Cts-Clinical and Translational Science最新文献

{"title":"MoLPre: A Machine Learning Model to Predict Metastasis of cT1 Solid Lung Cancer","authors":"Jie Lan,&nbsp;Heng Wang,&nbsp;Jing Huang,&nbsp;Weiyi Li,&nbsp;Min Ao,&nbsp;Wanfeng Zhang,&nbsp;Junhao Mu,&nbsp;Li Yang,&nbsp;Longke Ran","doi":"10.1111/cts.70186","DOIUrl":"https://doi.org/10.1111/cts.70186","url":null,"abstract":"<p>Given that more than 20% of patients with cT1 solid NSCLC showed nodal or extrathoracic metastasis, early detection of metastasis is crucial and urgent for improving therapeutic planning and patients' risk stratification in clinical practice. This study collected clinicopathological variables from the pulmonary nodule and lung cancer database of the First Affiliated Hospital of Chongqing Medical University, where patients with early-stage (cT1) solitary lung cancer were evaluated from 2018.11 to 2022.10. The random forest model and Shapley Additive Explanations (SHAP) were used to investigate the importance of clinical features in the feature selection part. Random Forest, Gradient Boosting, and AdaBoost classifiers were applied to build the final model, and the predictive discrimination of each model was compared based on the receiver operating characteristics (ROC) curve and precision and recall curve. With the evaluation of feature importance, 9 features were used to construct the prediction model finally. The Random Forest model yielded an average precision of 0.93 with an area under the curve (AUC) of 0.92 (95% CI: 0.88–0.94) compared with the Gradient Boosting and AdaBoost classifiers in the internal validation dataset, yielding an average precision of 0.87 and 0.91 with AUCs of 0.87 (95% CI: 0.84–0.93) and 0.90 (95% CI: 0.86–0.92), respectively. In addition, the Random Forest classifier performed best in 5 other 5 diagnostic indices. Furthermore, we embedded this model in a web application called MoLPre (https://molpre.cqmu.edu.cn/), a user-friendly tool assisting in the metastasis prediction of cT1 solid lung cancer.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Molnupiravir Exposure-Response Relationships for Virology Response and Mechanism of Action Biomarkers With Clinical Outcomes in Treatment of COVID-19","authors":"Akshita Chawla,&nbsp;Ruthie Birger,&nbsp;Brian M. Maas,&nbsp;Youfang Cao,&nbsp;Hong Wan,&nbsp;Julie Strizki,&nbsp;Arthur Fridman,&nbsp;Amanda Paschke,&nbsp;Carisa de Anda,&nbsp;Wei Gao,&nbsp;Matthew L. Rizk,&nbsp;Wendy Painter,&nbsp;Wayne Holman,&nbsp;Susanne Sardella,&nbsp;George Painter,&nbsp;Julie A. Stone","doi":"10.1111/cts.70184","DOIUrl":"https://doi.org/10.1111/cts.70184","url":null,"abstract":"<p>Molnupiravir, an orally administered drug for the treatment of mild-to-moderate COVID-19, is a prodrug of the ribonucleoside β-D-N4-hydroxycytidine (NHC). NHC incorporation in the SARS-CoV-2 RNA strand causes an accumulation of deleterious errors in the genome, resulting in reduced viral infectivity and replication. Exposure-response (E-R) analyses for viral RNA mutation rate and virologic outcomes were conducted using data from three phase 2/3 studies of molnupiravir (P006, MOVe-IN, and MOVe-OUT). Three dose levels (200, 400, and 800 mg every 12 hours [Q12H]) and placebo were evaluated. E-R datasets were generated for SARS-CoV-2 RNA mutation and longitudinal SARS-CoV-2 RNA viral load. E-R models were defined for RNA mutation rate and viral load change from baseline at days 5 and 10. The models supported plasma NHC AUC_0-12 as the appropriate pharmacokinetic driver for assessing E-R relationships. The highest percentage of participants with &gt; 20 low-frequency nucleotide substitutions (LNS) per 10,000 bases, a measure of likely meaningful drug effect, was predicted in the 800 mg Q12H treatment group. A strong drug effect on the reduction of viral load was observed on days 5 and 10. E-R relationships were best represented by an E_max structural model with reasonable consistency in the estimated AUC₅₀s (~2.3-fold), across the models, of 10,260 and 4390 nM*hr. for day 5 viral load change from baseline and LNS error rate, respectively. These biomarker E-R curves support the choice of 800 mg Q12H as providing near-maximal drug effect, consistent with findings from the previously published molnupiravir E-R model of clinical outcomes.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of ALXN1820 (Tarperprumig) in Healthy Adults: Results of a Phase I Study","authors":"Avner Sandhu,&nbsp;Tong Shen,&nbsp;Paz Martin Herrero,&nbsp;Chao-Xing Yuan,&nbsp;Samirah Qureshi,&nbsp;Xiaoyu Jiang,&nbsp;Ye Sheng,&nbsp;Christoph Gasteyger,&nbsp;Yang Dai","doi":"10.1111/cts.70190","DOIUrl":"https://doi.org/10.1111/cts.70190","url":null,"abstract":"<p>Properdin is an endogenous positive regulator of the complement alternative pathway (AP). Tarperprumig (ALXN1820), a novel humanized bispecific antibody, binds properdin and albumin and is being developed to treat complement-mediated diseases. This phase I, randomized, double-blind, placebo-controlled trial assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of tarperprumig in healthy adult participants. In cohorts 1 to 4 and 6, single doses of tarperprumig were administered via subcutaneous (SC) injection (12.5, 50, 150, 450, and 1200 mg doses). In cohorts 8 and 9, the 150 mg dose was given via SC injection once weekly for 5 doses. In cohort 5, a single dose of 450 mg was administered via intravenous infusion. Sixty participants were randomized (3:1) to tarperprumig or placebo. There were no discontinuations due to adverse events (AEs) in participants receiving tarperprumig. There were no serious AEs, events of serious infection, or deaths. No <i>N. meningitidis</i> infections occurred. Most AEs were mild and not treatment related. Tarperprumig exposure resulted in linear dose proportionality among all but one cohort. Mean absolute bioavailability of tarperprumig was 94%. AP activity decreased rapidly after tarperprumig administration. Complete AP inhibition (&lt; 1% of baseline value) was observed in all cohorts except for cohort 1 (12.5 mg SC). There was no change in complement classical or lectin pathway activity. Antidrug antibody titers were mostly low and did not impact PK. Tarperprumig was well tolerated and completely inhibited the AP in healthy adults. These results support continued investigation of tarperprumig to treat diseases involving complement activation.</p><p><b>Trial Registration:</b> EudraCT: 2021–002472-39/NCT04631562</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70190","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of the Molecular Mechanisms of Paraoxonase-2 Mediated Radiotherapy and Chemotherapy Resistance in Oral Squamous Cell Carcinoma","authors":"Mehta Vedant Kamal,&nbsp;Krishnananda Prabhu,&nbsp;Krishna Sharan,&nbsp;Ananth Pai,&nbsp;Sanjiban Chakrabarty,&nbsp;Rama Rao Damerla,&nbsp;Preethi S. Shetty,&nbsp;Vijetha Shenoy Belle,&nbsp;Mahadev Rao,&nbsp;Naveena A. N. Kumar","doi":"10.1111/cts.70201","DOIUrl":"https://doi.org/10.1111/cts.70201","url":null,"abstract":"<p>Oral squamous cell carcinoma (OSCC) is a common form of cancer, with 390,000 new cases estimated for 2022. OSCC has a poor prognosis, largely due to a high recurrence rate and resistance to therapy. Cancer cells develop resistance to standard therapy owing to various factors, such as genetic predispositions, alterations in the apoptotic pathway coupled with DNA repair pathways, drug efflux, and drug detoxification. This review is aimed at exploring the crucial role of paraoxonase 2 (PON2) in conferring resistance to chemotherapy and radiotherapy in OSCC cells. PON2, an antioxidant enzyme, protects cancer cells from the oxidative stress caused by these treatments. By influencing apoptotic pathways and DNA repair mechanisms, PON2 can reduce the effectiveness of therapy. This review is an attempt to explore the complex molecular mechanisms modulated by PON2, such as the mitigation of oxidative stress, enhancement of DNA repair, apoptosis regulation, drug efflux modulation, and drug detoxification, which decrease treatment efficacy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surfing the T Wave: A Primer on ECG T Wave Morphologies Encountered in Clinical Trials and Impact on the QT Interval and Patient Safety","authors":"Robert M. Lester,&nbsp;Sabina Paglialunga","doi":"10.1111/cts.70145","DOIUrl":"https://doi.org/10.1111/cts.70145","url":null,"abstract":"<p>Electrocardiogram (ECG) interpretation and measurement is an essential aspect of patient safety and pharmacovigilance in clinical trials. Changes in the T wave segment of an ECG can provide both diagnostic and prognostic information and may be affected by a variety of intrinsic and extrinsic factors related to drug administration. To add, regulators in their guidance encourage sponsors to provide analysis on treatment-emergent T wave morphology changes when submitting clinical study reports. Despite the T wave representing an important element of an ECG and impacting QT interval measurement, there is often a lack of recognition and incomplete understanding of the different T wave configurations that would affect subject management. Moreover, this topic has not been formally incorporated in pharmaceutical research. Therefore, this comprehensive review aims to profile normal and abnormal T wave morphologies that scientists and principal investigators might encounter during study conduct that would influence patient management and safety. This includes commentary on T wave pathophysiology, prognostic information, and short- and long-term management strategies when T wave abnormalities are present.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and Safety Profile of SNS812, a First in Human Fully Modified siRNA Targeting Wide-Spectrum SARS-CoV-2, in Healthy Subjects","authors":"Yi-Chung Chang,&nbsp;Yi-Fen Chen,&nbsp;Chi-Fan Yang,&nbsp;Hui-Ju Ho,&nbsp;Jen Fu Yang,&nbsp;Yuan-Lin Chou,&nbsp;Ching-Wen Lin,&nbsp;Pan-Chyr Yang","doi":"10.1111/cts.70202","DOIUrl":"10.1111/cts.70202","url":null,"abstract":"<p>Severe acute respiratory syndrome caused by the coronavirus (SARS-CoV-2) in the COVID-19 pandemic has highlighted the need for effective treatments, as rapid viral mutations complicate therapeutic development. SNS812, a fully modified inhaled siRNA that targets the conserved RNA-dependent RNA polymerase (RdRP) gene of SARS-CoV-2, has been shown to possess its suppression ability against wide-spectrum SARS-COV-2 variants preclinically. To evaluate the safety and tolerability of inhaled SNS812 in healthy participants, a randomized, double-blind, placebo-controlled phase 1 trial was conducted. To justify the first-in-human inhalation study, this research was divided into two parts: single ascending doses (0.3, 0.6, and 1.2 mg/kg) and multiple doses (0.6 and 1.2 mg/kg) of daily inhalation for seven consecutive days to assess the safety, tolerability, immunogenicity, and pharmacokinetics of SNS812. Of the 44 participants, 3 in the 0.3 mg/kg single-dose group, 2 in the 1.2 mg/kg multiple ascending doses group, and 1 in the placebo group reported treatment-emergent adverse events (TEAEs). No serious adverse events (SAEs), treatment-related adverse events (TRAEs), or TEAEs caused discontinuation or deaths were observed. PK showed rapid absorption of SNS812, with peak concentrations (median <i>T</i>_max) reached at 1.5–2 h, and an elimination half-life (t _1/2) between 4.96 and 7.08 h. No antidrug antibodies (ADAs) were detected in either group. The results demonstrated that the first-in-human, fully modified with wide-spectrum anti-SARS-COV2 siRNA by inhalation following a single dose and multiple doses was safe and well tolerated in healthy participants.</p><p><b>Trial Registration:</b> NCT05677893</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nontraditional Factors Influencing Cardiovascular Disease Risk: Correlation Among Framingham Risk Score, Body Composition Index, and Sleep-Breathing Monitoring Index","authors":"Libo Zhao,&nbsp;Xin Xue,&nbsp;Yinghui Gao,&nbsp;Weimeng Cai,&nbsp;Zhe Zhao,&nbsp;Dong Rui,&nbsp;Tingyu Nie,&nbsp;Tianjiao Li,&nbsp;Cong Ma,&nbsp;Li Fan,&nbsp;Lin Liu","doi":"10.1111/cts.70170","DOIUrl":"https://doi.org/10.1111/cts.70170","url":null,"abstract":"<p>To examine the correlation among body composition, sleep-breathing indicators, and Framingham risk score (FRS) to identify and amplify nontraditional factors that influence the risk of CVD in males, A total of 195 male participants underwent examinations for body composition and sleep-breathing monitoring. We compared the differences in individual factors across various FRS groups. We further conducted multiple linear regression analysis. A cutoff value of FRS ≥ 14 was utilized, and potential influencing factors were examined by logistic regression analysis. Statistical differences were observed in the levels of fasting blood glucose (FBG), CO₂, serum ferritin, hemoglobin (HB), and ECT/TBW among the FRS tripartite groups. However, no significant differences were found in AHI and MSpO₂. The multiple linear regression analysis revealed positive correlations between ECW/TBW and FBG with FRS (<i>β</i> = 0.324 and 0.324, <i>p</i> &lt; 0.001), while HB and muscle/fat mass exhibited negative correlations with the score (<i>β</i> = −0.185 and − 0.169, <i>p</i> &lt; 0.01). These five factors—ECW/TBW, FBG, HB, serum ferritin, and muscle/fat mass—collectively accounted for 28.6% of the variation in FRS. A higher ECW/TBW was significantly associated with FRS ≥ 14 (OR = 2.208, 95% CI: 1.503–3.244). Conversely, reduced levels of muscle/fat mass, HB, and basal metabolic rate (BMR) were significantly linked to moderate-to-high CVD risk (OR_ratio = 0.532, 95% CI: 0.284–0.996; OR_HB = 0.961, 95% CI: 0.932–0.991; OR_BMR = 0.997, 95% CI: 0.995–1.000). This study revealed correlations among ECW/TBW, HB, FBG, and muscle-to-fat mass ratio with the risk of CVD predicted using FRSs.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Informing Implementation Strategies for Pharmacogenomics in Cancer: Development of Survey Tools for Healthcare Professionals and Consumers","authors":"Marliese Alexander,&nbsp;Chiao Xin Lim,&nbsp;Senthil Lingaratnam,&nbsp;Sarah Glewis,&nbsp;Joanne Wickens,&nbsp;Abbey Hird,&nbsp;Zi Yue Chen,&nbsp;Alistair Bozkurt,&nbsp;Amit Khot,&nbsp;David Routledge,&nbsp;Sam Harris,&nbsp;Craig Underhill,&nbsp;Ashley Whitechurch,&nbsp;Lydia Leong,&nbsp;Marcus Pergolini,&nbsp;Gail Rowan,&nbsp;Monnette Samo,&nbsp;Chloe Georgiou,&nbsp;Peter Savas,&nbsp;Jenny Devine,&nbsp;Alysia Kepert,&nbsp;Safeera Y. Hussainy","doi":"10.1111/cts.70144","DOIUrl":"https://doi.org/10.1111/cts.70144","url":null,"abstract":"<p>Integration of clinical pharmacogenomics (PGx) within routine cancer care is limited despite frequent use of medicines impacted by PGx, evidence for the benefits of PGx, and the availability of international PGx clinical guidelines. Our study objective was to develop survey tools to assess PGx knowledge, attitudes, practices, perceptions, and education needs among (a) doctors, nurses, and pharmacists involved in cancer care (healthcare professionals, HCPs) and (b) adults who have received cancer treatment or their carers (consumers), with the view to informing implementation strategies for PGx in solid and hematologic cancers. Survey tools were developed in a three-phase (ph) mixed-methods approach. Content was informed by systematic literature review findings and framed by determinants of behavior as informed by the Theoretical Domains Framework (ph-1). Refinement occurred through four separate priority partnership meetings (ph-2). Meetings focused on clinical PGx practices within select cancer streams, and consumers' knowledge, attitudes, and preferences for PGx testing. Content/face validity and health literacy (Flesch Kincaid Grade Level) assessments informed final refinements (ph-3). Separate HCP and consumer survey tools were developed with six common sections: (1) introduction; (2) demographics; (3) experience; (4) knowledge, attitudes, practices and perceptions; (5) education; and (6) vignettes. Content and face validity were rated highly with acceptable health literacy assessments for questions within the consumer survey (median grade level 6; range 1–8). The developed survey tools will be used to generate evidence to inform local implementation strategies for PGx in cancer and promote broader integration of pharmacogenomics in routine clinical care.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Selective Serotonin Reuptake Inhibitors on Coagulation: Fact or Fiction?","authors":"Antoine Mokhtarian,&nbsp;Sophie Melicine,&nbsp;Virginie Siguret,&nbsp;Georges Jourdi","doi":"10.1111/cts.70164","DOIUrl":"https://doi.org/10.1111/cts.70164","url":null,"abstract":"<p>Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety yet are associated with an increased bleeding risk. While this risk is mainly linked to the decrease in platelet serotonin content, thus abnormal platelet functions, some studies suggest an inherent effect of SSRIs on coagulation. Hence, we performed a literature review to provide an overview of the different studies assessing SSRI's effects on coagulation assays routinely used in clinical practice. A search of the PubMed database yielded 22 relevant studies. Results were inconsistent: While some studies showed minor changes in routine coagulation assays, namely, prothrombin time and activated partial thromboplastin time, the majority found no significant effects of SSRIs on coagulation tests. Then, we specifically investigated the impact of citalopram, a commonly prescribed SSRI, on the thrombin generation assay (TGA) allowing the detection of any potential procoagulant or anticoagulant effect. TGA was performed in platelet-poor plasma from 14 healthy volunteers spiked with citalopram at therapeutic (0.1 and 0.5 μM) and supratherapeutic (50 μM) concentrations. TGA parameters were not significantly changed compared to the control condition regardless of the citalopram concentration. All in all, our findings failed to demonstrate any compromised coagulation function associated with SSRI therapy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Pharmacokinetics in Rats Using Machine Learning: A Comparative Study Between Empirical, Compartmental, and PBPK-Based Approaches","authors":"Moritz Walter,&nbsp;Ghaith Aljayyoussi,&nbsp;Bettina Gerner,&nbsp;Hermann Rapp,&nbsp;Christofer S. Tautermann,&nbsp;Pavel Balazki,&nbsp;Miha Skalic,&nbsp;Jens M. Borghardt,&nbsp;Lina Humbeck","doi":"10.1111/cts.70150","DOIUrl":"https://doi.org/10.1111/cts.70150","url":null,"abstract":"<p>A successful drug needs to combine several properties including high potency and good pharmacokinetic (PK) properties to sustain efficacious plasma concentration over time. To estimate required doses for preclinical animal efficacy models or for the clinics, in vivo PK studies need to be conducted. Although the prediction of ADME properties of compounds using machine learning (ML) models based on chemical structures is well established in drug discovery, the prediction of complete plasma concentration–time profiles has only recently gained attention. In this study, we systematically compare various approaches that integrate ML models with empiric or mechanistic PK models to predict PK profiles in rats after intravenous administration prior to synthesis. More specifically, we compare a standard noncompartmental analysis (NCA)-based approach (prediction of CL and V_ss), a pure ML approach (non-mechanistic PK description), a compartmental modeling approach, and a physiologically based pharmacokinetic (PBPK) approach. Our study based on internal preclinical data shows that the latter three approaches yield PK profile predictions of comparable accuracy across a large data set (evaluated as geometric mean fold errors for each profile of over 1000 small molecules). In summary, we demonstrate the improved ability to prioritize drug candidates with desirable PK properties prior to synthesis with ML predictions.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}