Cts-Clinical and Translational Science最新文献

{"title":"Dalzanemdor (SAGE-718), a novel, investigational N-methyl-D-aspartate receptor positive allosteric modulator: Safety, tolerability, and clinical pharmacology in randomized dose-finding studies in healthy participants and an open-label study in participants with Huntington's disease","authors":"Aaron Koenig,&nbsp;Michael Lewis,&nbsp;Jeff Wald,&nbsp;Sigui Li,&nbsp;Mustafa Varoglu,&nbsp;Jing Dai,&nbsp;Abdul Sankoh,&nbsp;Katrina Paumier,&nbsp;James Doherty,&nbsp;Mike Quirk","doi":"10.1111/cts.13852","DOIUrl":"10.1111/cts.13852","url":null,"abstract":"<p>N-methyl-D-aspartate receptor (NMDAR)-positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE-718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first-in-human, phase I, double-blind, dose-finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single-ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple-ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open-label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once-daily dosing. Following single and multiple doses in healthy participants, median terminal half-life was 8–118 h, and the median time to reach maximum plasma concentration was 4–7 h. Exposures were dose-proportional after single dose (6–46 ng/mL) and more than dose-proportional after multiple doses (6–41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13852","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141581448","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":"Protective effect of clusterin against interleukin-1β-induced apoptosis and inflammation in human knee osteoarthritis chondrocytes","authors":"Tachatra Ungsudechachai,&nbsp;Jiraphun Jittikoon,&nbsp;Sittisak Honsawek,&nbsp;Wanvisa Udomsinprasert","doi":"10.1111/cts.13881","DOIUrl":"10.1111/cts.13881","url":null,"abstract":"<p>Chondrocyte apoptosis is recognized as one of the pathological features involved in cartilage degeneration driving the onset and progression of knee osteoarthritis (OA). This study aimed to determine the molecular mechanism underlying the effect of clusterin (CLU), anti-apoptotic molecule, in human knee OA chondrocytes. Primary knee OA chondrocytes were isolated from the cartilage of knee OA patients and divided into five groups: (1) the cells treated with interleukin (IL)-1β, (2) CLU alone, (3) a combination of IL-1β and CLU, (4) LY294002 (PI3K inhibitor) along with IL-1β and CLU, and (5) the untreated cells. Production of apoptotic, inflammatory, anabolic, and catabolic mediators in knee OA chondrocytes was determined after treatment for 24 h. Our <i>in</i> <i>vitro</i> study uncovered that CLU significantly suppressed the production of inflammatory mediators [nitric oxide (NO), IL6, and tumor necrosis factor (TNF)-α] and apoptotic molecule (caspase-3, CASP3). CLU significantly upregulated messenger ribonucleic acid (mRNA) expressions of anabolic factors [SRY-box transcription factor-9 (<i>SOX9</i>) and aggrecan (<i>ACAN</i>)], but significantly downregulated mRNA expressions of <i>IL6</i>, nuclear factor kappa-B (<i>NF-κB</i>), <i>CASP3</i>, and matrix metalloproteinase-13 (<i>MMP13</i>). Anti-apoptotic and anti-inflammatory effects of CLU were mediated through activating PI3K/Akt signaling pathway. The findings suggest that CLU might have beneficial effects on knee OA chondrocytes by exerting anti-apoptotic and anti-inflammatory functions via PI3K/Akt pathway, making CLU a promising target for potential therapeutic interventions in knee OA.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13881","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565035","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":"The interactive walkway provides fit-for-purpose fall-risk biomarkers in the elderly: Comparison of zolpidem and suvorexant","authors":"Ingrid Koopmans,&nbsp;Daphne Geerse,&nbsp;Lara de Ridder,&nbsp;Melvyn Roerdink,&nbsp;Maria Joanna Juachon,&nbsp;Clemens Muehlan,&nbsp;Jasper Dingemanse,&nbsp;Joop van Gerven,&nbsp;Geert Jan Groeneveld,&nbsp;Rob Zuiker","doi":"10.1111/cts.13875","DOIUrl":"10.1111/cts.13875","url":null,"abstract":"<p>Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug-induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall-risk assessments in early clinical drug development. In this three-way crossover study, 18 healthy elderly (age: 65–80 years) subjects received 5 mg zolpidem, 10 mg suvorexant, or placebo in the morning. Assessments were performed pre-dose and approximately hourly until 9 h post-dose. IWW assessments included an 8-meter walking test, goal-directed stepping, obstacle-avoidance, and tandem-walking. Other pharmacodynamic measurements were the Timed-Up-and-Go (TUG) test at a comfortable and fast pace, adaptive tracking, and body sway. A decline in performance was observed for zolpidem compared with placebo for 3 h post-dose in IWW walking adaptability outcome measures, TUG, adaptive tracking, and body sway. For the IWW tasks, a decrease in walking speed (among others) was observed. IWW parameters were not affected by suvorexant compared with placebo at any timepoint. However, an increase of 9.8% (95%CI: 1.8%, 18.5%) in body sway was observed for suvorexant compared with placebo up to 3 h post-dose. The IWW successfully quantified drug effects of two hypnotic drugs and distinguished between zolpidem and suvorexant regarding their effects on walking. As a biomarker, the IWW demonstrated sensitivity in assessing dynamic balance and potential fall risk in early phase clinical drug development.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11231031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560188","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":"A phase I thorough QT/QTc study evaluating therapeutic and supratherapeutic doses of avacopan in healthy participants","authors":"Shichang Miao,&nbsp;Peter Staehr,&nbsp;Ezra Tai,&nbsp;Borje Darpo,&nbsp;Hongqi Xue,&nbsp;Danielle Armas,&nbsp;Kenneth Webster,&nbsp;Rajneet K. Oberoi","doi":"10.1111/cts.13878","DOIUrl":"10.1111/cts.13878","url":null,"abstract":"<p>This phase I thorough QTc, double-blind, randomized, placebo- and positive-controlled, parallel group, multiple-dose study evaluated avacopan's effect on cardiac repolarization using concentration-QTc (C-QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time-matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (−5.5 to 3.5 ms) was similar to placebo (−6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (−0.17 to 3.09) and 0.8 ms (−2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C-QTc analysis, avacopan's effect on ΔΔQTcF &gt;10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555907","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":"Plerixafor for pathogen-agnostic treatment in murine thigh infection and zebrafish sepsis","authors":"Martin O. Evans,&nbsp;Darren M. Smith,&nbsp;Adrian T. Kress,&nbsp;Robert J. Nadeau,&nbsp;Daniel J. Selig,&nbsp;Diana Caridha,&nbsp;Ratanachat Racharaks,&nbsp;Thomas Langowski,&nbsp;Michael S. Madejczyk,&nbsp;Chance Carbaugh,&nbsp;David Saunders,&nbsp;Mark Widder,&nbsp;Jason De Meese,&nbsp;Patricia J. Lee,&nbsp;Jesse P. DeLuca","doi":"10.1111/cts.13876","DOIUrl":"10.1111/cts.13876","url":null,"abstract":"<p>Plerixafor is a CXCR4 antagonist approved in 2008 by the FDA for hematopoietic stem cell collection. Subsequently, plerixafor has shown promise as a potential pathogen-agnostic immunomodulator in a variety of preclinical animal models. Additionally, investigator-led studies demonstrated plerixafor prevents viral and bacterial infections in patients with WHIM syndrome, a rare immunodeficiency with aberrant CXCR4 signaling. Here, we investigated whether plerixafor could be repurposed to treat sepsis or severe wound infections, either alone or as an adjunct therapy. In a <i>Pseudomonas aeruginosa</i> lipopolysaccharide (LPS)-induced zebrafish sepsis model, plerixafor reduced sepsis mortality and morbidity assessed by tail edema. There was a U-shaped response curve with the greatest effect seen at 0.1 μM concentration. We used <i>Acinetobacter baumannii</i> infection in a neutropenic murine thigh infection model. Plerixafor did not show reduced bacterial growth at 24 h in the mouse thigh model, nor did it amplify the effects of a rifampin antibiotic therapy, in varying regimens. While plerixafor did not mitigate or treat bacterial wound infections in mice, it did reduce sepsis mortality in zebra fish. The observed mortality reduction in our LPS model of zebrafish was consistent with prior research demonstrating a mortality benefit in a murine model of sepsis. However, based on our results, plerixafor is unlikely to be successful as an adjunct therapy for wound infections. Further research is needed to better define the scope of plerixafor as a pathogen-agnostic therapy. Future directions may include the use of longer acting CXCR4 antagonists, biased CXCR4 signaling, and optimization of animal models.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13876","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499559","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":"Alkylating agents-induced gonadotoxicity in prepubertal males: Insights on the clinical and preclinical front","authors":"Sruthi Sriram,&nbsp;Tiago Macedo,&nbsp;Annelies Mavinkurve-Groothuis,&nbsp;Marianne van de Wetering,&nbsp;Leendert H. J. Looijenga","doi":"10.1111/cts.13866","DOIUrl":"10.1111/cts.13866","url":null,"abstract":"<p>Rising cure rates in pediatric cancer patients warrants an increased attention toward the long-term consequences of the diagnosis and treatment in survivors. Chemotherapeutic agents can be gonadotoxic, rendering them at risk for infertility post-survival. While semen cryopreservation is an option that can be provided for most (post)pubertal boys before treatment, this is unfortunately not an option prepubertal in age, simply due to the lack of spermatogenesis. Over the last couple of years, studies have thus focused on better understanding the testis niche in response to various chemotherapeutic agents that are commonly administered and their direct and indirect impact on the germ cell populations. These are generally compounds that have a high risk of infertility and have been classified into risk categories in curated fertility guidelines. However, with it comes the lack of evidence and the challenge of using informative models and conditions most reflective of the physiological scenario, in short, the appropriate study designs for clinically relevant outcomes. Besides, the exact mechanism(s) of action for many of these “risk” compounds as well as other agents is unclear. Understanding their behavior and effect on the testis niche will pave the way for incorporating new strategies to ultimately combat infertility. Of the various drug classes, alkylating agents pose the highest risk of gonadotoxicity as per previously established studies as well as risk stratification guidelines. Therefore, this review will summarize the findings in the field of male fertility concerning gonadotoxicity of akylating agents as a result of chemotherapy exposure.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13866","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535855","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":"Regulation in the age of calamity: Changing the regulatory paradigm","authors":"Richard Hatchett,&nbsp;Mei Xuan Jessalyn Chan,&nbsp;Adam Hacker,&nbsp;Wei Chuen Tan-Koi,&nbsp;Silke Vogel,&nbsp;John CW Lim","doi":"10.1111/cts.13882","DOIUrl":"10.1111/cts.13882","url":null,"abstract":"<p>The Centre of Regulatory Excellence (CoRE) launched an annual lecture series in 2021 to commemorate CoRE's founding Chair, the late Professor Sir Alasdair Breckenridge. Completing a trilogy of lectures on scientific and regulatory issues during the COVID-19 pandemic,<span>^{1, 2}</span> this perspective piece is based on the 2023 lecture on “Regulation in the Age of Calamity” delivered by Dr Richard Hatchett, Chief Executive Officer of the Coalition of Epidemic Preparedness Innovations (CEPI).</p><p>“Polycrisis,” a term popularized by Adam Tooze and embraced by the World Economic Forum, is the overwhelming concurrence of multiple interconnected global risks. We have entered an age of calamity in which the forces that have disrupted and defined our world in recent decades, not least the force of infectious diseases, will continue in ever accelerating fashion.<span>³</span> The COVID-19 pandemic was the epitome of a perfect storm of mutually potentiating crises. It could also be the harbinger of an era characterized by increasingly severe and frequent zoonotic spillover events, with the transmission of pathogens from animal reservoir to humans. Data from 1963 to 2019 showed that outbreaks are increasing at an alarmingly accelerating rate, driven by habitat encroachment and climate change.<span>⁴</span> On this trajectory, it is estimated that mankind would witness four times as many spillover-driven outbreaks and 12 times as many deaths by 2050, compared with 2020.</p><p>To be better prepared in this age of calamity, the health regulatory paradigm should continue to evolve, with smart and agile regulation as a key enabler to proactively guide the advancement and application of science.</p><p>For health product regulators, it is crucial to review the context and way in which regulatory processes and procedures are applied as these may have been fit-for-purpose in the past or in routine situations but could be maladaptive in a crisis. The endeavor should be to go beyond the received wisdom that regulation always follows science, and instead change the paradigm so that regulation proactively helps guide the development and application of science.</p><p>In the case of COVID-19, the development and emergency authorization of the first vaccine was achieved in just 326 days, when traditionally this would have taken several years. This success was contributed in part by the accelerated regulatory response, and modelers have estimated that vaccines may have contributed to preventing as many as 20 million deaths in the year after they were first authorized.<span>⁵</span> However, the question also arises whether the millions of excess deaths that had occurred by December 8, 2020, when the first COVID-19 vaccines became publicly available, could have been moderated had vaccines been available even sooner.</p><p>Thus, CEPI's call to accelerate the development and ultimately the equitable delivery of a pandemic vaccin","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477918","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":"Strategies for developing 3D printed ovarian model for restoring fertility","authors":"Ramya Nair,&nbsp;Meghana Kasturi,&nbsp;Vidhi Mathur,&nbsp;Raviraja N. Seetharam,&nbsp;Kirthanashri S Vasanthan","doi":"10.1111/cts.13863","DOIUrl":"10.1111/cts.13863","url":null,"abstract":"<p>Ovaries play a crucial role in the regulation of numerous essential processes that occur within the intricate framework of female physiology. They are entrusted with the responsibility of both generating a new life and orchestrating a delicate hormonal symphony. Understanding their functioning is crucial for gaining insight into the complexities of reproduction, health, and fertility. In addition, ovaries secrete hormones that are crucial for both secondary sexual characteristics and the maintenance of overall health. A three-dimensional (3D) prosthetic ovary has the potential to restore ovarian function and preserve fertility in younger females who have undergone ovariectomies or are afflicted with ovarian malfunction. Clinical studies have not yet commenced, and the production of 3D ovarian tissue for human implantation is still in the research phase. The main challenges faced while creating a 3D ovary for in vivo implantation include sustenance of ovarian follicles, achieving vascular infiltration into the host tissue, and restoring hormone circulation. The complex ovarian microenvironment that is compartmentalized and rigid makes the biomimicking of the 3D ovary challenging in terms of biomaterial selection and bioink composition. The successful restoration of these properties in animal models has led to expectations for the development of human ovaries for implantation. This review article summarizes and evaluates the optimal 3D models of ovarian structures and their safety and efficacy concerns to provide concrete suggestions for future research.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494073","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":"Variational autoencoders for generative modeling of drug dosing determinants in renal, hepatic, metabolic, and cardiac disease states","authors":"Raginee R. Titar,&nbsp;Murali Ramanathan","doi":"10.1111/cts.13872","DOIUrl":"10.1111/cts.13872","url":null,"abstract":"<p>Physiological determinants of drug dosing (PDODD) are a promising approach for precision dosing. This study investigates the alterations of PDODD in diseases and evaluates a variational autoencoder (VAE) artificial intelligence model for PDODD. The PDODD panel contained 20 biomarkers, and 13 renal, hepatic, diabetes, and cardiac disease status variables. Demographic characteristics, anthropometric measurements (body weight, body surface area, waist circumference), blood (plasma volume, albumin), renal (creatinine, glomerular filtration rate, urine flow, and urine albumin to creatinine ratio), and hepatic (R-value, hepatic steatosis index, drug-induced liver injury index), blood cell (systemic inflammation index, red cell, lymphocyte, neutrophils, and platelet counts) biomarkers, and medical questionnaire responses from the National Health and Nutrition Examination Survey (NHANES) were included. The tabular VAE (TVAE) generative model was implemented with the Synthetic Data Vault Python library. The joint distributions of the generated data vs. test data were compared using graphical univariate, bivariate, and multidimensional projection methods and distribution proximity measures. The PDODD biomarkers related to disease progression were altered as expected in renal, hepatic, diabetes, and cardiac diseases. The continuous PDODD panel variables generated by the TVAE satisfactorily approximated the distribution in the test data. The TVAE-generated distributions of some discrete variables deviated from the test data distribution. The age distribution of TVAE-generated continuous variables was similar to the test data. The TVAE algorithm demonstrated potential as an AI model for continuous PDODD and could be useful for generating virtual populations for clinical trial simulations.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13872","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472192","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":"Integration of individual preclinical and clinical anti-infective PKPD data to predict clinical study outcomes","authors":"Vincent Aranzana-Climent,&nbsp;Wisse van Os,&nbsp;Amir Nutman,&nbsp;Jonathan Lellouche,&nbsp;Yael Dishon-Benattar,&nbsp;Nadya Rakovitsky,&nbsp;George L. Daikos,&nbsp;Anna Skiada,&nbsp;Ioannis Pavleas,&nbsp;Emanuele Durante-Mangoni,&nbsp;Ursula Theuretzbacher,&nbsp;Mical Paul,&nbsp;Yehuda Carmeli,&nbsp;Lena E. Friberg","doi":"10.1111/cts.13870","DOIUrl":"10.1111/cts.13870","url":null,"abstract":"<p>The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin–meropenem combination therapy in carbapenem-resistant Gram-negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic–pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting <i>Acinetobacter baumannii</i> isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model-predicted growth at 24 h of ≥2-log₁₀ (164/207) correlated positively with clinical failure (adjusted odds ratio, aOR = 2.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti-infective PKPD data can be integrated through pharmacodynamic modeling and identify patient- and pathogen-specific factors related to clinical outcomes – an approach that may improve understanding of study outcomes.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11217551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477917","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}