Aubin Michalon, Lionel Renaud, Matthias Machacek, Cédric Cortijo, Chandrasekhar Udata, Michele F Mercuri, Fabian Buller, Christoph Hock, Roger M Nitsch, Peter C Kahr, Jan Grimm
NI006 (aka ALXN2220) is a therapeutic antibody candidate in phase III clinical development for the depletion of amyloid transthyretin (ATTR) in patients with ATTR cardiomyopathy, an infiltrative cardiomyopathy leading to increased left ventricular wall thickness (LVWT). The mode-of-action consists in removal of disease-causing amyloid accumulations by activating phagocytic immune cells, a mechanism without precedent in cardiology. To select a safe and potentially efficacious dose range and treatment duration for a combined first-in-human and proof-of-concept clinical phase Ib study, we developed a mechanistic pharmacokinetic and pharmacodynamic (PK/PD) model that can predict NI006 exposure, its effects on cardiac amyloid load and on LWVT, which is a predictor of heart failure in this disease. The PK/PD model predictions supported 0.3 mg/kg monthly dosing as a safe starting dose and identified 10-60 mg/kg monthly as the potentially efficacious dose range with substantial and dose dependent cardiac amyloid burden reduction within 4 months for 60 mg/kg and 10 months for 10 mg/kg. These predictions were in good agreement with the observed primary results of the clinical phase Ib study where amyloid burden was measured by imaging. This novel translational PK/PD model provided important predictions to guide the design of the phase Ib study of NI006, indicating the value of this approach to integrate preclinical results into clinical trial design and increase translational success.
{"title":"Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling.","authors":"Aubin Michalon, Lionel Renaud, Matthias Machacek, Cédric Cortijo, Chandrasekhar Udata, Michele F Mercuri, Fabian Buller, Christoph Hock, Roger M Nitsch, Peter C Kahr, Jan Grimm","doi":"10.1002/cpt.3455","DOIUrl":"https://doi.org/10.1002/cpt.3455","url":null,"abstract":"<p><p>NI006 (aka ALXN2220) is a therapeutic antibody candidate in phase III clinical development for the depletion of amyloid transthyretin (ATTR) in patients with ATTR cardiomyopathy, an infiltrative cardiomyopathy leading to increased left ventricular wall thickness (LVWT). The mode-of-action consists in removal of disease-causing amyloid accumulations by activating phagocytic immune cells, a mechanism without precedent in cardiology. To select a safe and potentially efficacious dose range and treatment duration for a combined first-in-human and proof-of-concept clinical phase Ib study, we developed a mechanistic pharmacokinetic and pharmacodynamic (PK/PD) model that can predict NI006 exposure, its effects on cardiac amyloid load and on LWVT, which is a predictor of heart failure in this disease. The PK/PD model predictions supported 0.3 mg/kg monthly dosing as a safe starting dose and identified 10-60 mg/kg monthly as the potentially efficacious dose range with substantial and dose dependent cardiac amyloid burden reduction within 4 months for 60 mg/kg and 10 months for 10 mg/kg. These predictions were in good agreement with the observed primary results of the clinical phase Ib study where amyloid burden was measured by imaging. This novel translational PK/PD model provided important predictions to guide the design of the phase Ib study of NI006, indicating the value of this approach to integrate preclinical results into clinical trial design and increase translational success.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Over the past decade, consideration of real-world evidence (RWE) in regulatory settings has come into sharper focus. The European Medicines Agency (EMA) and the United States (US) Food and Drug Administration (FDA) have chosen different paths to explore integrating RWE into decision-making processes.<span><sup>1, 2</sup></span> In this issue of Clinical Pharmacology & Therapeutics (CPT), Prilla <i>et al</i>.<span><sup>1</sup></span> evaluate the EMA's experience during the second stage (2021–2023) of an RWE pilot program that began in 2019.</p><p>The EMA employs a three-pronged approach to RWE generation: internal research, the DARWIN EU® network, and external pathways. Prilla <i>et al</i>.<span><sup>1</sup></span> demonstrate that research topics, typically requested during or in anticipation of regulatory procedures, are topical, practical, and support the scope of regulators and downstream decision-makers. This multifaceted RWE generation strategy using a flexible and comprehensive framework could serve as a model for other regulatory bodies.</p><p>The 61 RWE requests during the study time period offer several proof points for integrating RWE into evidence assessment. The RWE requests that were delivered offered timely insights from rapidly completed studies, enhanced understanding of clinical issues from diverse data sources, and informed plans for addressing unanswered questions. Nearly a quarter of the topics evaluated related to children, a group typically underrepresented in clinical trials even for conditions with a high pediatric burden.<span><sup>1, 3-5</sup></span> Almost half concerned rare diseases or orphan drugs, areas often lacking robust clinical trial data and detailed literature.<span><sup>6, 7</sup></span> The diversity of therapeutic areas covered, from anti-infectives to antineoplastic agents, underscores the potential broad applicability of RWE across disease areas. These RWE request pattern reflects global unmet regulatory needs that various policies have sought to address.</p><p>The prominence of requests related to age subgroups, pediatric investigational plans (PIP), and post-authorization study design suggests RWE's utility in compiling evidence for other historically underrepresented populations. In the United States, the FDA's Diversity Action Plan (DAP) requirement, updated in July 2024, presents opportunities for RWE to complement enrollment efforts at several junctures: creation of DAPs for registration enabling trials, evidentiary gaps at the time of regulatory procedures, and post-marketing requirements.<span><sup>8, 9</sup></span> A similar assessment in the United States of regulatory questions addressed with RWE, regardless of approval outcome, would be revealing.</p><p>The EMA's experience also outlines current limits of RWE in regulatory settings. Over a third of requests that completed feasibility assessment were unable to proceed, primarily due to lack of fit-for-purpose data.<span><sup>1</sup></s
{"title":"Real-World Evidence in Regulatory Decision Making: Time for Evidence Integration","authors":"Rebecca A. Miksad","doi":"10.1002/cpt.3444","DOIUrl":"https://doi.org/10.1002/cpt.3444","url":null,"abstract":"<p>Over the past decade, consideration of real-world evidence (RWE) in regulatory settings has come into sharper focus. The European Medicines Agency (EMA) and the United States (US) Food and Drug Administration (FDA) have chosen different paths to explore integrating RWE into decision-making processes.<span><sup>1, 2</sup></span> In this issue of Clinical Pharmacology & Therapeutics (CPT), Prilla <i>et al</i>.<span><sup>1</sup></span> evaluate the EMA's experience during the second stage (2021–2023) of an RWE pilot program that began in 2019.</p><p>The EMA employs a three-pronged approach to RWE generation: internal research, the DARWIN EU® network, and external pathways. Prilla <i>et al</i>.<span><sup>1</sup></span> demonstrate that research topics, typically requested during or in anticipation of regulatory procedures, are topical, practical, and support the scope of regulators and downstream decision-makers. This multifaceted RWE generation strategy using a flexible and comprehensive framework could serve as a model for other regulatory bodies.</p><p>The 61 RWE requests during the study time period offer several proof points for integrating RWE into evidence assessment. The RWE requests that were delivered offered timely insights from rapidly completed studies, enhanced understanding of clinical issues from diverse data sources, and informed plans for addressing unanswered questions. Nearly a quarter of the topics evaluated related to children, a group typically underrepresented in clinical trials even for conditions with a high pediatric burden.<span><sup>1, 3-5</sup></span> Almost half concerned rare diseases or orphan drugs, areas often lacking robust clinical trial data and detailed literature.<span><sup>6, 7</sup></span> The diversity of therapeutic areas covered, from anti-infectives to antineoplastic agents, underscores the potential broad applicability of RWE across disease areas. These RWE request pattern reflects global unmet regulatory needs that various policies have sought to address.</p><p>The prominence of requests related to age subgroups, pediatric investigational plans (PIP), and post-authorization study design suggests RWE's utility in compiling evidence for other historically underrepresented populations. In the United States, the FDA's Diversity Action Plan (DAP) requirement, updated in July 2024, presents opportunities for RWE to complement enrollment efforts at several junctures: creation of DAPs for registration enabling trials, evidentiary gaps at the time of regulatory procedures, and post-marketing requirements.<span><sup>8, 9</sup></span> A similar assessment in the United States of regulatory questions addressed with RWE, regardless of approval outcome, would be revealing.</p><p>The EMA's experience also outlines current limits of RWE in regulatory settings. Over a third of requests that completed feasibility assessment were unable to proceed, primarily due to lack of fit-for-purpose data.<span><sup>1</sup></s","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 5","pages":"1153-1155"},"PeriodicalIF":6.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alzahra Hamdan, Niels Hendrickx, Andrew C. Hooker, Xiaomei Chen, Emmanuelle Comets, Andreas Traschütz, Rebecca Schüle, ARCA Study Group, EVIDENCE-RND Consortium, France Mentré, Matthis Synofzik, Mats O. Karlsson
Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra-rare genetic diseases. While disease-modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real-world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix–Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75–90% less with 5 years vs. 2 years), and larger drug effects (~ 70–80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well-controlled type I error, compared to total score models or end-of-treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra-rare genetic ataxias.
{"title":"Longitudinal Analysis of Natural History Progression of Rare and Ultra-Rare Cerebellar Ataxias Using Item Response Theory","authors":"Alzahra Hamdan, Niels Hendrickx, Andrew C. Hooker, Xiaomei Chen, Emmanuelle Comets, Andreas Traschütz, Rebecca Schüle, ARCA Study Group, EVIDENCE-RND Consortium, France Mentré, Matthis Synofzik, Mats O. Karlsson","doi":"10.1002/cpt.3466","DOIUrl":"10.1002/cpt.3466","url":null,"abstract":"<p>Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra-rare genetic diseases. While disease-modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real-world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix–Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75–90% less with 5 years vs. 2 years), and larger drug effects (~ 70–80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well-controlled type I error, compared to total score models or end-of-treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra-rare genetic ataxias.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 6","pages":"1593-1605"},"PeriodicalIF":6.3,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Norah Mwebaza, Michelle E Roh, Yourong Z Geng, Leonard Opio, Bishop Opira, Florence Marzan, Moses W Mwima, Timothy Ssemukuye, Kevin Guo, David Gingrich, Nikoletta Fotaki, Abel Kakuru, Jimmy Kizza, Miriam Aguti, Harriet Adrama, Moses Kamya, Grant Dorsey, Philip J Rosenthal, Francesca T Aweeka, Liusheng Huang
Co-administration of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug-drug interactions require investigation. We conducted intensive and sparse pharmacokinetic (PK) studies in a subset of Ugandan women participating in a randomized controlled trial of monthly IPTp with SP vs. DP vs. DP + SP. Intensive PK sampling was performed from day 0 to 23 after dosing at 28 weeks gestation in 87 participants across treatment arms. Sparse sampling was performed on day 28 (trough) after dosing at 20 and 28 gestational weeks in additional 196 participants receiving SP vs. DP + SP. Intensive PK analysis demonstrated that compared with SP alone, co-administration of DP + SP was associated with lower maximal concentrations, the area under the concentration-time curves (AUC), and day 23 concentrations of sulfadoxine (25%, 25%, and 27%) and pyrimethamine (26%, 34%, and 32%) (P < 0.05 for all comparisons). Sparse PK results demonstrated participants co-administered DP + SP had lower trough concentrations after dosing at 20 and 28 gestational weeks for sulfadoxine (6%, P = 0.68 and 31%, P = 0.023, respectively) and pyrimethamine (18%, P = 0.032 and 33%, P < 0.001, respectively) compared with SP alone. Co-administration of DP + SP was associated with a 19% reduction in piperaquine AUC (P = 0.046), but no significant difference in other PK parameters compared with DP alone. In summary, co-administration of DP + SP was associated with significantly reduced SP exposure, with a greater magnitude during the third vs. second trimester. The clinical consequences of this interaction are yet unknown.
{"title":"Drug-Drug Interaction Between Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine During Malaria Chemoprevention in Pregnant Women.","authors":"Norah Mwebaza, Michelle E Roh, Yourong Z Geng, Leonard Opio, Bishop Opira, Florence Marzan, Moses W Mwima, Timothy Ssemukuye, Kevin Guo, David Gingrich, Nikoletta Fotaki, Abel Kakuru, Jimmy Kizza, Miriam Aguti, Harriet Adrama, Moses Kamya, Grant Dorsey, Philip J Rosenthal, Francesca T Aweeka, Liusheng Huang","doi":"10.1002/cpt.3471","DOIUrl":"10.1002/cpt.3471","url":null,"abstract":"<p><p>Co-administration of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug-drug interactions require investigation. We conducted intensive and sparse pharmacokinetic (PK) studies in a subset of Ugandan women participating in a randomized controlled trial of monthly IPTp with SP vs. DP vs. DP + SP. Intensive PK sampling was performed from day 0 to 23 after dosing at 28 weeks gestation in 87 participants across treatment arms. Sparse sampling was performed on day 28 (trough) after dosing at 20 and 28 gestational weeks in additional 196 participants receiving SP vs. DP + SP. Intensive PK analysis demonstrated that compared with SP alone, co-administration of DP + SP was associated with lower maximal concentrations, the area under the concentration-time curves (AUC), and day 23 concentrations of sulfadoxine (25%, 25%, and 27%) and pyrimethamine (26%, 34%, and 32%) (P < 0.05 for all comparisons). Sparse PK results demonstrated participants co-administered DP + SP had lower trough concentrations after dosing at 20 and 28 gestational weeks for sulfadoxine (6%, P = 0.68 and 31%, P = 0.023, respectively) and pyrimethamine (18%, P = 0.032 and 33%, P < 0.001, respectively) compared with SP alone. Co-administration of DP + SP was associated with a 19% reduction in piperaquine AUC (P = 0.046), but no significant difference in other PK parameters compared with DP alone. In summary, co-administration of DP + SP was associated with significantly reduced SP exposure, with a greater magnitude during the third vs. second trimester. The clinical consequences of this interaction are yet unknown.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hsiu-Ting Chien, Fang-Ju Lin, Jyh-Ming Jimmy Juang, Shu-Wen Lin
Researchers have studied potential corrected QT interval (QTc) prolongation from drug-drug interactions (DDIs), raising unresolved questions about their real-world impact. This retrospective case-crossover study investigated the effects of QT-prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT-prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95-3.02)). The risk was higher with drugs of "known risks" (OR: 3.78 (2.91-4.90)) and "conditional risk" (OR: 2.08 (1.65-2.62)). DDIs, particularly involving multiple "known risk" drugs (OR: 7.86 (4.96-12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75-11.30)), or the concurrent use of ≥4 QT-prolonging drugs with any risk (OR: 5.28 (3.96-7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care.
{"title":"The Impact of QT-Prolonging Medications and Drug-Drug Interactions on QTc Interval Prolongation in Hospitalized Patients: A Case-Crossover Study.","authors":"Hsiu-Ting Chien, Fang-Ju Lin, Jyh-Ming Jimmy Juang, Shu-Wen Lin","doi":"10.1002/cpt.3469","DOIUrl":"https://doi.org/10.1002/cpt.3469","url":null,"abstract":"<p><p>Researchers have studied potential corrected QT interval (QTc) prolongation from drug-drug interactions (DDIs), raising unresolved questions about their real-world impact. This retrospective case-crossover study investigated the effects of QT-prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT-prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95-3.02)). The risk was higher with drugs of \"known risks\" (OR: 3.78 (2.91-4.90)) and \"conditional risk\" (OR: 2.08 (1.65-2.62)). DDIs, particularly involving multiple \"known risk\" drugs (OR: 7.86 (4.96-12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75-11.30)), or the concurrent use of ≥4 QT-prolonging drugs with any risk (OR: 5.28 (3.96-7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ju Hwan Kim, Ahhyung Choi, Gihwan Bae, Eun-Jeong Joo, Min Joo Choi, Kyungmin Huh, Hyungmin Lee, Jungyeon Kim, Dong-Hwi Kim, Min-Gyu Yoo, Il Uk Jo, Poong Hoon Lee, Geun Woo Lee, Hee Sun Jung, Jaehun Jung, Ju-Young Shin
There had been concerns about the acute complications during or shortly after coronavirus disease 2019 (COVID-19) treatment with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL). This study aimed to compare the risks of selected acute safety events in patients treated with or without NMVr or MOL using the COVID-19 oral treatment safety assessment data, constructed through the linkage of nationwide databases: National COVID-19 registry, Real-time Prescription Surveillance, and National Health Insurance data. We identified all adults diagnosed with COVID-19 between January and November 2022, and then constructed two cohorts by matching up to four patients without antiviral treatment records to NMVr or MOL users using propensity score matching. Outcomes of interest were incident-selected cardiac (i.e., atrial fibrillation, other arrhythmia, bradycardia), neurological (i.e., seizure, neuropathy, encephalomyelitis), and miscellaneous (i.e., acute pancreatitis, acute liver injury, dysgeusia) events. A total of 739,935 NMVr users were matched with 2,951,690 comparators and 150,431 MOL users with 759,521 comparators. NMVr users were at lower risk for developing selected cardiac events (hazard ratio 0.74 [95% CI 0.65-0.87] for atrial fibrillation, 0.81 [0.65-0.99] for other arrhythmia, and 0.82 [0.70-0.96] for bradycardia) and dysgeusia (0.58 [0.45-0.74]). For MOL users, the risk was lower for atrial fibrillation (0.72 [0.53-0.96]) and dysgeusia (0.34 [0.18-0.65]). Overall, there were no increased risks of acute complications during and shortly after treatment with oral COVID-19 antivirals. Rather, the findings underscore their effectiveness in attenuating the risk of potential acute sequelae of COVID-19.
{"title":"Selected Acute Safety Events Following the Use of Nirmatrelvir/Ritonavir or Molnupiravir for COVID-19: A Nationwide Cohort Study in South Korea.","authors":"Ju Hwan Kim, Ahhyung Choi, Gihwan Bae, Eun-Jeong Joo, Min Joo Choi, Kyungmin Huh, Hyungmin Lee, Jungyeon Kim, Dong-Hwi Kim, Min-Gyu Yoo, Il Uk Jo, Poong Hoon Lee, Geun Woo Lee, Hee Sun Jung, Jaehun Jung, Ju-Young Shin","doi":"10.1002/cpt.3461","DOIUrl":"https://doi.org/10.1002/cpt.3461","url":null,"abstract":"<p><p>There had been concerns about the acute complications during or shortly after coronavirus disease 2019 (COVID-19) treatment with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL). This study aimed to compare the risks of selected acute safety events in patients treated with or without NMVr or MOL using the COVID-19 oral treatment safety assessment data, constructed through the linkage of nationwide databases: National COVID-19 registry, Real-time Prescription Surveillance, and National Health Insurance data. We identified all adults diagnosed with COVID-19 between January and November 2022, and then constructed two cohorts by matching up to four patients without antiviral treatment records to NMVr or MOL users using propensity score matching. Outcomes of interest were incident-selected cardiac (i.e., atrial fibrillation, other arrhythmia, bradycardia), neurological (i.e., seizure, neuropathy, encephalomyelitis), and miscellaneous (i.e., acute pancreatitis, acute liver injury, dysgeusia) events. A total of 739,935 NMVr users were matched with 2,951,690 comparators and 150,431 MOL users with 759,521 comparators. NMVr users were at lower risk for developing selected cardiac events (hazard ratio 0.74 [95% CI 0.65-0.87] for atrial fibrillation, 0.81 [0.65-0.99] for other arrhythmia, and 0.82 [0.70-0.96] for bradycardia) and dysgeusia (0.58 [0.45-0.74]). For MOL users, the risk was lower for atrial fibrillation (0.72 [0.53-0.96]) and dysgeusia (0.34 [0.18-0.65]). Overall, there were no increased risks of acute complications during and shortly after treatment with oral COVID-19 antivirals. Rather, the findings underscore their effectiveness in attenuating the risk of potential acute sequelae of COVID-19.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paarth Parekh, Jason Sherfey, Begum Alaybeyoglu, Murat Cirit
Accurate clinical translation of preclinical research remains challenging, primarily due to species-specific differences and disease and patient heterogeneity. An important recent advancement has been development of microphysiological systems that consist of multiple human cell types that recapitulate key characteristics of their respective human systems, allowing essential physiologic processes to be accurately assessed during drug development. However, an unmet need remains regarding a quantitative method to evaluate the similarity between diverse sample types for various contexts of use (CoU)-specific pathways. To address this gap, this study describes the development of pathway-based similarity measurement (PBSM), which leverages RNA-seq data and pathway-based information to assess the human relevance of preclinical models for specific CoU. PBSM offers a quantitative method to compare the transcriptomic similarity of preclinical models to human tissues, shown here as proof of concept for liver and cardiac tissues, enabling improved model selection and validation. Thus, PBSM can successfully support CoU selection for preclinical models, assess the impact of different gene sets on similarity calculations, and differentiate among various in vitro and in vivo models. PBSM has the potential to reduce the translational gap in drug development by allowing quantitative evaluation of the similarity of preclinical models to human tissues, facilitating model selection, and improving understanding of context-specific applications. PBSM can serve as a foundation for enhancing the physiological relevance of in vitro models and supporting the development of more effective therapeutic interventions.
{"title":"Pathway-Based Similarity Measurement to Quantify Transcriptomics Similarity Between Human Tissues and Preclinical Models.","authors":"Paarth Parekh, Jason Sherfey, Begum Alaybeyoglu, Murat Cirit","doi":"10.1002/cpt.3465","DOIUrl":"https://doi.org/10.1002/cpt.3465","url":null,"abstract":"<p><p>Accurate clinical translation of preclinical research remains challenging, primarily due to species-specific differences and disease and patient heterogeneity. An important recent advancement has been development of microphysiological systems that consist of multiple human cell types that recapitulate key characteristics of their respective human systems, allowing essential physiologic processes to be accurately assessed during drug development. However, an unmet need remains regarding a quantitative method to evaluate the similarity between diverse sample types for various contexts of use (CoU)-specific pathways. To address this gap, this study describes the development of pathway-based similarity measurement (PBSM), which leverages RNA-seq data and pathway-based information to assess the human relevance of preclinical models for specific CoU. PBSM offers a quantitative method to compare the transcriptomic similarity of preclinical models to human tissues, shown here as proof of concept for liver and cardiac tissues, enabling improved model selection and validation. Thus, PBSM can successfully support CoU selection for preclinical models, assess the impact of different gene sets on similarity calculations, and differentiate among various in vitro and in vivo models. PBSM has the potential to reduce the translational gap in drug development by allowing quantitative evaluation of the similarity of preclinical models to human tissues, facilitating model selection, and improving understanding of context-specific applications. PBSM can serve as a foundation for enhancing the physiological relevance of in vitro models and supporting the development of more effective therapeutic interventions.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kaisa Litonius, Noora Kulla, Petra Falkenbach, Kati Kristiansson, E Katriina Tarkiainen, Liisa Ukkola-Vuoti, Kristiina Cajanus, Mari Korhonen, Sofia Khan, Johanna Sistonen, Arto Orpana, Mats Lindstedt, Tommi Nyrönen, Markus Perola, Miia Turpeinen, Ville Kytö, Aleksi Tornio, Mikko Niemi
Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients. We investigated factors associated with receiving pharmacogenetically actionable drugs and developed a literature-based cost-benefit model for pre-emptive pharmacogenetic panel testing. In a 2-year follow-up, 60.4% of the patients in the nationwide cohort purchased at least one pharmacogenetically actionable drug, most commonly ibuprofen (25.0%) and codeine (19.4%). Of the genotyped subset, 98.8% carried at least one actionable pharmacogenetic genotype and 23.3% had at least one actionable gene-drug pair. Patients suffering from musculoskeletal or cardiovascular diseases were more prone to receive pharmacogenetically actionable drugs during inpatient episode. The cost-benefit model included frequently dispensed drugs in the university hospital cohort, comprising ondansetron (19.4%), simvastatin (7.4%), clopidogrel (5.0%), warfarin (5.1%), (es)citalopram (5.3%), and azathioprine (0.5%). For untargeted pre-emptive pharmacogenetic testing of all university hospital patients, the model indicated saving €17.49 in direct healthcare system costs per patient in 2 years without accounting for the cost of the test itself. Therefore, it might be reasonable to target pre-emptive pharmacogenetic testing to patient groups most likely to receive pharmacogenetically actionable drugs.
{"title":"Value of Pharmacogenetic Testing Assessed with Real-World Drug Utilization and Genotype Data.","authors":"Kaisa Litonius, Noora Kulla, Petra Falkenbach, Kati Kristiansson, E Katriina Tarkiainen, Liisa Ukkola-Vuoti, Kristiina Cajanus, Mari Korhonen, Sofia Khan, Johanna Sistonen, Arto Orpana, Mats Lindstedt, Tommi Nyrönen, Markus Perola, Miia Turpeinen, Ville Kytö, Aleksi Tornio, Mikko Niemi","doi":"10.1002/cpt.3458","DOIUrl":"https://doi.org/10.1002/cpt.3458","url":null,"abstract":"<p><p>Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients. We investigated factors associated with receiving pharmacogenetically actionable drugs and developed a literature-based cost-benefit model for pre-emptive pharmacogenetic panel testing. In a 2-year follow-up, 60.4% of the patients in the nationwide cohort purchased at least one pharmacogenetically actionable drug, most commonly ibuprofen (25.0%) and codeine (19.4%). Of the genotyped subset, 98.8% carried at least one actionable pharmacogenetic genotype and 23.3% had at least one actionable gene-drug pair. Patients suffering from musculoskeletal or cardiovascular diseases were more prone to receive pharmacogenetically actionable drugs during inpatient episode. The cost-benefit model included frequently dispensed drugs in the university hospital cohort, comprising ondansetron (19.4%), simvastatin (7.4%), clopidogrel (5.0%), warfarin (5.1%), (es)citalopram (5.3%), and azathioprine (0.5%). For untargeted pre-emptive pharmacogenetic testing of all university hospital patients, the model indicated saving €17.49 in direct healthcare system costs per patient in 2 years without accounting for the cost of the test itself. Therefore, it might be reasonable to target pre-emptive pharmacogenetic testing to patient groups most likely to receive pharmacogenetically actionable drugs.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yawen Yuan, Wenting Hu, Changcheng Chen, Ruen Yao, Shunguo Zhang, Xiao Zhu, Bulong Xu, Zhonghui Huang, Shengyuan Zhang, Xuexian Wang, Mei Zheng, Xiaohui Huang, Joseph F Standing
Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.
{"title":"Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients.","authors":"Yawen Yuan, Wenting Hu, Changcheng Chen, Ruen Yao, Shunguo Zhang, Xiao Zhu, Bulong Xu, Zhonghui Huang, Shengyuan Zhang, Xuexian Wang, Mei Zheng, Xiaohui Huang, Joseph F Standing","doi":"10.1002/cpt.3462","DOIUrl":"https://doi.org/10.1002/cpt.3462","url":null,"abstract":"<p><p>Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Raj Vuppalanchi, Mary M Cruz, Taufik Momin, Farheen Shaikh, Kimberly Swint, Harilal Patel, Deven Parmar
Saroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns.
沙格列扎镁是一种 PPAR α/γ 双激动剂,目前正处于治疗原发性胆汁性胆管炎 (PBC) 的 III 期临床阶段,研究人员评估了它在不同肝功能损害程度 (HI) 的胆汁淤积性肝病 (CLD) 患者和严重肾功能损害 (RI) 患者中的药代动力学 (PK) 特征、安全性和药效学。共进行了三项 PK 研究,将沙格列扎与健康对照组进行比较:研究 1 对 12 名轻度或中度 HI 的 PBC 肝硬化患者进行了为期 4 周、每天口服 1 或 2 毫克的研究;研究 2 评估了 8 名非肝硬化 CLD 患者的单剂量 PK(2 或 4 毫克);研究 3 评估了 8 名严重 RI 患者的单剂量 PK(2 毫克)。第 1 天,与正常人相比,轻度 HI 患者的沙格列扎尔暴露量增加了 14.6-42%,但到第 28 天,暴露量水平相似,表明没有蓄积。在中度 HI 中,第 1 天和第 28 天的暴露量显著增加了 50.4-85%,尽管半衰期相似,但清除率降低了 34-46%。中度 HI 组的暴露量比非肝硬化组高 59%。沙格列扎尔(1 毫克和 2 毫克)可在 4 周后将基线 ALP 异常者的碱性磷酸酶 (ALP) 水平降低 17-40%。非肝硬化CLD(2毫克和4毫克)和严重RI(2毫克)患者的单剂量PK值与匹配对照组相当,没有明显的安全性问题。总体而言,沙格列扎尔(1 毫克和 2 毫克)在胆汁淤积性肝硬化轻度 HI 和重度 RI 患者中安全且耐受性良好,没有重大 PK 变化。中度 HI 会增加暴露量并降低清除率,但不存在任何安全问题。
{"title":"Pharmacokinetic, Safety, and Pharmacodynamic Profiles of Saroglitazar Magnesium in Cholestatic Cirrhosis With Hepatic Impairment and Participants With Renal Impairment.","authors":"Raj Vuppalanchi, Mary M Cruz, Taufik Momin, Farheen Shaikh, Kimberly Swint, Harilal Patel, Deven Parmar","doi":"10.1002/cpt.3450","DOIUrl":"https://doi.org/10.1002/cpt.3450","url":null,"abstract":"<p><p>Saroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}