Clinical Pharmacology & Therapeutics最新文献

{"title":"Promise of Quantitative Proteomics in the Qualification of New Approach Methodologies.","authors":"Bhagwat Prasad","doi":"10.1002/cpt.70049","DOIUrl":"https://doi.org/10.1002/cpt.70049","url":null,"abstract":"<p><p>The shift from animal models to new approach methodologies (NAMs) in drug development requires experimental models that accurately reflect human biology. Characterizing protein abundance and composition in NAMs like microphysiological systems (MPS), enabling comparison with human tissues, allows identification of physiological differences, development of scaling factors for in silico models, monitoring of biomarkers, cellular heterogeneity, and interindividual variability. Thus, characterization of NAMs by quantitative proteomics is important for enhancing their translational and regulatory relevance.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937205","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":"Analysis by Age, Sex, Race, and Ethnicity of Participants in Clinical Trials Supporting Recently Approved Novel Therapies.","authors":"Neali H Lucas, Jinzhong Liu, Aden Asefa, Ariel S Armstrong, Mary Thanh Hai","doi":"10.1002/cpt.3578","DOIUrl":"https://doi.org/10.1002/cpt.3578","url":null,"abstract":"<p><p>Trial populations that are representative of the intended population for therapies build evidence supporting the generalizability of results to the intended population and improve adoption of novel therapies upon approval. We evaluated the demographic composition of trial populations in 62 pivotal studies supporting approval of novel therapies for human immunodeficiency virus, migraines, multiple sclerosis, and type 2 diabetes. Enrollment at all sites, US sites, and sites outside the United States was evaluated relative to US prevalence. Enrollment of Asian participants relative to US prevalence varied across evaluated drug programs. In most cases, enrollment of Black or African American participants across all sites combined was below disease prevalence. Enrollment for White participants was consistently above disease prevalence. For most programs, Hispanic or Latino participant enrollment met or approximated disease prevalence. For females, enrollment met or exceeded US prevalence in more than half of the therapies evaluated. Enrollment of Black or African American, White, and Hispanic or Latino participants from US sites in most trials approximated or exceeded US disease prevalence, whereas enrollment of Asian participants at US sites was generally below disease prevalence. Across evaluated trials, enrollment relative to disease prevalence varied at sites inside the United States compared to non-US sites for Black and Asian participants. Enrollment by ethnicity, sex, or age group was generally similar for US and non-US sites. Considering the demographics of countries where trial sites are located across development programs may enhance the ability to recruit participants that meaningfully reflect the population that would use therapies if approved.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937332","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":"Impact of Race on Profiles of Platelet Reactivity and Clinical Outcomes in Clopidogrel-Treated Participants.","authors":"Luis Ortega-Paz, Cameron D Thomas, Claudio Laudani, Salvatore Giordano, Francesco Franchi, Kayla R Tunehag, Fabiana Rollini, Selina Durukan, Joseph S Rossi, Maryam Farahmandsadr, George A Stouffer, Latonya Been, Ellen C Keeley, Julio D Duarte, Amber L Beitelshees, Craig R Lee, Larisa H Cavallari, Dominick J Angiolillo","doi":"10.1002/cpt.70045","DOIUrl":"10.1002/cpt.70045","url":null,"abstract":"<p><p>Black individuals undergoing percutaneous coronary intervention (PCI) experience higher rates of major adverse cardiovascular events (MACE) than non-Black individuals. This study assessed the racial differences in platelet reactivity and clinical outcomes among clopidogrel-treated participants. Two cohorts were analyzed. The pharmacodynamic (PD) cohort involved patients with atherosclerotic cardiovascular disease on maintenance clopidogrel therapy undergoing platelet function testing. The primary outcome was high platelet reactivity (HPR, i.e., P2Y₁₂ reaction unit [PRU] > 208). The PCI cohort included participants undergoing PCI on clopidogrel-based dual antiplatelet therapy. The primary outcome was 1-year MACE, defined as the composite of cardiovascular death, myocardial infarction (MI), ischemic stroke, or stent thrombosis. Data on clinically significant bleeding and CYP2C19 genotyping alleles were collected. The PD and PCI cohorts included 728 (32.1% Black) and 2,770 (20.5% Black) participants, respectively. Black participants had higher PRU levels (184 [IQR 128-234] vs. 144 [IQR 88-195]; P < 0.001) and higher prevalence of HPR (39.3% vs. 20.6%; P < 0.001). Independent predictors of HPR included Black race, hemoglobin levels, and presence of CYP2C19 loss-of-function allele. In the PCI cohort, Black participants had a higher risk of MACE (HR 1.47; 95% CI 1.02-2.11; P = 0.037), primarily driven by MI (HR 1.71; 95% CI 1.09-2.67; P = 0.019), with no significant difference in clinically significant bleeding (HR 1.08; 95% CI 0.65-1.80; P = 0.768). Black participants on clopidogrel exhibit higher platelet reactivity, increased rates of HPR, and an elevated risk of MACE within 1 year after PCI, without significant differences in bleeding compared to non-Black participants.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12450309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937071","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":"Association Between Daily Timing of Everolimus and Survival in High-Risk HR+/HER2- Early Breast Cancer: A Sub-Analysis of the UCBG-UNIRAD Trial.","authors":"Enora Laas, Anne-Sophie Hamy, Thomas Bachelot, Paul Gougis, Jérôme Lemonnier, Fabrice André, David Cameron, Judith Bliss, Sylvie Chabaud, Anne-Claire Hardy-Bessard, Magali Lacroix-Triki, Djelila Allouache, Marc Debled, Mario Campone, Laurence Venat-Bouvet, Paul Cottu, Mathilde Martinez, Julien Grenier, Florence Dalenc, Elise Dumas, Fabien Reyal, Bernard Asselain, Frédérique Penault-Llorca, Francis Lévi, Sylvie Giacchetti","doi":"10.1002/cpt.70030","DOIUrl":"https://doi.org/10.1002/cpt.70030","url":null,"abstract":"<p><p>In the UNIRAD phase III trial, evening intake of tamoxifen was previously associated with improved disease-free survival (DFS), while no timing effect was observed for aromatase inhibitors. This sub-study evaluated whether the timing of everolimus intake affects DFS in patients receiving adjuvant endocrine therapy (ET). A total of 1278 patients with high-risk HR+/HER2- early breast cancer were randomized to receive adjuvant ET with either placebo or everolimus. Patients prospectively recorded the timing of both ET and everolimus intake using four time slots: morning (06:00-11:59), afternoon (12:00-17:59), evening (18:00-23:59), and night (00:00-05:59). The relationship between intake timing and DFS was a pre-specified secondary endpoint. Timing data were available for 513 of 632 patients (81.2%) in the everolimus arm. After a median follow-up of 60.6 months, 15 local relapses, 55 metastases, and 36 deaths were reported. Overall, everolimus timing had no significant association with DFS (HR = 0.84, 95% CI 0.53-1.35, P = 0.4). However, a significant interaction was found between everolimus timing and ET type (P = 0.001). Among tamoxifen users, evening/night intake of everolimus significantly improved DFS compared to morning/afternoon intake (HR = 0.17, 95% CI 0.05-0.59, P = 0.005), independently of tamoxifen timing. No timing effect was observed in patients on aromatase inhibitors (HR = 1.56, P = 0.1). In multivariate analysis, evening/night everolimus with tamoxifen remained an independent predictor of improved DFS (HR = 0.13, P = 0.002). Evening or nighttime intake of everolimus may enhance the efficacy of tamoxifen-based adjuvant therapy in high-risk HR+/HER2- early breast cancer.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937287","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":"New Approach Methodologies: What Clinical Pharmacologists Should Prepare For.","authors":"Yanguang Cao, William Polacheck","doi":"10.1002/cpt.70046","DOIUrl":"10.1002/cpt.70046","url":null,"abstract":"<p><p>As new approach methodologies (NAMs) gain regulatory momentum for Investigational new drug (IND) applications, clinical pharmacologists are uniquely positioned to collaborate with preclinical and translational teams in the development, quantification, and implementation of these methodologies. Their involvement is critical to ensuring a reduction in animal use to support early-phase drug development.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937232","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":"Spatiotemporal Characterization of Sulfasalazine and 5-ASA Pharmacokinetics Using a Noninvasive Intestinal Sampling Device.","authors":"Jingwei Cai, Jordan S Mar, Bennett Kapili, Kelly M Storek, Jasmina Uzunovic, Elizabeth Skippington, Daniela Keilberg, Dewakar Sangaraju, Alexis Auster, Cyrus Khojasteh, Horace Rhee, George Triadafilopoulos, Dari Shalon, Mary Keir","doi":"10.1002/cpt.70035","DOIUrl":"https://doi.org/10.1002/cpt.70035","url":null,"abstract":"<p><p>Sulfasalazine, a cornerstone therapy for inflammatory bowel disease, relies on bacterial azo-reduction to release its active component, 5-aminosalicylic acid (5-ASA), which is further metabolized into inactive N-acetyl-5-aminosalicylic acid (N-acetyl-5-ASA) by bacterial N-acetyltransferase. Due to complex pharmacokinetics, patient-specific microbial metabolism, and the lack of accurate, convenient direct sampling method for gastrointestinal drug concentrations, sulfasalazine clinical efficacy remains variable. The CapScan® luminal sampling device enables region-specific, minimally invasive collection of intestinal contents. To better understand sulfasalazine pharmacokinetics in relation to intestinal and systemic drug concentrations and bacterial metabolic capacity, 10 healthy volunteers ingested CapScan devices following sulfasalazine administration. Upon retrieval from the stool, CapScan samples were assigned intestinal locations based on metabolomic and metagenomic profiling. Systemic sulfasalazine peaked at 4 hours post-ingestion, while 5-ASA and N-acetyl-5-ASA peaked at 8 hours. In the gastrointestinal tract, maximal sulfasalazine concentration was observed in the proximal small intestine (SI), decreasing distally as 5-ASA and N-acetyl-5-ASA concentrations increased, peaking in the stool. 5-ASA plasma concentrations positively correlated with distal SI concentrations 4 hours after sulfasalazine ingestion. Putative bacterial azoreductase genes were detected in all gastrointestinal regions, while putative bacterial acetyltransferase genes were detected in all regions except the proximal SI. This study revealed spatially distinct luminal concentrations of sulfasalazine and its metabolites, with a strong correlation between distal SI 5-ASA levels and early plasma exposure, highlighting GI region-specific absorption and microbial metabolism. These findings support the potential utility of luminal sampling to enhance understanding of drug pharmacokinetics and inform future strategies for optimizing oral drug delivery.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937233","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":"Quantitative Model-Informed Dose Selection for a Milvexian Phase III Study in Patients With Atrial Fibrillation.","authors":"Wangda Zhou, Emily Bozenhardt, Gregory E Alexander, Matthew L Zierhut, Samira Merali, Antoinette Ajavon-Hartmann, Peter Zannikos, Hyunmoon Back, EunYoung Suh, Navin Goyal, Mahesh N Samtani, Alexei N Plotnikov, Chandni Valiathan","doi":"10.1002/cpt.70037","DOIUrl":"https://doi.org/10.1002/cpt.70037","url":null,"abstract":"<p><p>Milvexian, an activated factor XI inhibitor, is being evaluated in the LIBREXIA phase III program for the prevention of thrombotic events, including in patients with atrial fibrillation (LIBREXIA AF). To guide the selection of a phase III dose regimen for LIBREXIA AF, two main approaches were used: (1) population pharmacokinetics and exposure-response modeling of milvexian phase I and phase II (AXIOMATIC-TKR) study data was performed to characterize the relationship between milvexian population pharmacokinetics and clinical efficacy, safety, and coagulation biomarkers; and (2) a model-based meta-analysis was developed using published clinical trial data from comparator anticoagulants in total hip or knee replacement patients. When used to simulate exposures for an atrial fibrillation population, the milvexian 100 mg twice-daily dose regimen had a concentration maximum peak-to-trough ratio of 1.35. At this regimen, the simulated median venous thromboembolism rate was 9.4% (lower than enoxaparin at ~21%). No relationship between bleeding and milvexian exposure was observed. Simulations using the model-based meta-analysis estimated that milvexian 100 mg twice-daily would lead to a systemic embolism odds ratio of 0.84 (95% CI: 0.65, 1.12) compared with apixaban 5 mg twice-daily for patients with atrial fibrillation. This integrated model-informed dose-selection approach supported 100 mg twice-daily as a regimen of milvexian to be evaluated in the phase III milvexian LIBREXIA AF study.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937235","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":"Levofloxacin in Bone and Joint Infections: Development of an Application for Model-Informed Precision Dosing.","authors":"Léo Mimram, Sophie Magreault, Florian Lemaitre, Françoise Jaureguy, Frédéric Mechaï, Kamélia Doukhi, Vincent Jullien, Emmanuelle Comets, Julie Bertrand","doi":"10.1002/cpt.70044","DOIUrl":"https://doi.org/10.1002/cpt.70044","url":null,"abstract":"<p><p>Levofloxacin is a valuable antibiotic in the treatment of bone and joint infections. Due to the known risk of treatment failure and bacterial resistance, the development of tools facilitating pharmacokinetic/pharmacodynamic parameter monitoring to inform precision dosing is needed. Therefore, we assessed the use of Bayesian estimation to predict AUC_0-24 and C_max of levofloxacin under various sampling scenarios realistic in clinical routine. Furthermore, we developed a free web-based application allowing model-informed precision dosing. All published population pharmacokinetic models of ofloxacin and levofloxacin in bone and joint infections were researched and their predictive performance was compared using a real-life data cohort. We used simulated data to validate the robustness of various scenarios for Bayesian estimation of AUC_0-24 and C_max with up to three samples, including the potential impact of an incorrectly reported sampling time at peak concentration. Relative bias and relative root mean square error were estimated to assess accuracy and precision, respectively. One of the three published levofloxacin models showed negligible mean relative prediction error (0.02 ± 0.09). We modified it to a closed form approximation to facilitate the implementation in the application. The 2-sample scenario (T0h-T3h) allowed accurate and precise AUC_0-24 estimations for 500 mg q12h and 750 mg q24h dosing regimens. None of the tested scenarios allowed a satisfactory estimation of C_max. We finally developed and validated a free web-based application (https://levoshiny.iame-research.center/) using the selected model. The Shiny application will be useful in clinical practice to individualize dose regimens based on the AUC_0-24 obtained using the proposed limited sampling strategy.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937042","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":"Results of the ACCOuNT Trial: A Multi-Institutional Prospective Pharmacogenomics Implementation Trial for African American Inpatients.","authors":"Zhong Huang, Kevin J O'Leary, Edith A Nutescu, Matthew Jack, Thomas Chen, Gregory W Ruhnke, James C Lee, David George, Larry K House, Randall Knoebel, Luke V Rasmussen, Seth Hartman, Anish Choksi, Kiang-Teck J Yeo, Minoli A Perera, Mark J Ratain, David O Meltzer, Peter H O'Donnell","doi":"10.1002/cpt.70024","DOIUrl":"https://doi.org/10.1002/cpt.70024","url":null,"abstract":"<p><p>Pharmacogenomics implementation efforts have increased over the last decade, but no published prospective pharmacogenomics trials have formally evaluated utility in underrepresented populations. We present final results from the ACCOuNT trial, a multi-institutional prospective study [NCT03225820] in which African American inpatients were genotyped and pharmacogenomic results made available via an integrated, scalable pharmacogenomics clinical decision support (PGx CDS) system to guide prescribing. We hypothesized that PGx CDS utilization would improve genomically concordant prescribing during inpatient admissions. We recruited 531 patients, of which 187 were readmitted (60.4% female, median age = 55 [range: 19-88], median readmissions/patient = 2 [range: 1-17]), resulting in 518 evaluable admissions during which the effect of available pharmacogenomic results was measured. In 50% of admissions, care teams utilized PGx CDS. 12% of inpatient prescriptions had pharmacogenomic annotations, with only 3.6% pharmacogenomically associated with increased caution (\"discordant\"); no PGx high-risk medications were prescribed. PGx CDS use by provider teams did not decrease genomically discordant prescribing (3.9% vs. 3.3% without PGx CDS use, P = 0.53). Nevertheless, inpatient care teams repeatedly consulted PGx CDS ostensibly to affirm genomically concordant prescriptions, as 48% of all admissions and 91% of discharges included pharmacogenomically annotated medications, mostly genomically concordant. Notably, timing of PGx CDS utilization correlated tightly with prescribing timing (correlation coefficient = 0.84, P < 0.05). In the first results of a multi-institutional, prospective pharmacogenomics trial focused on underrepresented patients, we found the relevance of currently actionable pharmacogenomics information for guiding inpatient prescribing to be modest; but observed frequent use of concordant pharmacogenomics to affirm prescribing.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937185","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":"Integrated Population Pharmacokinetic, Pharmacodynamic, and Safety Analyses to Inform Dosage Selection in the Clinical Development of the ATR Inhibitor Tuvusertib.","authors":"Jatinder Kaur Mukker, Paul Matthias Diderichsen, Farina Hellmann, Timothy A Yap, Ruth Plummer, Anthony W Tolcher, Johann S de Bono, Ioannis Gounaris, Zoltan Szucs, Astrid Zimmermann, Irina Kareva, Jayaprakasam Bolleddula, Annick Seithel-Keuth, Giuseppe Locatelli, Marta Enderlin, Christine Hicking, Anup Zutshi, Wei Gao, Rainer Strotmann, Lisa Benincosa, Karthik Venkatakrishnan","doi":"10.1002/cpt.70029","DOIUrl":"https://doi.org/10.1002/cpt.70029","url":null,"abstract":"<p><p>We present model-informed selection of the recommended dose for expansion (RDE) of investigational oral ATR inhibitor tuvusertib, by integrating clinical pharmacokinetics (PK), pharmacodynamics (PD), and safety data from DDRiver Solid Tumors 301 trial Part A1 (NCT04170153). A population PK (POPPK) model was developed to characterize PK and hemoglobin (HGB) reduction after multicycle treatment was simulated using a semi-mechanistic, multivariate POPPK/PD model of reticulocyte (RET), red blood cell (RBC), and HGB dynamics. A semi-mechanistic PK-efficacy model characterized concentration-dependent tumor growth inhibition (TGI) in ARID1A mutant xenograft models. The clinical exposure-PD relationship was described for phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) as a biomarker of ATR inhibition. POPPK simulations predict the average steady-state concentrations to exceed phosphorylated checkpoint kinase 1 (pCHK1) IC₉₀ at 100-180 mg once daily (QD) and 180 mg QD 2 weeks (w) on/1w off. Exposure-related PD suggested target engagement of ≥80% at ≥130 mg QD. POPPK/PD modeling showed partial HGB recovery and lower rates of Grade ≥3 anemia after multicycle treatment with 180 mg QD 2w on/1w off vs. 130 mg and 180 mg QD. Lesser HGB reduction was predicted for 100 mg QD vs. higher QD doses. Translational modeling indicated no effect of the one-week dosing break on TGI at 180 mg QD. The analysis supports tuvusertib 180 mg QD 2w on/1w off as the RDE and 100 mg QD as the no-regret dose for clinical evaluation. This example underscores the value of integrated quantitative pharmacology analyses to inform dose selection using a totality of evidence approach.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936996","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}