentration between two chromatography steps. Case studies were designed with 15 runs to test the strategy with a range of deviations induced in the feed and process conditions. The retentate concentration was controlled to within 10% of the target value in all runs. The combination of real-time sensor data and model-based control effectively enabled automated and tightly controlled operation of the SPTFF step and is a key enabler of quality by design in continuous mAb manufacturing.</p>","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":" ","pages":"83"},"PeriodicalIF":4.5,"publicationDate":"2022-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40613809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison Between Pure Component Modeling Approaches for Monitoring Pharmaceutical Powder Blends with Near-Infrared Spectroscopy in Continuous Manufacturing Schemes.","authors":"Adam J Rish,&nbsp;Samuel R Henson,&nbsp;Md Anik Alam,&nbsp;Yang Liu,&nbsp;James K Drennen,&nbsp;Carl A Anderson","doi":"10.1208/s12248-022-00725-x","DOIUrl":"https://doi.org/10.1208/s12248-022-00725-x","url":null,"abstract":"<p><p>Near-infrared (NIR) spectroscopy has become an important process analytical technology (PAT) for monitoring and implementing control in continuous manufacturing (CM) schemes. However, NIR requires complex multivariate models to properly extract the relevant information and the traditional model of choice, partial least squares, can be unfavorable on account of its high material and time investments for generating calibrations. To account for this, pure component-based approaches have been gaining attention due to their higher flexibility and ease of development. In the present study, the application of two pure component approaches, classical least squares (CLS) models and iterative optimization technology (IOT) algorithms, to pharmaceutical powder blends in a continuous feed frame was considered. The approaches were compared from both a model performance and practical implementation perspective. IOT were found to demonstrate superior performance in predicting drug content compared to CLS. The practical implementation of each modelling approach was also given consideration.</p>","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":" ","pages":"82"},"PeriodicalIF":4.5,"publicationDate":"2022-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40610355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Titer and Signal to Noise (S/N) for Determination of Anti-drug Antibody Magnitude Using Clinical Data from an Industry Consortium.","authors":"Marta Starcevic Manning,&nbsp;Mohamed Hassanein,&nbsp;Michael A Partridge,&nbsp;Vibha Jawa,&nbsp;Johanna Mora,&nbsp;Josiah Ryman,&nbsp;Breann Barker,&nbsp;Christian Braithwaite,&nbsp;Kevin Carleton,&nbsp;Laura Hay,&nbsp;Charles Hottenstein,&nbsp;Robert J Kubiak,&nbsp;Viswanath Devanarayan","doi":"10.1208/s12248-022-00728-8","DOIUrl":"https://doi.org/10.1208/s12248-022-00728-8","url":null,"abstract":"<p><p>During biotherapeutic drug development, immunogenicity is evaluated by measuring anti-drug antibodies (ADAs). The presence and magnitude of ADA responses is assessed using a multi-tier workflow where samples are screened, confirmed, and titered. Recent reports suggest that the assay signal to noise ratio (S/N) obtained during the screening tier correlates well with titer. To determine whether S/N could more broadly replace titer, anonymized ADA data from a consortium of sponsors was collected and analyzed. Datasets from clinical programs with therapeutics of varying immunogenicity risk levels (low to high), common ADA assay platforms (ELISA and MSD) and formats (bridging, direct, solid-phase extraction with acid dissociation), and titration approaches (endpoint and interpolated) were included in the analysis. A statistically significant correlation between S/N and titer was observed in all datasets, with a strong correlation (Spearman's r > 0.8) in 11 out of 15 assays (73%). For assays with available data, conclusions regarding ADA impact on pharmacokinetics and pharmacodynamics were similar using S/N or titer. Subject ADA kinetic profiles were also comparable using the two measurements. Determination of antibody boosting in patients with pre-existing responses could be accomplished using similar approaches for titer and S/N. Investigation of factors that impacted the accuracy of ADA magnitude measurements revealed advantages and disadvantages to both approaches. In general, S/N had superior precision and ability to detect potentially low affinity/avidity responses compared to titer. This analysis indicates that S/N could serve as an equivalent and in some cases preferable alternative to titer for assessing ADA magnitude and evaluation of impact on clinical responses.</p>","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":" ","pages":"81"},"PeriodicalIF":4.5,"publicationDate":"2022-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40584366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Simulation Study of the Comparative Performance of Partial Area under the Curve (pAUC) and Partial Area under the Effect Curve (pAUEC) Metrics in Crossover Versus Replicated Crossover Bioequivalence Studies for Concerta and Ritalin LA.","authors":"Andre J Jackson,&nbsp;Henry C Foehl","doi":"10.1208/s12248-022-00726-w","DOIUrl":"https://doi.org/10.1208/s12248-022-00726-w","url":null,"abstract":"<p><p>Concerta and Ritalin LA are methylphenidate (MPH) drugs with different release mechanisms. Generic bioequivalence (BE) to these conventionally uses pAUC (partial area under the curve) as metrics in addition to C_max (maximum concentration), AUC0-t (area from time 0 to time t), and AUC0-infinity. The recommended BE design was a standard two-formulation, two-sequence, and two-period crossover; however, the currently recommended design is a replicated crossover to better define subject-by-formulation interaction variance. The current purpose was to compare via simulation, using literature MPH models, the performance of the pAUC metrics in establishing BE via the standard crossover design versus a replicated design, and the relationship of the pAUC metrics to PD (pharmacodynamics) metrics, e.g., SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale) composite scores pAUEC (partial area under the effect curve). One-thousand, 40-subject studies were simulated with model literature parameters. An indirect response model described the SKAMP composite scores corrected for placebo. Performance of the pAUC metrics was demonstrated by the calculation of 90% confidence intervals (CIs) for each k0fast (fast absorption rate constant) and kaslow (slow absorption rate constant) test/reference (T/R) ratio. The 90% CIs resulting from changes in the k0fast and kaslow ratios, e.g., T/R, showed greater sensitivity to changes in the ratios at quotients below 0.8 than above for both Concerta and Ritalin LA. Ritalin LA pAUC values were insensitive to increases in either ratio once the ratio exceeded 1.0 and the study design. Correlations between least squares means (LSM) for pAUC and the SKAMP pAUEC for the composite scores were near 90%.</p>","PeriodicalId":269037,"journal":{"name":"The AAPS Journal","volume":" ","pages":"80"},"PeriodicalIF":4.5,"publicationDate":"2022-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40568577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}