AAPS Journal最新文献

{"title":"Natural Broccoli Sprout-Derived Exosomes Encapsulating Bioactive Molecules as a Novel Nanomedicine for Repair of Intestinal Inflammation.","authors":"Tianzhi Yang, Spencer Canham, Thilina Kasthuriarachchi, Alexis Kirkendall, Marissa Kinney, Mohammad Asikur Rahman, Sung Hun Bae, Tao Zhang, Suzanne L Ishaq, Yanyan Li, Shuhua Bai","doi":"10.1208/s12248-026-01241-y","DOIUrl":"10.1208/s12248-026-01241-y","url":null,"abstract":"<p><p>Dietary bioactives from broccoli sprouts exhibit anti-inflammatory properties in the prevention and management of inflammatory bowel disease (IBD), but are limited by instability during gastrointestinal (GI) transit and insufficient delivery to inflamed intestinal tissues. Here, we report the discovery and functional characterization of broccoli sprout-derived exosomes (BSDExo) as a naturally occurring nanomedicine that encapsulates endogenous bioactive molecules, including sulforaphane (SFN) and plant miRNAs, and promotes intestinal epithelial repair. BSDExo exhibited a nanoscale size of 40.1 ± 17.2 nm, expressed conserved exosomal protein markers, and were enriched in regulatory miRNAs. Importantly, BSDExo effectively protected encapsulated SFN under simulated gastric and intestinal conditions, demonstrating strong vesicle stability and controlled release. BSDExo (25 µg/mL quantified by total proteins) promoted the proliferation of normal colon epithelial CCD841 CoN cells with a cell viability of 154 ± 5% (p < 0.05). Cellular uptake of fluorescence-labeled BSDExo significantly increased with more severe inflammation stimulation in CCD841 CoN and Caco-2 cells. Secretion of interleukin 8 (IL-8) from inflammation-stimulated colon cells was significantly reduced by the BSDExo treatment (p < 0.05). BSDExo also significantly recovered the epithelial barrier integrity in Caco-2 monolayer that was damaged by LPS or DSS, as assessed by transepithelial electrical resistance (TEER) values (p < 0.05). This study identifies BSDExo as GI-stable, bioactive-rich nanovesicles that selectively target inflamed intestinal epithelium, enhance epithelial repair, and represent a first-in-class, diet-derived nanomedicine with translational potential for IBD.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147788183","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":"p-Sulfonatocalixarene-Based Complexation Mitigates Hepatorenal Toxicity of Anticancer Alkaloids without Loss of Efficacy: A Strategy for Selective Detoxification.","authors":"Lihua Tan, Zhongli Jing, Xuan Yu, Yi Liu, Yanan Liu, Meng Wang, Xiaoliang Ren","doi":"10.1208/s12248-026-01229-8","DOIUrl":"10.1208/s12248-026-01229-8","url":null,"abstract":"<p><p>p-Sulfonatocalix[n]arenes (SCnA, where n = 6, 8) have emerged as promising supramolecular hosts for encapsulating active pharmaceutical ingredients (APIs) through host-guest complexation, enhancing solubility, stability, and bioavailability. In this study, SCnA was employed to complex hepatotoxic and nephrotoxic alkaloids derived from Traditional Chinese Medicines (TCM), with the objective of reducing hepatorenal toxicity while preserving antitumor efficacy. The cytocompatibility of six alkaloids and their SCnA complexes was evaluated across human embryonic kidney (Hek293), normal liver (L02), breast cancer (MDA-MB-231), and hepatoma (HepG2) cell lines. A high-content assay (HCA) integrated with three fluorescent probes was utilized to simultaneously quantify multiparametric cellular changes, including nucleus number and area, mitochondrial count and area, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels. Complexation with SC6A or SC8A significantly reduced the cytotoxicity of tetrandrine, chelerythrine, and dauricine in Hek293 and L02 cells, while antitumor activity against MDA-MB-231 and HepG2 cells was maintained. HCA revealed that the complexes increased nuclei count, nuclear area, mitochondrial number, mitochondrial area, and MMP, while decreasing ROS levels. Notably, the suppression of normal cell proliferation correlated positively with binding constant values, yet complexation did not interfere with antiproliferative effects in tumor cells. We hypothesize that the heightened mitochondrial fission and oxidative stress susceptibility in cancer cells, owing to their reliance on mitochondrial energy production, underlie the differential cytotoxicity. These findings demonstrate that SCnA complexation selectively attenuates alkaloid-induced toxicity in normal cells without diminishing anticancer potency, underscoring its potential as a versatile strategy for safe and effective drug delivery.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730618","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":"Integrating In-vitro Permeability Assays within PBPK Modeling to Predict CNS Distribution of Standard and Engineered Antibodies.","authors":"Seunghyun Kim, Etienne Lessard, Binbing Ling, Kerry Rennie, Arsalan Haqqani, Anil R Maharaj","doi":"10.1208/s12248-026-01233-y","DOIUrl":"10.1208/s12248-026-01233-y","url":null,"abstract":"<p><p>The typically low, molecule-dependent permeability of antibodies across the blood-brain barrier (BBB) has driven the development of engineered constructs with optimized BBB transcytosis to facilitate efficient brain delivery. Physiologically-based pharmacokinetic (PBPK) modeling provides a framework to predict brain disposition and inform drug development; however, current models lack true a priori predictive capability and remain dependent on in-vivo data. In-vitro brain endothelial cell permeability (P_app) assays provide antibody-specific estimates of brain transport, though these assays have yet to be integrated into PBPK models. This study developed and cross-validated an integrated in-vitro-in-vivo-extrapolation (IVIVE) PBPK framework that uses P_app values to predict antibody-specific cerebrospinal fluid (CSF) concentrations a priori. Seven antibodies were evaluated, including four standard (non-FC5-fused) and three TMEM30A-binding constructs (FC5-fused). PBPK modeling was conducted using PK-Sim®/MoBi®. P_app values were used to estimate antibody-specific brain transport parameters. For comparison, a conventional modeling approach was implemented, where brain transport was inferred to be similar to a reference antibody (trastuzumab). Model performance was assessed by comparing predicted versus observed CSF exposures (area-under-the-concentration-time-curve) in rats following intravenous administration. Integration of P_app data substantially improved brain exposure predictions, reducing the absolute average percentage prediction error for CSF exposure from 296.1% (conventional approach) to 53.4% (IVIVE-PBPK). The framework accurately captured the brain disposition of both standard and FC5-fused antibodies without requiring pre-existing in-vivo CSF data. Overall, this P_app-informed PBPK modeling approach enables a priori, mechanistic prediction of antibody brain exposure, supporting candidate selection and reducing reliance on animal studies in brain drug development.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147718762","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":"Single-Eye NfL Measurement Using NULISA Technology Enables Reduction in Animal Use.","authors":"Jeongsup Shim, Jessica Chen, Vahan B Indjeian, Saloumeh K Fischer","doi":"10.1208/s12248-026-01240-z","DOIUrl":"10.1208/s12248-026-01240-z","url":null,"abstract":"<p><p>Neurofilament light chain (NfL) is a pivotal biomarker for neuroaxonal damage. However, its quantification in volume-limited matrices, such as mouse aqueous humor (AH) (2 to 6 µL per eye), has historically required pooling samples from multiple animals due to the low sensitivity and high sample volume requirements of standard immunoassays. Such pooling increases animal requirements and precludes individual-level data analysis. To overcome these limitations, we developed and evaluated a NfL HomeBrew (HB) assay using the NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) technology. NULISA offers superior analytical sensitivity and requires less than 10 µL volume. Our results demonstrate that the NfL HB NULISA performs comparably to the Simoa reference assay and provides superior sensitivity to the Ella platform. Crucially, the assay reliably quantified NfL in as little as 2 µL of individual mouse AH, with 90% of samples yielding quantifiable results. This approach eliminates the need for sample pooling, effectively reducing animal use by up to eightfold while preserving data integrity at the individual animal level. These findings establish the NULISA platform as a highly sensitive, ethically advantageous solution for neurobiological research in volume-restricted models.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147693163","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":"Biodistribution of Cerivastatin, Repaglinide, Glyburide, Rosuvastatin, and Valsartan in Cynomolgus Monkeys and PBPK Analysis.","authors":"Rui Li, Samantha Jordan, Mark Niosi, Manthena V S Varma, Li Di","doi":"10.1208/s12248-026-01237-8","DOIUrl":"10.1208/s12248-026-01237-8","url":null,"abstract":"<p><p>Cynomolgus monkeys are widely utilized for understanding and predicting human pharmacokinetics (PK) of OATP1B substrates due to their close evolutionary relationship with humans and the high degree of transporter protein homology similarities. We note that some OATP1B tool substrates (e.g., cerivastatin and repaglinide) have steady state volume of distribution (V_SS) values in monkeys that are larger than corresponding V_SS values reported for humans. To understand V_SS and tissue biodistribution of substrate drugs in monkeys, we have performed a series of monkey PK and tissue distribution studies, as well as data analysis with physiologically based pharmacokinetic (PBPK) modeling for several OATP1B substrates (i.e., cerivastatin, repaglinide, glyburide, rosuvastatin, and valsartan). We find that there are unexpectedly high accumulations of these compounds in monkey intestines potentially involving transporter mediated active uptake, which contributed to the higher-than-expected V_SS values.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640412","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":"Predicting Aberrant Fc-fusion Protein Pharmacokinetics from In Silico Structural Properties and Physiologically Based Pharmacokinetic (PBPK) Modeling.","authors":"Danilo Tomasoni, Alessio Paris, Roberto Visintainer, Kevin D Cook, Aochiu Chen, Isabel Figueroa, Veena A Thomas, Luca Marchetti","doi":"10.1208/s12248-026-01232-z","DOIUrl":"10.1208/s12248-026-01232-z","url":null,"abstract":"<p><p>The fusion of therapeutic proteins to the Fc domain of monoclonal antibodies (mAbs) generally improves the proteins' pharmacokinetic (PK) characteristics, extending in vivo half-lives due to the binding of the Fc domain to the FcRn receptor. Yet, several of these Fc-fusion biologics have been observed to have unexpected rapid clearance associated with non-specific off-target binding. Variability in non-specific clearance is often challenging to predict, not well understood, and ultimately can delay the drug development process. In this investigation, we present a computational approach leveraging in silico protein structural properties to extend a physiologically based pharmacokinetic (PBPK) model of mAbs validated on in vivo plasma PK profiles in mice. Selected model parameters affecting protein half-life have been scaled by analytical functions of a panel of calculated in silico protein properties identified by a novel and ad hoc symbolic regression procedure. The resulting extended model has been successfully validated against an independent set of protein plasma PKs, indicating that it can generalize to novel biologics of the same class. Moreover, the extended PBPK model has a median absolute average fold error (AAFE) of 1.18 (min = 1.09; max = 1.51), where values less than 2 typically indicate a good fit. The results enable the de-risking of aberrant PK behaviors, ultimately leading to the selection of Fc-fusion proteins with increased therapeutic value for patients.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147635070","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":"Virtual Bioequivalence Assessment of Long-Acting Injectable Suspensions Using PBPK Modeling: Part 2. Type I Error and Safe Space Analyses.","authors":"Natalie M Morris, Masoud Jamei, Khondoker Alam, Eleftheria Tsakalozou, Mark Donnelly, Kairui Feng, Frederic Y Bois","doi":"10.1208/s12248-026-01215-0","DOIUrl":"10.1208/s12248-026-01215-0","url":null,"abstract":"<p><p>We present an analysis of statistical type I error and safe space calculations in virtual bioequivalence (VBE) assessments using a previously published physiologically-based pharmacokinetic (PBPK) model for 3-month long-acting paliperidone palmitate (PP) injectable suspensions. The type I error for the two-one-sided t test (TOST) applied to virtual parallel design bioequivalence (BE) trials was estimated through approximation of 'simulated BE boundaries'. This was defined as the range of formulation critical quality attribute values (CQA, which in this paper pertains to mean drug particle radius), corresponding to simulated population-level geometric mean ratios (GMRs) for key pharmacokinetic (PK) metrics of between 0.8 to 1.25. Monte Carlo simulations were then used to combine these limits with power calculations to display estimates of the safe space for BE extending from a predefined particle radius. Type I error for detecting formulation difference in the model was controlled at 5% for PK endpoints. The simulated BE boundaries for 3-month PP LAI suspension mean particle radius extended over 5 µm, but acceptable statistical power (≥ 80%) was obtained only when the mean particle radius was within 1 µm of the reference formulation. For PBPK models, type I error calculations are notably more complex than power calculations because the simulated BE boundaries for CQAs need to be determined before the error assessment. This study appears to be the first to discuss the intersection of type I error control and safe space estimation in PBPK modeling for a BE assessment. Our case study shows the conditions that allow for a controlled type I error in a VBE assessment. Safe space is shown to depend on both formulation characteristics and the statistical power afforded by BE studies, offering valuable insights for formulation design considerations.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610597","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":"Spatiotemporal Profiling of Intratumoral Free Payload Distribution via MALDI Imaging Mass Spectrometry: Implications for Drug-to-Antibody Ratio Optimization in Antibody-Drug Conjugates.","authors":"Tingting Cai, Ziyi Li, Qiaofang Yan, Guangcun Huang, Kaiying Jia, Xiaotong Chen, Junling Dun, Jinghua Zou, Meiling Tan, Yue Wu, Fan Wang","doi":"10.1208/s12248-026-01235-w","DOIUrl":"10.1208/s12248-026-01235-w","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADCs), comprising monoclonal antibodies and cytotoxic payloads, present inherent complexities in molecular design. The drug-to-antibody ratio (DAR) represents a critical determinant of ADC behavior, influencing pharmacokinetics and tissue distribution. In vivo studies in tumor-bearing murine models demonstrated comparable efficacy between DAR4 and DAR8 ADCs (DAR4: 6 mg/kg, DAR8: 3 mg/kg), suggesting that DAR alone does not dictate therapeutic outcome. Immunohistochemical (IHC) staining of human IgG, used to map intact ADC localization, demonstrated superior tumor penetration by DAR4 ADCs relative to their DAR8 counterparts. However, this enhanced penetration did not translate to improved therapeutic efficacy. To elucidate the mechanistic underpinning of DAR optimization, we leveraged matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) to spatially resolve the free payload distribution in tumors. The optimized MALDI imaging method enabled sensitive detection of released payload, revealing similar intensity and distribution pattern for both DAR4 and DAR8 ADCs at 2 and 24 h post-dosing. This spatiotemporal uniformity of payload correlated with consistent pharmacodynamic (PD) responses. Moreover, equivalent payload signal intensities across DAR variants corroborated quantitative analyses of tumor lysates and subsequent efficacy data, reinforcing the pivotal role of intratumoral payload in driving in vivo efficacy. These findings underscore that DAR optimization is both target-dependent and payload-specific, suggesting that ADC design should prioritize factors governing active payload release over passive distribution metrics. The MALDI-IMS methodology developed in this study provides unprecedented spatial resolution of bioactive payload dynamics, establishing a robust platform for dissecting efficacy determinants in preclinical ADC development.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610529","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":"Virtual Bioequivalence Assessment of Long-acting Injectable Suspensions Using PBPK Modeling: Part 1. Impact of particle Size on Formulation Variability.","authors":"Natalie M Morris, Alexandre Djehizian, Naresh Mittapelly, Krishna Chaitanya Telaprolu, Bryan W Holland, Kevin McNally, Sebastian Polak, Masoud Jamei, Khondoker Alam, Eleftheria Tsakalozou, Mark Donnelly, Kairui Feng, Frederic Y Bois","doi":"10.1208/s12248-026-01213-2","DOIUrl":"10.1208/s12248-026-01213-2","url":null,"abstract":"<p><p>This study presents a workflow for virtual bioequivalence (VBE) assessment of 3-month paliperidone palmitate (PP) long-acting injectable (LAI) suspensions using a novel physiologically-based pharmacokinetic (PBPK) model. The mechanistic absorption and PBPK model was implemented in the Simcyp® Simulator and calibrated against individual concentration-time profiles derived from a published and validated population pharmacokinetic model. The model was able to accurately simulate drug concentration profiles after PP administration. Across 1000 subjects, four model-predicted bioequivalence (BE) metrics, including C_max,ss and AUC_tau,ss, differed by at most 10% from validation data. The initial mean drug particle radius was assessed as the critical formulation attribute in the VBE analysis. We conducted extensive VBE simulations to evaluate the required sample size of parallel trial designs for a given statistical power. The statistical power of two-one-sided t tests (TOST) to declare BE was estimated from the passing rate of Monte Carlo simulated VBE trials. Power calculations using the validated model indicated that a VBE trial with a minimum of 160 subjects per arm is required to achieve at least 80% power for declaring BE when the formulations are identical in terms of mean particle size. If the mean drug particle radius between test and reference formulations differs by 20%, the required sample size for BE demonstration approximately doubles to maintain the same power. This suggests that particle size affects formulation variability. The power calculations demonstrated that BE assessments were very sensitive to formulation differences in drug particle radius and to the parametrization of the model. These findings emphasize the critical need for rigorous model validation to ensure reliable VBE assessments.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610587","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":"PBPK Modelling of PROTACs: Learnings from ARV-110 as a Case Example.","authors":"Farzaneh Salem, Ali Tabatabaeian Nimavardi, Abhishek Srivastava, Katharina Krollik, Andreas Reichel, David Cebrian, Kunal S Taskar, James W T Yates, Caroline Rynn, Heide Marika Duevel","doi":"10.1208/s12248-026-01231-0","DOIUrl":"10.1208/s12248-026-01231-0","url":null,"abstract":"<p><p>The study presents a comprehensive evaluation of physiologically-based pharmacokinetic (PBPK) modeling for Proteolysis Targeting Chimeras (PROTACs), using ARV-110 (Bavdegalutamide) as a case example. We sought to develop a PBPK model that accurately predicts the human pharmacokinetics (PK) of ARV-110 and began with a bottom-up approach to predict ARV-110 PK in mice and rats using available ADME and physicochemical data. Owing to the observed in vitro-in vivo extrapolation (IVIVE) gaps in clearance, the published in vivo data was used for refinement, resulting in a middle-out PBPK model bridging this discrepancy. PBPK predictions were extrapolated to human and validated against observed clinical PK for single and multiple doses in healthy volunteers and cancer patients revealing IVIVE gaps for human clearance. Similar to rodents, a middle-out modeling approach was then used to refine the human PBPK prediction. This model effectively captured plasma drug concentration-time profiles reported for preclinical and clinical studies, including studies involving impact of food and drug-drug interactions with itraconazole and esomeprazole. All observed human concentrations were within 5th and 95th percentile of predictions and PK parameters were within two-fold of the observed in vivo data. Following administration of a single dose (280 mg) of ARV-110, the observed vs. predicted AUC_0-inf for high fat, medium fat and low fat studies were 13563.0 vs. 7646.0 ng.h/ml, 4358.0 vs. 4618.3 ng.h/ml and 1919.0 vs. 1403.3 ng.h/ml. This work provides a translational PBPK framework for predicting human oral PK of PROTACs and emphasizes challenges in generating robust preclinical data to enhance prediction accuracy.</p>","PeriodicalId":50934,"journal":{"name":"AAPS Journal","volume":"28 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147534185","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}