Molecular Pharmaceutics最新文献

{"title":"Actionable Predictions of Human Pharmacokinetics at the Drug Design Stage.","authors":"Leonid Komissarov, Nenad Manevski, Katrin Groebke Zbinden, Torsten Schindler, Marinka Zitnik, Lisa Sach-Peltason","doi":"10.1021/acs.molpharmaceut.4c00311","DOIUrl":"10.1021/acs.molpharmaceut.4c00311","url":null,"abstract":"<p><p>We present a novel computational approach for predicting human pharmacokinetics (PK) that addresses the challenges of early stage drug design. Our study introduces and describes a large-scale data set of 11 clinical PK end points, encompassing over 2700 unique chemical structures to train machine learning models. To that end multiple advanced training strategies are compared, including the integration of in vitro data and a novel self-supervised pretraining task. In addition to the predictions, our final model provides meaningful epistemic uncertainties for every data point. This allows us to successfully identify regions of exceptional predictive performance, with an absolute average fold error (AAFE/geometric mean fold error) of less than 2.5 across multiple end points. Together, these advancements represent a significant leap toward actionable PK predictions, which can be utilized early on in the drug design process to expedite development and reduce reliance on nonclinical studies.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the Long-Term Stability of Biologics with Short-Term Data.","authors":"Michael Dillon, Jun Xu, Geetha Thiagarajan, Daniel Skomski, Adam Procopio","doi":"10.1021/acs.molpharmaceut.4c00609","DOIUrl":"10.1021/acs.molpharmaceut.4c00609","url":null,"abstract":"<p><p>Understanding the long-term stability of biologics is crucial to ensure safe, effective, and cost-efficient life-saving therapeutics. Current industry and regulatory practices require arduous real-time data collection over three years; thus, reducing this bottleneck while still ensuring product quality would enhance the speed of medicine to patients. We developed a parallel-pathway kinetic model, combined with Monte Carlo simulations for prediction intervals, to predict the long-term (2+ years) stability of biotherapeutic critical quality attributes (aggregates, fragments, charge variants, purity, and potency) with short-term (3-6 months) data from intended, accelerated, and stressed temperatures. We rigorously validated the model with 18 biotherapeutic drug products, composed of IgG1 and IgG4 monoclonal antibodies, antibody-drug conjugates, dual protein coformulations, and a fusion protein, including high concentration (≥100 mg/mL) formulations, in liquid and lyophilized presentations. For each drug product, we accurately predicted the long-term trends of multiple quality attributes using just 6 months of data. Further, we demonstrated superior stability prediction via our methods compared with industry-standard linear regression methods. The robust and repeatable results of this work across an unprecedented suite of 18 biotherapeutic compounds suggest that kinetic models with Monte Carlo simulation can predict the long-term stability of biologics with short-term data.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Does the Powder Mixture of Ibuprofen and Caffeine Attenuate the Solubility of Ibuprofen? Comparative Study for the Xanthine Derivatives to Recognize Their Intermolecular Interactions Using Fourier-Transform Infrared (FTIR) Spectra, Differential Scanning Calorimetry (DSC), and X-ray Powder Diffractometry (XRPD).","authors":"Shoya Suenaga, Hikaru Kataoka, Kanji Hasegawa, Ryotaro Koga, Chihiro Tsunoda, Wataru Kuwashima, Tomohiro Tsuchida, Satoru Goto","doi":"10.1021/acs.molpharmaceut.4c00429","DOIUrl":"10.1021/acs.molpharmaceut.4c00429","url":null,"abstract":"<p><p>Molecular interactions between active pharmaceutical ingredients (APIs) and xanthine (XAT) derivatives were analyzed using singular value decomposition (SVD). XAT derivatives were mixed with equimolar amounts of ibuprofen (IBP) and diclofenac (DCF), and their dissolution behaviors were measured using high-performance liquid chromatography. The solubility of IBP decreased in mixtures with caffeine (CFN) and theophylline (TPH), whereas that of DCF increased in mixtures with CFN and TPH. No significant differences were observed between the mixtures of theobromine (TBR) or XAT with IBP and DCF. Mixtures with various molar ratios were analyzed using differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared spectroscopy to further explore these interactions. The results were subjected to SVD. This analysis provides valuable insights into the differences in interaction strength and predicted interaction sites between XAT derivatives and APIs based on the combinations that form mixtures. The results also showed the impact of the XAT derivatives on the dissolution behavior of IBP and DCF. Although IBP and DCF were found to form intermolecular interactions with CFN and TPH, these effects resulted in a reduction of the solubility of IBP and an increase in the solubility of DCF. The current approach has the potential to predict various interactions that may occur in different combinations, thereby contributing to a better understanding of the impact of health supplements on pharmaceuticals.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Continuous Intestinal Absorption Model to Predict Drug Enterohepatic Recirculation in Healthy Humans: Nalbuphine as a Model Substrate.","authors":"Ken Korzekwa, Swati Nagar, David Clark, Thomas Sciascia, Amale Hawi","doi":"10.1021/acs.molpharmaceut.4c00424","DOIUrl":"10.1021/acs.molpharmaceut.4c00424","url":null,"abstract":"<p><p>Nalbuphine (NAL) is a κ-agonist/μ-antagonist opioid being developed as an oral extended formulation (ER) for the treatment of chronic cough in idiopathic pulmonary fibrosis and itch in prurigo nodularis. NAL is extensively glucuronidated and likely undergoes enterohepatic recirculation (EHR). The purpose of this work is to develop pharmacokinetic models for NAL absorption and enterohepatic recirculation (EHR). Clinical pharmacokinetic (PK) data sets in healthy subjects from three trials that included IV, oral solution, and ER tablets in fed and fasted state and two published trials were used to parametrize a novel partial differential equation (PDE)-based model, termed \"PDE-EHR\" model. Experimental inputs included in vitro dissolution and permeability data. The model incorporates a continuous intestinal absorption framework, explicit liver and gall bladder compartments, and compartments for systemic drug disposition. The model was fully PDE-based with well-stirred compartments achieved by rapid diffusion. The PDE-EHR model accurately reproduces NAL concentration-time profiles for all clinical data sets. NAL disposition simulations required inclusion of both parent and glucuronide recirculation. Inclusion of intestinal P-glycoprotein efflux in the simulations suggests that NAL is not expected to be a victim or perpetrator of P-glycoprotein-mediated drug interactions. The PDE-EHR model is a novel tool to predict EHR and food/formulation effects on drug PK. The results strongly suggest that even intravenous dosing studies be conducted in fasted subjects when EHR is suspected. The modeling effort is expected to aid in improved prediction of dosing regimens and drug disposition in patient populations.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Mechanistic Multiparameter Optimization and Large-Scale <i>In Vitro</i> to <i>In Vivo</i> Pharmacokinetics Correlations to Small-Molecule Therapeutic Projects.","authors":"Fabio Broccatelli, Vijayabhaskar Veeravalli, Daniel Cashion, Javier L Baylon, Franco Lombardo, Lei Jia","doi":"10.1021/acs.molpharmaceut.4c00256","DOIUrl":"10.1021/acs.molpharmaceut.4c00256","url":null,"abstract":"<p><p>Computational chemistry and machine learning are used in drug discovery to predict the target-specific and pharmacokinetic properties of molecules. Multiparameter optimization (MPO) functions are used to summarize multiple properties into a single score, aiding compound prioritization. However, over-reliance on subjective MPO functions risks reinforcing human bias. Mechanistic modeling approaches based on physiological relevance can be adapted to meet different potential key objectives of the project (<i>e.g</i>., minimizing dose, maximizing safety margins, and/or minimizing drug-drug interaction risk) while retaining the same underlying model structure. The current work incorporates recent approaches to predict <i>in vivo</i> pharmacokinetic (PK) properties and validates <i>in vitro</i> to <i>in vivo</i> correlation analysis to support mechanistic PK MPO. Examples of use and impact in small-molecule drug discovery projects are provided. Overall, the mechanistic MPO identifies 83% of the compounds considered as short-listed for clinical experiments in the top second percentile, and 100% in the top 10th percentile, resulting in an area under the receiver operating characteristic curve (AUCROC) > 0.95. In addition, the MPO score successfully recapitulates the chronological progression of the optimization process across different scaffolds. Finally, the MPO scores for compounds characterized in pharmacokinetics experiments are markedly higher compared with the rest of the compounds being synthesized, highlighting the potential of this tool to reduce the reliance on <i>in vivo</i> testing for compound screening.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological Fate Tracking of Nitric Oxide-Propelled Microneedle Delivery System Using an Aggregation-Caused Quenching Probe.","authors":"Ziyao Chang, Yuhuan Wu, Yangyan Chen, Xuequn Bai, Tingting Peng, Chuanbin Wu, Xin Pan, Zhengwei Huang","doi":"10.1021/acs.molpharmaceut.4c00435","DOIUrl":"10.1021/acs.molpharmaceut.4c00435","url":null,"abstract":"<p><p>Nanoparticle-loaded dissolving microneedles (DMNs) have attracted increasing attention due to their ability to provide high drug loading, adjustable drug release behavior, and enhanced therapeutic efficiency. However, such delivery systems still face unsatisfied drug delivery efficiency due to insufficient driving force to promote nanoparticle penetration and the lack of <i>in vivo</i> fate studies to guide formulation design. Herein, an aggregation-caused quenching (ACQ) probe (P4) was encapsulated in l-arginine (l-Arg)-based nanomicelles, which was further formulated into nitric oxide (NO)-propelled nanomicelle-integrated DMNs (P4/l-Arg NMs@DMNs) to investigate their biological fate. The P4 probe could emit intense fluorescence signals in intact nanomicelles, while quenching with the dissociation of nanomicelles, providing a \"distinguishable\" method for tracking the fate of nanomicelles at a different status. l-Arg was demonstrated to self-generate NO under the tumor microenvironment with excessive reactive oxygen species (ROS), providing a pneumatic force to promote the penetration of nanomicelles in both three-dimensional (3D)-cultured tumor cells and melanoma-bearing mice. Compared with passive microneedles (P4 NMs@DMNs) without a NO propellant, the P4/l-Arg NMs@DMNs possessed a good NO production performance and higher nanoparticle penetration capacity. In conclusion, this study offered an ACQ probe-based biological fate tracking approach to demonstrate the potential of NO-propelled nanoparticle-loaded DMNs in penetration enhancement for topical tumor therapy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Microenvironment Responsive RNA Drug Delivery Systems: Intelligent Platforms for Sophisticated Release.","authors":"Guihua Wang, Mengxia Zhang, Weiwei Lai, Yuan Gao, Shuxian Liao, Qian Ning, Shengsong Tang","doi":"10.1021/acs.molpharmaceut.4c00334","DOIUrl":"10.1021/acs.molpharmaceut.4c00334","url":null,"abstract":"<p><p>Cancer is a significant health concern, increasingly showing insensitivity to traditional treatments, highlighting the urgent need for safer and more practical treatment options. Ribonucleic acid (RNA) gene therapy drugs have demonstrated promising potential in preclinical and clinical trials for antitumor therapy by regulating tumor-related gene expression. However, RNA's poor membrane permeability and stability restrict its effectiveness in entering and being utilized in cells. An appropriate delivery system is crucial for achieving targeted tumor effects. The tumor microenvironment (TME), characterized by acidity, hypoxia, enzyme overexpression, elevated glutathione (GSH) concentration, and excessive reactive oxygen species (ROS), is essential for tumor survival. Furthermore, these distinctive features can also be harnessed to develop intelligent drug delivery systems. Various nanocarriers that respond to the TME have been designed for RNA drug delivery, showing the advantages of tumor targeting and low toxicity. This Review discusses the abnormal changes of components in TME, therapeutic RNAs' roles, underlying mechanisms, and the latest developments in utilizing vectors that respond to microenvironments for treating tumors. We hope it provides insight into creating and optimizing RNA delivery vectors to improve their effectiveness.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Evaluation of DOTA-FAPI-Maleimide as a Novel Radiotracer for Tumor Theranostic with Extended Circulation.","authors":"Lixia Feng, Wenzhu Hu, Xinying Zeng, Zheng Wei, Yu Long, Mengting Li, Si Sun, Zhide Guo, Xiaoli Lan, Xianzhong Zhang, Rongqiang Zhuang, Dawei Jiang","doi":"10.1021/acs.molpharmaceut.4c00327","DOIUrl":"10.1021/acs.molpharmaceut.4c00327","url":null,"abstract":"<p><p>This study aimed to evaluate a novel albumin-binding strategy for addressing the challenge of insufficient tumor retention of fibroblast activation protein inhibitors (FAPIs). Maleimide, a molecule capable of covalent binding to free thiol groups, was modified to conjugate with FAPI-04 in order to enhance its binding to endogenous albumin, resulting in an extended blood circulation half-life and increased tumor uptake. DOTA-FAPI-maleimide was prepared and radiolabeled with Ga-68 and Lu-177, followed by cellular assays, pharmacokinetic analysis, PET/CT, and SPECT/CT imaging to assess the probe distribution in various tumor-bearing models. Radiolabeling of the modified probe was successfully achieved with a radiochemical yield of over 99% and remained stable for 144 h. Cellular assays showed that the ligand concentration required for 50% inhibition of the probe was 1.20 ± 0.31 nM, and the <i>K</i>_d was 0.70 ± 0.07 nM with a <i>B</i>_max of 7.94 ± 0.16 fmol/cell, indicative of higher specificity and affinity of DOTA-FAPI-maleimide compared to other FAPI-04 variants. In addition, DOTA-FAPI-maleimide exhibited a persistent blood clearance half-life of 7.11 ± 0.34 h. PET/CT images showed a tumor uptake of 2.20 ± 0.44%ID/g at 0.5 h p.i., with a tumor/muscle ratio of 5.64 in HT-1080-FAP tumor-bearing models. SPECT/CT images demonstrated long-lasting tumor retention. At 24 h p.i., the tumor uptake of [¹⁷⁷Lu]Lu-DOTA-FAPI-maleimide reached 5.04 ± 1.67%ID/g, with stable tumor retention of 3.40 ± 1.95%ID/g after 4 days p.i. In conclusion, we developed and evaluated the thiol group-attaching strategy, which significantly extended the circulation and tumor retention of the adapted FAPI tracer. We envision its potential application for clinical cancer theranostics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Situ Eutectic Formation in a Polymeric Matrix via Hot-Melt Reactive Extrusion and the Use of Partial Least Squares Regression Modeling for Reaction Yield Determination.","authors":"Gavin P Andrews, Alice Culkin, David S Jones, Shu Li","doi":"10.1021/acs.molpharmaceut.4c00152","DOIUrl":"10.1021/acs.molpharmaceut.4c00152","url":null,"abstract":"<p><p>There has been a significant volume of work investigating the design and synthesis of new crystalline multicomponent systems via examining complementary functional groups that can reliably interact through the formation of noncovalent bonds, such as hydrogen bonds (H-bonds). Crystalline multicomponent molecular adducts formed using this approach, such as cocrystals, salts, and eutectics, have emerged as drug product intermediates that can lead to effective drug property modifications. Recent advancement in the production for these multicomponent molecular adducts has moved from batch techniques that rely upon intensive solvent use to those that are solvent-free, continuous, and industry-ready, such as reactive extrusion. In this study, a novel eutectic system was found when processing albendazole and maleic acid at a 1:2 molar ratio and successfully prepared using mechanochemical methods including liquid-assisted grinding and hot-melt reactive extrusion. The produced eutectic was characterized to exhibit a 100 °C reduction in melting temperature and enhanced dissolution performance (>12-fold increase at 2 h point), when compared to the native drug compound. To remove handling of the eutectic as a formulation intermediate, an end-to-end continuous-manufacturing-ready process enables feeding of the raw parent reagents in their respective natural forms along with a chosen polymeric excipient, Eudragit EPO. The formation of the eutectic was confirmed to have taken place in situ in the presence of the polymer, with the reaction yield determined using a multivariate calibration model constructed by combining spectroscopic analysis with partial least-squares regression modeling. The ternary extrudates exhibited a dissolution profile similar to that of the 1:2 prepared eutectic, suggesting a physical distribution (or suspension) of the in situ synthesized eutectic contents within the polymeric matrix.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141969994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flow Activation Energy of High-Concentration Monoclonal Antibody Solutions and Protein-Protein Interactions Influenced by NaCl and Sucrose.","authors":"Guangcui Yuan, Paul F Salipante, Steven D Hudson, Richard E Gillilan, Qingqiu Huang, Harold W Hatch, Vincent K Shen, Alexander V Grishaev, Suzette Pabit, Rahul Upadhya, Sudeep Adhikari, Jainik Panchal, Marco A Blanco, Yun Liu","doi":"10.1021/acs.molpharmaceut.4c00460","DOIUrl":"10.1021/acs.molpharmaceut.4c00460","url":null,"abstract":"<p><p>The solution viscosity and protein-protein interactions (PPIs) as a function of temperature (4-40 °C) were measured at a series of protein concentrations for a monoclonal antibody (mAb) with different formulation conditions, which include NaCl and sucrose. The flow activation energy (<i>E</i>_η) was extracted from the temperature dependence of solution viscosity using the Arrhenius equation. PPIs were quantified via the protein diffusion interaction parameter (<i>k</i>_D) measured by dynamic light scattering, together with the osmotic second virial coefficient and the structure factor obtained through small-angle X-ray scattering. Both viscosity and PPIs were found to vary with the formulation conditions. Adding NaCl introduces an attractive interaction but leads to a significant reduction in the viscosity. However, adding sucrose enhances an overall repulsive effect and leads to a slight decrease in viscosity. Thus, the averaged (attractive or repulsive) PPI information is not a good indicator of viscosity at high protein concentrations for the mAb studied here. Instead, a correlation based on the temperature dependence of viscosity (i.e., <i>E</i>_η) and the temperature sensitivity in PPIs was observed for this specific mAb. When <i>k</i>_D is more sensitive to the temperature variation, it corresponds to a larger value of <i>E</i>_η and thus a higher viscosity in concentrated protein solutions. When <i>k</i>_D is less sensitive to temperature change, it corresponds to a smaller value of <i>E</i>_η and thus a lower viscosity at high protein concentrations. Rather than the absolute value of PPIs at a given temperature, our results show that the temperature sensitivity of PPIs may be a more useful metric for predicting issues with high viscosity of concentrated solutions. In addition, we also demonstrate that caution is required in choosing a proper protein concentration range to extract <i>k</i>_D. In some excipient conditions studied here, the appropriate protein concentration range needs to be less than 4 mg/mL, remarkably lower than the typical concentration range used in the literature.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}