AAPS Journal最新文献_第10页

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-11-30 DOI: 10.1208/s12248-023-00873-8

Morgan C Marsh, Shawn C Owen

引用次数: 0

Correction: A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications. 更正:一种用于预测药代动力学应用的连续再循环的新型微流体肝组织芯片。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-11-20 DOI: 10.1208/s12248-023-00872-9

Shiny Amala Priya Rajan, Jason Sherfey, Shivam Ohri, Lauren Nichols, J Tyler Smith, Paarth Parekh, Eugene P Kadar, Frances Clark, Billy T George, Lauren Gregory, David Tess, James R Gosset, Jennifer Liras, Emily Geishecker, R Scott Obach, Murat Cirit

引用次数: 0

Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development. 临床桥接研究和建模方法，以实现以患者为中心的抽样技术在帕德维尼临床开发。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-11-16 DOI: 10.1208/s12248-023-00866-7

Hester Kramer, Ceyhun Bicer, Christian Otoul, Chiara Rospo, Merran Macpherson, Mark Watling, Massimo Bani, David Sciberras, Hugues Chanteux

{"title":"Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development.","authors":"Hester Kramer, Ceyhun Bicer, Christian Otoul, Chiara Rospo, Merran Macpherson, Mark Watling, Massimo Bani, David Sciberras, Hugues Chanteux","doi":"10.1208/s12248-023-00866-7","DOIUrl":"10.1208/s12248-023-00866-7","url":null,"abstract":"Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra®) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra®) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"26 1","pages":"1"},"PeriodicalIF":4.5,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136400138","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

The AAPS Journal Theme Issue: "Perspectives on Clinical Drug Development of Long-Acting Injectables". AAPS杂志主题议题:“长效注射剂临床药物开发展望”。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-11-14 DOI: 10.1208/s12248-023-00871-w

Huybrecht T'jollyn, Oliver Ackaert

引用次数: 0

Drug Dissolution in Oral Drug Absorption: Workshop Report. 口服药物吸收中的药物溶出度：研讨会报告。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-11-07 DOI: 10.1208/s12248-023-00865-8

Kimberly Raines, Payal Agarwal, Patrick Augustijns, Alaadin Alayoubi, Lucas Attia, Annette Bauer-Brandl, Martin Brandl, Parnali Chatterjee, Hansong Chen, Yuly Chiang Yu, Carrie Coutant, Ana Luisa Coutinho, David Curran, Jennifer Dressman, Bryan Ericksen, Leah Falade, Yi Gao, Zongming Gao, Debasis Ghosh, Tapash Ghosh, Anitha Govada, Elizabeth Gray, Ruiqiong Guo, Dana Hammell, Andre Hermans, Rohit Jaini, Hanlin Li, Haritha Mandula, Shuaiqian Men, Johanna Milsmann, Huong Moldthan, Rebecca Moody, Dana E Moseson, Anette Müllertz, Roshni Patel, Kalpana Paudel, Christos Reppas, Rajesh Savkur, Kerstin Schaefer, Abu Serajuddin, Lynne S Taylor, Rutu Valapil, Kevin Wei, Werner Weitschies, Shinji Yamashita, James E Polli

{"title":"Drug Dissolution in Oral Drug Absorption: Workshop Report.","authors":"Kimberly Raines, Payal Agarwal, Patrick Augustijns, Alaadin Alayoubi, Lucas Attia, Annette Bauer-Brandl, Martin Brandl, Parnali Chatterjee, Hansong Chen, Yuly Chiang Yu, Carrie Coutant, Ana Luisa Coutinho, David Curran, Jennifer Dressman, Bryan Ericksen, Leah Falade, Yi Gao, Zongming Gao, Debasis Ghosh, Tapash Ghosh, Anitha Govada, Elizabeth Gray, Ruiqiong Guo, Dana Hammell, Andre Hermans, Rohit Jaini, Hanlin Li, Haritha Mandula, Shuaiqian Men, Johanna Milsmann, Huong Moldthan, Rebecca Moody, Dana E Moseson, Anette Müllertz, Roshni Patel, Kalpana Paudel, Christos Reppas, Rajesh Savkur, Kerstin Schaefer, Abu Serajuddin, Lynne S Taylor, Rutu Valapil, Kevin Wei, Werner Weitschies, Shinji Yamashita, James E Polli","doi":"10.1208/s12248-023-00865-8","DOIUrl":"10.1208/s12248-023-00865-8","url":null,"abstract":"The in-person workshop \"Drug Dissolution in Oral Drug Absorption\" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of \"dissolved drug,\" particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"103"},"PeriodicalIF":4.5,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71488498","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

A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications. 一种用于预测药代动力学应用的新型连续再循环微流体肝组织芯片。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00870-x

Shiny Amala Priya Rajan, Jason Sherfey, Shivam Ohri, Lauren Nichols, J Tyler Smith, Paarth Parekh, Eugene P Kadar, Frances Clark, Billy T George, Lauren Gregory, David Tess, James R Gosset, Jennifer Liras, Emily Geishecker, R Scott Obach, Murat Cirit

{"title":"A Novel Milli-fluidic Liver Tissue Chip with Continuous Recirculation for Predictive Pharmacokinetics Applications.","authors":"Shiny Amala Priya Rajan, Jason Sherfey, Shivam Ohri, Lauren Nichols, J Tyler Smith, Paarth Parekh, Eugene P Kadar, Frances Clark, Billy T George, Lauren Gregory, David Tess, James R Gosset, Jennifer Liras, Emily Geishecker, R Scott Obach, Murat Cirit","doi":"10.1208/s12248-023-00870-x","DOIUrl":"10.1208/s12248-023-00870-x","url":null,"abstract":"A crucial step in lead selection during drug development is accurate estimation and optimization of hepatic clearance using in vitro methods. However, current methods are limited by factors such as lack of physiological relevance, short culture/incubation times that are not consistent with drug exposure patterns in patients, use of drug absorbing materials, and evaporation during long-term incubation. To address these technological needs, we developed a novel milli-fluidic human liver tissue chip (LTC) that was designed with continuous media recirculation and optimized for hepatic cultures using human primary hepatocytes. Here, we characterized the LTC using a series of physiologically relevant metrics and test compounds to demonstrate that we could accurately predict the PK of both low- and high-clearance compounds. The non-biological characterization indicated that the cyclic olefin copolymer (COC)-based LTC exhibited negligible evaporation and minimal non-specific binding of drugs of varying ionic states and lipophilicity. Biologically, the LTC exhibited functional and polarized hepatic culture with sustained metabolic CYP activity for at least 15 days. This long-term culture was then used for drug clearance studies for low- and high-clearance compounds for at least 12 days, and clearance was estimated for a range of compounds with high in vitro-in vivo correlation (IVIVC). We also demonstrated that LTC can be induced by rifampicin, and the culture age had insignificant effect on depletion kinetic and predicted clearance value. Thus, we used advances in bioengineering to develop a novel purpose-built platform with high reproducibility and minimal variability to address unmet needs for PK applications.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"102"},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566036","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

Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications. 调节乳液性质会影响用于药物递送应用的聚（己内酯）颗粒的尺寸。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00869-4

Ashbey N Manning, Claire E Rowlands, Hope Saindon, Brittany E Givens

{"title":"Tuning the Emulsion Properties Influences the Size of Poly(Caprolactone) Particles for Drug Delivery Applications.","authors":"Ashbey N Manning, Claire E Rowlands, Hope Saindon, Brittany E Givens","doi":"10.1208/s12248-023-00869-4","DOIUrl":"10.1208/s12248-023-00869-4","url":null,"abstract":"Advances in drug delivery have been accelerated with the addition of polymeric drug carriers. Direct delivery to a target site is a promising step in developing effective drug and gene therapies to treat disease. The efficacy of these drug carriers heavily relies on cell uptake without compromising critical cellular processes that promote cell viability. Drug release from biodegradable polymers is mediated largely by polymer degradation, and therefore the rate of polymer degradation dictates the feasibility of drug delivery applications. Traditionally, poly(caprolactone) (PCL) has only been used in long-term biomedical applications because the degradation time is much slower than other polymers. However, the biocompatibility of this polymer and the potential for longer delivery windows renders it a promising polymer candidate for drug delivery. In this work, we outline sixteen emulsion solvent evaporation preparation methods for PCL nanoparticles and microparticles to develop particles between 300 nm and 1.7 μm and with zeta potentials of -1.8 mV. We further investigated particles in a size range suitable for systemic tumor delivery and inhaled aerosol delivery to determine cell biocompatibility with the polymer in lung adenocarcinoma, endometrial adenocarcinoma, and human embryonic kidney cells. We determined these particles aren't detrimental to cell viability below particle monolayer coverage atop cells and therefore these formulations hold promise for the next stage of development as sustained-release drug delivery carriers.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"100"},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566038","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

Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors. 用于病毒载体基因治疗的转基因产物的种间标度：使用来自11种病毒载体的数据的方法评估。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-27 DOI: 10.1208/s12248-023-00867-6

Tao Zhang, Peng Zou

{"title":"Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors.","authors":"Tao Zhang, Peng Zou","doi":"10.1208/s12248-023-00867-6","DOIUrl":"10.1208/s12248-023-00867-6","url":null,"abstract":"The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose-response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose-response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight^-0.25 (AS by W^-0.25) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"101"},"PeriodicalIF":4.5,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"61566037","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

Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development. 建模和模拟在临床前和临床长效注射药物开发中的作用。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-17 DOI: 10.1208/s12248-023-00864-9

Maxime Siemons, Bram Schroyen, Nicolas Darville, Navin Goyal

{"title":"Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development.","authors":"Maxime Siemons, Bram Schroyen, Nicolas Darville, Navin Goyal","doi":"10.1208/s12248-023-00864-9","DOIUrl":"10.1208/s12248-023-00864-9","url":null,"abstract":"Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our understanding of the injection space and aid in describing the long-acting injectable (LAI) drug's behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of employing a model-based framework in the LAI preclinical and clinical space. This review provides a brief overview of the LAI development process before delving deeper into the current status of modeling and simulation approaches in characterizing the preclinical and clinical LAI pharmacokinetics, focused on aqueous crystalline suspensions. A closer look is provided on in vitro release methods, available biopharmaceutical models and reported in vitro/in vivo correlations (IVIVCs) that may advance LAI drug development. The overview allows identifying the opportunities for use of model-informed drug development approaches and potential gaps where further research may be most warranted. Continued investment in improving our understanding of LAI PK across species through translational approaches may facilitate the future development of LAI drug products.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"99"},"PeriodicalIF":4.5,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240633","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: 1

Quantitative Translation of Substrate Intrinsic Clearance from Recombinant CYP1A1 to Humans. 从重组CYP1A1到人的底物内在清除的定量翻译。

IF 4.5 3区医学

AAPS Journal Pub Date : 2023-10-05 DOI: 10.1208/s12248-023-00863-w

Li Di

{"title":"Quantitative Translation of Substrate Intrinsic Clearance from Recombinant CYP1A1 to Humans.","authors":"Li Di","doi":"10.1208/s12248-023-00863-w","DOIUrl":"10.1208/s12248-023-00863-w","url":null,"abstract":"CYP1A1 is a cytochrome P450 family 1 enzyme that is mostly expressed in the extrahepatic tissues. To understand the CYP1A1 contribution to drug clearance in humans, we examined the in vitro-in vivo extrapolation (IVIVE) of intrinsic clearance (CLint) for a set of drugs that are in vitro CYP1A1 substrates. Despite being strong in vitro CYP1A1 substrates, 82% of drugs gave good IVIVE with predicted CLint within 2-3-fold of the observed values using human liver microsomes and hepatocytes, suggesting they were not in vivo CYP1A1 substrates due to the lack of extrahepatic contribution to CLint. Only three drugs (riluzole, melatonin and ramelteon) that are CYP1A2 substrates yielded significant underprediction of in vivo CLint up to 11-fold. The fold of CLint underprediction was linearly proportional to human recombinant CYP1A1 (rCYP1A1) CLint, indicating they were likely to be in vivo CYP1A1 substrates. Using these three substrates, a calibration curve can be developed to enable direct translation from in vitro rCYP1A1 CLint to in vivo extrahepatic contributions in humans. In vivo CYP1A1 substrates are planar and small, which is consistent with the structure of the active site. This is in contrast to the in vitro substrates, which include large and nonplanar molecules, suggesting rCYP1A1 is more accessible than what is in vivo. The impact of CYP1A1 on first-pass intestinal metabolism was also evaluated and shown to be minimal. This is the first study providing new insights on in vivo translation of CYP1A1 contributions to human clearance using in vitro rCYP1A1 data.","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"25 6","pages":"98"},"PeriodicalIF":4.5,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41164815","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