Pub Date : 2024-05-06DOI: 10.1101/2024.05.06.24306928
Niklas Walther, Robert Schultz-Heienbrok, Heino Staß, Victor M. Corman, Nils C. Gassen, Marcel A. Müller, Christian Drosten, Martin Witzenrath, Hweeling Lee, Maximilian G. Posch
Aim Niclosamide is an established anthelmintic substance and a promising candidate for treating cancer, viral infections, and other diseases. However, its solubility in aqueous media is low, and the systemic bioavailability of the commercially available chewing tablet is poor, limiting the use of niclosamide for systemic treatment. A liquid oral formulation using polyethylene glycol 400 was developed and investigated in healthy volunteers to assess safety, tolerability, and pharmacokinetics in comparison to the marketed tablet. (ClinicalTrials.gov: NCT04644705)
{"title":"Clinical safety and pharmacokinetics of a novel oral niclosamide formulation compared with marketed niclosamide chewing tablets in healthy volunteers: a three-part randomized, double-blind, placebo-controlled trial","authors":"Niklas Walther, Robert Schultz-Heienbrok, Heino Staß, Victor M. Corman, Nils C. Gassen, Marcel A. Müller, Christian Drosten, Martin Witzenrath, Hweeling Lee, Maximilian G. Posch","doi":"10.1101/2024.05.06.24306928","DOIUrl":"https://doi.org/10.1101/2024.05.06.24306928","url":null,"abstract":"<strong>Aim</strong> Niclosamide is an established anthelmintic substance and a promising candidate for treating cancer, viral infections, and other diseases. However, its solubility in aqueous media is low, and the systemic bioavailability of the commercially available chewing tablet is poor, limiting the use of niclosamide for systemic treatment. A liquid oral formulation using polyethylene glycol 400 was developed and investigated in healthy volunteers to assess safety, tolerability, and pharmacokinetics in comparison to the marketed tablet. (ClinicalTrials.gov: NCT04644705)","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140942489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-12DOI: 10.1101/2024.04.08.24301402
Zahra Sadouki, Emmanuel Q. Wey, Sateesh Iype, David Nasralla, Jonathan Potts, Mike Spiro, Alan Williams, Timothy D. McHugh, Frank Kloprogge
Background & aims An extensively-drug resistant (XDR) NDM and OXA-48 producing E. coli contributing to repeat episodes of biliary sepsis was isolated from the blood stream of a 45-55 year-old male with a background of IgG4 related sclerosing cholangitis. The patient was awaiting orthotopic liver transplant (OLT). There is no standardized antibiotic prophylaxis regimen however in line with the Infectious Diseases Society of America (IDSA) guidance an antibiotic prophylactic regimen of Ceftazidime-Avibactam (CZA) 2.5g TDS with Aztreonam (ATM) 2g TDS IV was proposed.
{"title":"Personalized CZA-ATM dosing against an XDR E. coli in liver transplant patients; the application of the in vitro hollow fibre infection model (HFIM)","authors":"Zahra Sadouki, Emmanuel Q. Wey, Sateesh Iype, David Nasralla, Jonathan Potts, Mike Spiro, Alan Williams, Timothy D. McHugh, Frank Kloprogge","doi":"10.1101/2024.04.08.24301402","DOIUrl":"https://doi.org/10.1101/2024.04.08.24301402","url":null,"abstract":"<strong>Background & aims</strong> An extensively-drug resistant (XDR) NDM and OXA-48 producing <em>E. coli</em> contributing to repeat episodes of biliary sepsis was isolated from the blood stream of a 45-55 year-old male with a background of IgG4 related sclerosing cholangitis. The patient was awaiting orthotopic liver transplant (OLT). There is no standardized antibiotic prophylaxis regimen however in line with the Infectious Diseases Society of America (IDSA) guidance an antibiotic prophylactic regimen of Ceftazidime-Avibactam (CZA) 2.5g TDS with Aztreonam (ATM) 2g TDS IV was proposed.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1101/2024.04.02.24305135
Shifang Li, Meijiao Gong
Hypothyroidism is a common condition of thyroid hormone insufficiency, and there is growing evidence of its link with additional diseases. It remains unclear whether these associations share a common genetic architecture. To address this gap, by leveraging summary-level genetic data from the UK Biobank of hypothyroidism and the FinnGen study of three complex diseases (sarcoidosis, chronic sinusitis, and interstitial lung disease (ILD) endpoints), we evaluated their shared genetic etiology. A significant genetic correlation was found between hypothyroidism and the three diseases. Cross-trait analyses utilizing the MTAG and CPASSOC models revealed 12, 2, and 12 shared loci between hypothyroidism and chronic sinusitis, ILD endpoints, and sarcoidosis, respectively. The SNP heritability enrichment analysis across 37 tissues and 136 cell types at the single-cell level identified candidate tissues and cell types that were shared by the diseases. Interestingly, we found a positive genetic relationship between these four diseases and central memory CD4+ T cells in the blood, supported by strong colocalization evidence (posterior probability >0.9). Mendelian randomization and colocalization analysis showed a link between hypothyroidism and sarcoidosis with two genes (DOCK6 and CD226) in the blood. Furthermore, among the hypothyroidism-driven plasma proteins, RIPK2 was identified as a potentially actionable mediator of hypothyroidism’s effect on ILD endpoints. Overall, our findings contribute to improving our understanding of the molecular basis of these diseases’ intricate relationships, as well as providing insights toward disease prevention and comorbidity management.
{"title":"Shared genetic etiology between hypothyroidism and complex diseases: a large-scale genome-wide cross-trait analysis","authors":"Shifang Li, Meijiao Gong","doi":"10.1101/2024.04.02.24305135","DOIUrl":"https://doi.org/10.1101/2024.04.02.24305135","url":null,"abstract":"Hypothyroidism is a common condition of thyroid hormone insufficiency, and there is growing evidence of its link with additional diseases. It remains unclear whether these associations share a common genetic architecture. To address this gap, by leveraging summary-level genetic data from the UK Biobank of hypothyroidism and the FinnGen study of three complex diseases (sarcoidosis, chronic sinusitis, and interstitial lung disease (ILD) endpoints), we evaluated their shared genetic etiology. A significant genetic correlation was found between hypothyroidism and the three diseases. Cross-trait analyses utilizing the MTAG and CPASSOC models revealed 12, 2, and 12 shared loci between hypothyroidism and chronic sinusitis, ILD endpoints, and sarcoidosis, respectively. The SNP heritability enrichment analysis across 37 tissues and 136 cell types at the single-cell level identified candidate tissues and cell types that were shared by the diseases. Interestingly, we found a positive genetic relationship between these four diseases and central memory CD4+ T cells in the blood, supported by strong colocalization evidence (posterior probability >0.9). Mendelian randomization and colocalization analysis showed a link between hypothyroidism and sarcoidosis with two genes (DOCK6 and CD226) in the blood. Furthermore, among the hypothyroidism-driven plasma proteins, RIPK2 was identified as a potentially actionable mediator of hypothyroidism’s effect on ILD endpoints. Overall, our findings contribute to improving our understanding of the molecular basis of these diseases’ intricate relationships, as well as providing insights toward disease prevention and comorbidity management.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1101/2024.04.01.24305180
Cheng-qun Chen, Li-ping Du, Qing Liu, Qing-hua Ren, Zhen-feng Zhu, Gui-fang Sun, Yu-shen Li, Yang Yang, Shu-zhang Du, Yue-dong Qi
The prevalence of fundus lesion-related diseases is increasing, which ophthalmic anti-VEGF drugs have become the drugs of choice for the treatment of fundus lesions diseases. To evaluate the clinical value of three ophthalmic anti-VEGF drugs in the treatment of fundus lesions diseases, to guide the rational use of the clinic. Inpatients with fundus lesions who had intravitreal injections of Aflibercept, Conbercept and Leizumab during 2020 were studied and six indicators were selected for a comprehensive evaluation. In terms of safety, Aflibercept, Conbercept, and Leizumab experienced adverse effects of elevated Intraocular Pressure (IOP). In terms of effectiveness, Leizumab was strong, that of Aflibercept was stronger and that of Conbercept was weaker. In terms of economic, there was no significant difference in the cost of Aflibercept, Conbercept and Leizumab and a significant difference in the total treatment cost and the cost of surgery. In terms of appropriateness, Aflibercept was more suitable than Conbercept, and there was no significant difference between Leizumab and Aflibercept. In terms of accessibility, Aflibercept, Conbercept and Leizumab were all accessible to urban residents in Henan Province. For rural people, these are unreachable. In terms of innovation, Aflibercep was the most innovative, followed by Leizumab and finally Conbercept. In terms of effectiveness and accessibility, Leizumab performed best compared to Aflibercept and Conbercept. In terms of accessibility and innovation, Aflibercept performed best compared to Conbercept and Leizumab. In terms of safety and economic, Aflibercept, Conbercept and Leizumab performed comparably.
{"title":"Comprehensive evaluation of the use of intravitreal injection of anti-vascular endothelial growth factor drugs in patients with fundus lesions based on real-world data","authors":"Cheng-qun Chen, Li-ping Du, Qing Liu, Qing-hua Ren, Zhen-feng Zhu, Gui-fang Sun, Yu-shen Li, Yang Yang, Shu-zhang Du, Yue-dong Qi","doi":"10.1101/2024.04.01.24305180","DOIUrl":"https://doi.org/10.1101/2024.04.01.24305180","url":null,"abstract":"The prevalence of fundus lesion-related diseases is increasing, which ophthalmic anti-VEGF drugs have become the drugs of choice for the treatment of fundus lesions diseases. To evaluate the clinical value of three ophthalmic anti-VEGF drugs in the treatment of fundus lesions diseases, to guide the rational use of the clinic. Inpatients with fundus lesions who had intravitreal injections of Aflibercept, Conbercept and Leizumab during 2020 were studied and six indicators were selected for a comprehensive evaluation. In terms of safety, Aflibercept, Conbercept, and Leizumab experienced adverse effects of elevated Intraocular Pressure (IOP). In terms of effectiveness, Leizumab was strong, that of Aflibercept was stronger and that of Conbercept was weaker. In terms of economic, there was no significant difference in the cost of Aflibercept, Conbercept and Leizumab and a significant difference in the total treatment cost and the cost of surgery. In terms of appropriateness, Aflibercept was more suitable than Conbercept, and there was no significant difference between Leizumab and Aflibercept. In terms of accessibility, Aflibercept, Conbercept and Leizumab were all accessible to urban residents in Henan Province. For rural people, these are unreachable. In terms of innovation, Aflibercep was the most innovative, followed by Leizumab and finally Conbercept. In terms of effectiveness and accessibility, Leizumab performed best compared to Aflibercept and Conbercept. In terms of accessibility and innovation, Aflibercept performed best compared to Conbercept and Leizumab. In terms of safety and economic, Aflibercept, Conbercept and Leizumab performed comparably.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140573693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-22DOI: 10.1101/2024.03.21.24304663
Kelli Keats, MRC-ICU Investigator Team, Andrea Sikora
INTRODUCTION: Intravenous (IV) medications are a fundamental cause of fluid overload (FO) in the intensive care unit (ICU); however, the association between IV medication use (including volume), administration timing, and FO occurrence remains unclear. METHODS: This retrospective cohort study included consecutive adults admitted to an ICU ≥72 hours with available fluid balance data. FO was defined as a positive fluid balance ≥7% of admission body weight within 72 hours of ICU admission. After reviewing medication administration record (MAR) data in three-hour periods, IV medication exposure was categorized into clusters using principal component analysis (PCA) and Restricted Boltzmann Machine (RBM). Medication regimens of patients with and without FO were compared within clusters to assess for temporal clusters associated with FO using the Wilcoxon rank sum test. Exploratory analyses of the medication cluster most associated with FO for medications frequently appearing and used in the first 24 hours was conducted. RESULTS: FO occurred in 127/927 (13.7%) of the patients enrolled. Patients received a median (IQR) of 31 (13-65) discrete IV medication administrations over the 72-hour period. Across all 47,803 IV medication administrations, ten unique IV medication clusters were identified with 121-130 medications in each cluster. Among the ten clusters, cluster 7 had the greatest association with FO; the mean number of cluster 7 medications received was significantly greater in patients in the FO cohort compared to patients who did not experience FO (25.6 vs.10.9. p<0.0001). 51 of the 127 medications in cluster 7 (40.2%) appeared in > 5 separate 3-hour periods during the 72-hour study window. The most common cluster 7 medications included continuous infusions, antibiotics, and sedatives/analgesics. Addition of cluster 7 medications to a prediction model with APACHE II score and receipt of diuretics improved the ability for the model to predict fluid overload (AUROC 5.65, p =0.0004). CONCLUSIONS: Using ML approaches, a unique IV medication cluster was strongly associated with FO. Incorporation of this cluster improved the ability to predict development of fluid overload in ICU patients compared with traditional prediction models. This method may be further developed into real-time clinical applications to improve early detection of adverse outcomes.
{"title":"Unsupervised machine learning analysis to identify patterns of ICU medication use for fluid overload prediction","authors":"Kelli Keats, MRC-ICU Investigator Team, Andrea Sikora","doi":"10.1101/2024.03.21.24304663","DOIUrl":"https://doi.org/10.1101/2024.03.21.24304663","url":null,"abstract":"INTRODUCTION: Intravenous (IV) medications are a fundamental cause of fluid overload (FO) in the intensive care unit (ICU); however, the association between IV medication use (including volume), administration timing, and FO occurrence remains unclear. METHODS: This retrospective cohort study included consecutive adults admitted to an ICU ≥72 hours with available fluid balance data. FO was defined as a positive fluid balance ≥7% of admission body weight within 72 hours of ICU admission. After reviewing medication administration record (MAR) data in three-hour periods, IV medication exposure was categorized into clusters using principal component analysis (PCA) and Restricted Boltzmann Machine (RBM). Medication regimens of patients with and without FO were compared within clusters to assess for temporal clusters associated with FO using the Wilcoxon rank sum test. Exploratory analyses of the medication cluster most associated with FO for medications frequently appearing and used in the first 24 hours was conducted. RESULTS: FO occurred in 127/927 (13.7%) of the patients enrolled. Patients received a median (IQR) of 31 (13-65) discrete IV medication administrations over the 72-hour period. Across all 47,803 IV medication administrations, ten unique IV medication clusters were identified with 121-130 medications in each cluster. Among the ten clusters, cluster 7 had the greatest association with FO; the mean number of cluster 7 medications received was significantly greater in patients in the FO cohort compared to patients who did not experience FO (25.6 vs.10.9. p<0.0001). 51 of the 127 medications in cluster 7 (40.2%) appeared in > 5 separate 3-hour periods during the 72-hour study window. The most common cluster 7 medications included continuous infusions, antibiotics, and sedatives/analgesics. Addition of cluster 7 medications to a prediction model with APACHE II score and receipt of diuretics improved the ability for the model to predict fluid overload (AUROC 5.65, p =0.0004). CONCLUSIONS: Using ML approaches, a unique IV medication cluster was strongly associated with FO. Incorporation of this cluster improved the ability to predict development of fluid overload in ICU patients compared with traditional prediction models. This method may be further developed into real-time clinical applications to improve early detection of adverse outcomes.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140203431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-20DOI: 10.1101/2024.03.19.24304542
Charlotte Koldeweij, Caroline Dibbets, Bryony Dean Franklin, Hubertina C.J. Scheepers, Saskia N de Wildt
Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, and therefore drug efficacy and safety, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic models and expanding clinical data in pregnancy may support antenatal doses. In this article, we introduce a comprehensive and user-driven Framework for Dose Selection in Pregnancy (FDSP), developed and validated to support the clinical implementation of best-evidence and in some cases, model-informed doses for pregnant women and/or fetuses. After initial development and validation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was validated and assessed for usability by a multidisciplinary working committee of end-users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose-related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit-risk assessment. An antenatal dose recommendation for sertraline, as a proof-of-concept, was formulated using this approach and endorsed for clinical use by the working committee. The FDSP, as demonstrated by the example of sertraline, is fit for supporting the development of best-evidence acceptable and clinically feasible antenatal doses.
{"title":"A user-driven framework for dose selection in pregnancy: proof-of-concept for sertraline","authors":"Charlotte Koldeweij, Caroline Dibbets, Bryony Dean Franklin, Hubertina C.J. Scheepers, Saskia N de Wildt","doi":"10.1101/2024.03.19.24304542","DOIUrl":"https://doi.org/10.1101/2024.03.19.24304542","url":null,"abstract":"Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, and therefore drug efficacy and safety, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic models and expanding clinical data in pregnancy may support antenatal doses. In this article, we introduce a comprehensive and user-driven Framework for Dose Selection in Pregnancy (FDSP), developed and validated to support the clinical implementation of best-evidence and in some cases, model-informed doses for pregnant women and/or fetuses. After initial development and validation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was validated and assessed for usability by a multidisciplinary working committee of end-users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose-related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit-risk assessment. An antenatal dose recommendation for sertraline, as a proof-of-concept, was formulated using this approach and endorsed for clinical use by the working committee. The FDSP, as demonstrated by the example of sertraline, is fit for supporting the development of best-evidence acceptable and clinically feasible antenatal doses.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140203317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-13DOI: 10.1101/2024.03.11.24304117
Georgi I Kapitanov, Sarah A Head, David Flowers, Joshua F Apgar, Joshuaine Grant
Blinatumomab is a bispecific T-cell engager (BiTE) that binds to CD3 on T cells and CD19 on B cells. It has been approved for use in B-cell acute lymphoblastic leukemia (B-ALL) with a regimen that requires continuous infusion (cIV) for four weeks per treatment cycle. It is currently in clinical trials for Non-Hodgkin lymphoma (NHL) with cIV administration. Recently, there have been studies investigating dose-response after subcutaneous (SC) dosing in B-ALL and in NHL to determine whether this more convenient method of delivery would have a similar efficacy/safety profile as continuous infusion. We constructed mechanistic PKPD models of blinatumomab activity in B-ALL and NHL patients, investigating the amount of CD3:blinatumomab:CD19 trimers the drug forms at different dosing administrations and regimens. The modeling and analysis demonstrate that the explored SC doses in B-ALL and NHL achieve similar trimer numbers as the cIV doses in those indications. We further simulated various subcutaneous dosing regimens, and identified conditions where trimer formation dynamics are similar between constant infusion and subcutaneous dosing. Based on the model results, subcutaneous dosing is a viable and convenient strategy for blinatumomab and is projected to result in similar trimer numbers as constant infusion.
Blinatumomab是一种双特异性T细胞吸引剂（BiTE），能与T细胞上的CD3和B细胞上的CD19结合。它已被批准用于 B 细胞急性淋巴细胞白血病（B-ALL），治疗方案为每个治疗周期连续输注（cIV）四周。目前，该药物正在用于非霍奇金淋巴瘤（NHL）的临床试验中，采用 cIV 给药。最近，有研究调查了B-ALL和NHL皮下注射（SC）后的剂量反应，以确定这种更方便的给药方法是否具有与连续输注相似的疗效/安全性。我们构建了blinatumomab在B-ALL和NHL患者中的活性机理PKPD模型，研究了不同给药剂量和给药方案下药物形成的CD3:blinatumomab:CD19三聚体的数量。建模和分析表明，在 B-ALL 和 NHL 中探索的皮下注射剂量能达到与 cIV 剂量相似的三聚体数量。我们进一步模拟了各种皮下给药方案，确定了持续输注和皮下给药之间三聚体形成动态相似的条件。根据模型结果，皮下给药对 blinatumomab 来说是一种可行且方便的策略，预计会产生与持续输注相似的三聚体数量。
{"title":"Blinatumomab Trimer Formation: Insights From A Mechanistic PKPD Model Into The Implications For Switching From Infusion To Subcutaneous Dosing Regimen","authors":"Georgi I Kapitanov, Sarah A Head, David Flowers, Joshua F Apgar, Joshuaine Grant","doi":"10.1101/2024.03.11.24304117","DOIUrl":"https://doi.org/10.1101/2024.03.11.24304117","url":null,"abstract":"Blinatumomab is a bispecific T-cell engager (BiTE) that binds to CD3 on T cells and CD19 on B cells. It has been approved for use in B-cell acute lymphoblastic leukemia (B-ALL) with a regimen that requires continuous infusion (cIV) for four weeks per treatment cycle. It is currently in clinical trials for Non-Hodgkin lymphoma (NHL) with cIV administration. Recently, there have been studies investigating dose-response after subcutaneous (SC) dosing in B-ALL and in NHL to determine whether this more convenient method of delivery would have a similar efficacy/safety profile as continuous infusion. We constructed mechanistic PKPD models of blinatumomab activity in B-ALL and NHL patients, investigating the amount of CD3:blinatumomab:CD19 trimers the drug forms at different dosing administrations and regimens. The modeling and analysis demonstrate that the explored SC doses in B-ALL and NHL achieve similar trimer numbers as the cIV doses in those indications. We further simulated various subcutaneous dosing regimens, and identified conditions where trimer formation dynamics are similar between constant infusion and subcutaneous dosing. Based on the model results, subcutaneous dosing is a viable and convenient strategy for blinatumomab and is projected to result in similar trimer numbers as constant infusion.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140125814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-09DOI: 10.1101/2024.03.07.24303937
Joseph A. DiMasi, Abigail Dirks, Zachary Smith, Sarah Valentine, Jennifer C. Goldsack, Thomas Metcalfe, Upinder Grewal, Lada Leyens, Ute Conradi, Daniel Karlin, Lesley Maloney, Kenneth A. Getz, Bert Hartog
Background: In the last few decades developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted. Data and Methods: We obtained data from the Digital Medicine Society (DiMe) Library of Digital Endpoints and the U.S. clinical trials registry, ClinicalTrials.gov. The benefit metrics are changes in trial phase duration and enrollment associated with the use of digital endpoints. The cost metric was obtained from an industry survey of the costs of including digital endpoints in clinical trials. We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess financial value. The value measure is the increment in eNPV that occurs when digital endpoints are employed. We also calculated a return on investment (ROI) as the ratio of the estimated increment in eNPV to the mean digital endpoint implementation cost. Results: For phase 2 trials, the increase in eNPV varied from $2.2 million to $3.3 million, with ROIs between 32% to 48% per indication. The net benefits were substantially higher for phase 3 trials, with the increase in eNPV varying from $27 million to $48 million, with ROIs that were four to seven times the investment. Conclusions: The use of digital endpoints in clinical trials can provide substantial extra value to sponsors developing new drugs, with high ROIs.
{"title":"ASSESSING THE NET FINANCIAL BENEFITS OF EMPLOYING DIGITAL ENDPOINTS IN CLINICAL TRIALS","authors":"Joseph A. DiMasi, Abigail Dirks, Zachary Smith, Sarah Valentine, Jennifer C. Goldsack, Thomas Metcalfe, Upinder Grewal, Lada Leyens, Ute Conradi, Daniel Karlin, Lesley Maloney, Kenneth A. Getz, Bert Hartog","doi":"10.1101/2024.03.07.24303937","DOIUrl":"https://doi.org/10.1101/2024.03.07.24303937","url":null,"abstract":"Background: In the last few decades developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted. Data and Methods: We obtained data from the Digital Medicine Society (DiMe) Library of Digital Endpoints and the U.S. clinical trials registry, ClinicalTrials.gov. The benefit metrics are changes in trial phase duration and enrollment associated with the use of digital endpoints. The cost metric was obtained from an industry survey of the costs of including digital endpoints in clinical trials. We developed an expected net present value (eNPV) model of the cash flows for new drug development and commercialization to assess financial value. The value measure is the increment in eNPV that occurs when digital endpoints are employed. We also calculated a return on investment (ROI) as the ratio of the estimated increment in eNPV to the mean digital endpoint implementation cost. Results: For phase 2 trials, the increase in eNPV varied from $2.2 million to $3.3 million, with ROIs between 32% to 48% per indication. The net benefits were substantially higher for phase 3 trials, with the increase in eNPV varying from $27 million to $48 million, with ROIs that were four to seven times the investment. Conclusions: The use of digital endpoints in clinical trials can provide substantial extra value to sponsors developing new drugs, with high ROIs.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140075264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-08DOI: 10.1101/2024.03.06.24303800
Maria Brbic, Michihiro Yasunaga, Prabhat Agarwal, Jure Leskovec
Optimal treatments depend on numerous factors such as drug chemical properties, disease biology, and patient characteristics to which the treatment is applied. To realize the promise of AI in healthcare, there is a need for designing systems that can capture patient heterogeneity and relevant biomedical knowledge. Here we present PlaNet, a geometric deep learning framework that reasons over population variability, disease biology, and drug chemistry by representing knowledge in the form of a massive clinical knowledge graph that can be enhanced by language models. Our framework is applicable to any sub-population, any drug as well drug combinations, any disease, and to a wide range of pharmacological tasks. We apply the PlaNet framework to reason about outcomes of clinical trials: PlaNet predicts drug efficacy and adverse events, even for experimental drugs and their combinations that have never been seen by the model. Furthermore, PlaNet can estimate the effect of changing population on the trial outcome with direct implications on patient stratification in clinical trials. PlaNet takes fundamental steps towards AI-guided clinical trials design, offering valuable guidance for realizing the vision of precision medicine using AI.
{"title":"Predicting drug outcome of population via clinical knowledge graph","authors":"Maria Brbic, Michihiro Yasunaga, Prabhat Agarwal, Jure Leskovec","doi":"10.1101/2024.03.06.24303800","DOIUrl":"https://doi.org/10.1101/2024.03.06.24303800","url":null,"abstract":"Optimal treatments depend on numerous factors such as drug chemical properties, disease biology, and patient characteristics to which the treatment is applied. To realize the promise of AI in healthcare, there is a need for designing systems that can capture patient heterogeneity and relevant biomedical knowledge. Here we present PlaNet, a geometric deep learning framework that reasons over population variability, disease biology, and drug chemistry by representing knowledge in the form of a massive clinical knowledge graph that can be enhanced by language models. Our framework is applicable to any sub-population, any drug as well drug combinations, any disease, and to a wide range of pharmacological tasks. We apply the PlaNet framework to reason about outcomes of clinical trials: PlaNet predicts drug efficacy and adverse events, even for experimental drugs and their combinations that have never been seen by the model. Furthermore, PlaNet can estimate the effect of changing population on the trial outcome with direct implications on patient stratification in clinical trials. PlaNet takes fundamental steps towards AI-guided clinical trials design, offering valuable guidance for realizing the vision of precision medicine using AI.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"246 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140075359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-08DOI: 10.1101/2024.03.06.24303892
Arthur Gougeon, Ikram Aribi, Sofia Guernouche, Jean-Christophe Lega, James M. Wright, Céline Verstuyft, Audrey Lajoinie, François Gueyffier, Guillaume Grenet
Background: Statin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Adjusting statin dosages for solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype has been proposed to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias. Methods: We searched for published systematic reviews evaluating the association between SLCO1B1 genotype and SAMS. We collected the odds ratio (OR) of this association in each clinical study. We assessed the presence of publication bias using the visual inspection of a funnel plot and Egger?s test and used the Bayes Factor (BFPublication-bias) of the Robust Bayesian Meta-Analysis (RoBMA) as a sensitivity analysis. We evaluated the effect of publication bias by comparing qualitatively and quantitatively (ratio of OR [ROR]) OR of the meta-analysis i) uncorrected for potential publication bias (ORUncorrected) and ii) corrected using the trim-and-fill (ORTrim&Fill). We also used the RoBMA (ORRoBMA) for corrected OR as a sensitivity analysis. Our primary analysis covered the associations between any SLCO1B1 genotype and any statin drug. Secondary analysis focused on SLCO1B1 genotypes and statin drug subgroups. Results: We included 8 cohort and 11 case-control studies, totaling 62 OR of three SLCO1B1 genotypes and five statin drugs plus one ?mixed? statin treatment. All controls were statin-tolerant patients. In the primary analysis, the funnel plot was suggestive of publication bias, confirmed by Egger?s test (p=0.001) and RoBMA (BFPublication-bias=18). Correcting the estimate for publication bias resulted in loss of the association, from a significant ORUncorrected (1.31 95% CI [1.13?1.53]) to corrected ORs suggesting no difference: i) ORTrim&Fill (1.07 95% CI [0.89?1.30]) and ii) ORRoBMA (1.02 95% CI [1.00?1.33]). The RORTrim&Fill and the RORRoBMA suggested that publication bias overestimated the association by 18% and 23%, respectively. The results were similar for the most studied SLCO1B1 genotype, as for simvastatin and atorvastatin. Conclusion: The effect of the SLCO1B1 genotype on the risk of developing SAMS is overestimated in the published literature. This could lead prescribers to incorrectly decreasing statin doses or even avoiding statin use, leading to a loss of the potential cardiovascular benefit of statins.
{"title":"Publication bias in pharmacogenetics of statin-associated muscle symptoms, an umbrella review with a meta-epidemiological study","authors":"Arthur Gougeon, Ikram Aribi, Sofia Guernouche, Jean-Christophe Lega, James M. Wright, Céline Verstuyft, Audrey Lajoinie, François Gueyffier, Guillaume Grenet","doi":"10.1101/2024.03.06.24303892","DOIUrl":"https://doi.org/10.1101/2024.03.06.24303892","url":null,"abstract":"Background: Statin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Adjusting statin dosages for solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype has been proposed to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias. Methods: We searched for published systematic reviews evaluating the association between SLCO1B1 genotype and SAMS. We collected the odds ratio (OR) of this association in each clinical study. We assessed the presence of publication bias using the visual inspection of a funnel plot and Egger?s test and used the Bayes Factor (BFPublication-bias) of the Robust Bayesian Meta-Analysis (RoBMA) as a sensitivity analysis. We evaluated the effect of publication bias by comparing qualitatively and quantitatively (ratio of OR [ROR]) OR of the meta-analysis i) uncorrected for potential publication bias (ORUncorrected) and ii) corrected using the trim-and-fill (ORTrim&Fill). We also used the RoBMA (ORRoBMA) for corrected OR as a sensitivity analysis. Our primary analysis covered the associations between any SLCO1B1 genotype and any statin drug. Secondary analysis focused on SLCO1B1 genotypes and statin drug subgroups.\u0000Results: We included 8 cohort and 11 case-control studies, totaling 62 OR of three SLCO1B1 genotypes and five statin drugs plus one ?mixed? statin treatment. All controls were statin-tolerant patients. In the primary analysis, the funnel plot was suggestive of publication bias, confirmed by Egger?s test (p=0.001) and RoBMA (BFPublication-bias=18). Correcting the estimate for publication bias resulted in loss of the association, from a significant ORUncorrected (1.31 95% CI [1.13?1.53]) to corrected ORs suggesting no difference: i) ORTrim&Fill (1.07 95% CI [0.89?1.30]) and ii) ORRoBMA (1.02 95% CI [1.00?1.33]). The RORTrim&Fill and the RORRoBMA suggested that publication bias overestimated the association by 18% and 23%, respectively. The results were similar for the most studied SLCO1B1 genotype, as for simvastatin and atorvastatin. Conclusion: The effect of the SLCO1B1 genotype on the risk of developing SAMS is overestimated in the published literature. This could lead prescribers to incorrectly decreasing statin doses or even avoiding statin use, leading to a loss of the potential cardiovascular benefit of statins.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":"87 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140075263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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