Miriam M Moser, Karl Rössler, Dorian Hirschmann, Leon Gramss, Ammar Tahir, Walter Plöchl, Johannes Herta, Andrea Reinprecht, Markus Zeitlinger, Arthur Hosmann
There is accumulating evidence that cerebrospinal fluid (CSF) concentrations of nimodipine correlate with long-term outcome of patients after subarachnoidal hemorrhage (aSAH) by impeding cerebral ischemia. However, pharmacological data on simultaneous serum vs. CSF and intraparenchymal nimodipine values are rarely reported in larger patient groups. Nimodipine concentrations were determined in plasma, CSF, and cerebral interstitial fluid (ISF), at steady state after oral (6 × 60 mg/day) and intravenous (0.5, 1, 1.5 and 2 mg/h) administrations in 10 patients after aSAH. Area under the concentration time curve (AUC0-24) for intravenous nimodipine was highest at an infusion rate of 2 mg/h in plasma (1335.87 ± 591.09 mg*h/L), followed by CSF (39.53 ± 23.07 mg*h/L), resulting in an overall CSF penetration ratio of 3.8% (±1.5) (AUCCSF/AUCplasma). In contrast, nimodipine levels were significantly lower in both plasma (AUC0-24 298.32 ± 206.52 mg*h/L) and CSF (AUC0-24 34.8 ± 16.56 mg*h/L) after oral administration. In cerebral ISF, low amounts of nimodipine were detectable in only 4 patients at an infusion rate of 1.5 and 2 mg/h as well as following oral administration. We found significantly higher CSF nimodipine levels in patients during intravenous compared to oral administration. In contrast, only low amounts of nimodipine were detected in the ISF after both oral and intravenous administration. Our findings strongly suggest that the main clinical nimodipine effect of impeding life threatening cerebral ischemia is mediated through significant higher CSF levels after intravenous administration, more likely effective than oral administration.
{"title":"Cerebral Ischemia Protection After Aneurysmal Subarachnoid Hemorrhage: CSF Nimodipine Levels After Intravenous Versus Oral Nimodipine Administration.","authors":"Miriam M Moser, Karl Rössler, Dorian Hirschmann, Leon Gramss, Ammar Tahir, Walter Plöchl, Johannes Herta, Andrea Reinprecht, Markus Zeitlinger, Arthur Hosmann","doi":"10.1002/cpt.3499","DOIUrl":"10.1002/cpt.3499","url":null,"abstract":"<p><p>There is accumulating evidence that cerebrospinal fluid (CSF) concentrations of nimodipine correlate with long-term outcome of patients after subarachnoidal hemorrhage (aSAH) by impeding cerebral ischemia. However, pharmacological data on simultaneous serum vs. CSF and intraparenchymal nimodipine values are rarely reported in larger patient groups. Nimodipine concentrations were determined in plasma, CSF, and cerebral interstitial fluid (ISF), at steady state after oral (6 × 60 mg/day) and intravenous (0.5, 1, 1.5 and 2 mg/h) administrations in 10 patients after aSAH. Area under the concentration time curve (AUC<sub>0-24</sub>) for intravenous nimodipine was highest at an infusion rate of 2 mg/h in plasma (1335.87 ± 591.09 mg*h/L), followed by CSF (39.53 ± 23.07 mg*h/L), resulting in an overall CSF penetration ratio of 3.8% (±1.5) (AUC<sub>CSF</sub>/AUC<sub>plasma</sub>). In contrast, nimodipine levels were significantly lower in both plasma (AUC<sub>0-24</sub> 298.32 ± 206.52 mg*h/L) and CSF (AUC<sub>0-24</sub> 34.8 ± 16.56 mg*h/L) after oral administration. In cerebral ISF, low amounts of nimodipine were detectable in only 4 patients at an infusion rate of 1.5 and 2 mg/h as well as following oral administration. We found significantly higher CSF nimodipine levels in patients during intravenous compared to oral administration. In contrast, only low amounts of nimodipine were detected in the ISF after both oral and intravenous administration. Our findings strongly suggest that the main clinical nimodipine effect of impeding life threatening cerebral ischemia is mediated through significant higher CSF levels after intravenous administration, more likely effective than oral administration.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666548","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}
Evidence of the effectiveness of β-blockers in heart failure (HF) and atrial fibrillation (AF) in a contemporary cohort is controversial. This study investigated the association between the use of β-blockers and prognosis in hospitalized HF patients with and without AF in Japan. Patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2021. Associations of β-blocker use and prognosis were compared by propensity score matching among the AF or non-AF group. A mixed-effects survival model was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Among 428,650 patients discharged with HF in 4,433 hospitals, 175,174 (40.9%) were ≥ 85 years old, 151,873 (35.4%) had complicated AF, and 236,457 (55.2%) were β-blocker users. In a matched AF group, β-blocker use was associated with a lower composite outcome of all-cause mortality or HF rehospitalization (HR [95% CI], 0.95 [0.93-0.97]). A similar result was obtained in a matched non-AF group (0.95 [0.94-0.96]). In addition, the HRs in patients aged ≥ 85 years and female patients were 1.00 [0.98-1.02] and 1.01 [0.98-1.03] in the AF group and 1.03 [1.01-1.05] and 0.98 [0.97-1.00] in the non-AF group, respectively. The favorable prognostic associations of β-blocker use were observed regardless of AF in patients across a broad spectrum of HF in a superaged society.
{"title":"Contemporary Use of β-Blockers in Heart Failure Patients With and Without Atrial Fibrillation: A Nationwide Database Analysis.","authors":"Michikazu Nakai, Yoshitaka Iwanaga, Koshiro Kanaoka, Yoko Sumita, Yuichi Nishioka, Tomoya Myojin, Katsuki Okada, Tatsuya Noda, Tomoaki Imamura, Yoshihiro Miyamoto","doi":"10.1002/cpt.3496","DOIUrl":"https://doi.org/10.1002/cpt.3496","url":null,"abstract":"<p><p>Evidence of the effectiveness of β-blockers in heart failure (HF) and atrial fibrillation (AF) in a contemporary cohort is controversial. This study investigated the association between the use of β-blockers and prognosis in hospitalized HF patients with and without AF in Japan. Patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2021. Associations of β-blocker use and prognosis were compared by propensity score matching among the AF or non-AF group. A mixed-effects survival model was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Among 428,650 patients discharged with HF in 4,433 hospitals, 175,174 (40.9%) were ≥ 85 years old, 151,873 (35.4%) had complicated AF, and 236,457 (55.2%) were β-blocker users. In a matched AF group, β-blocker use was associated with a lower composite outcome of all-cause mortality or HF rehospitalization (HR [95% CI], 0.95 [0.93-0.97]). A similar result was obtained in a matched non-AF group (0.95 [0.94-0.96]). In addition, the HRs in patients aged ≥ 85 years and female patients were 1.00 [0.98-1.02] and 1.01 [0.98-1.03] in the AF group and 1.03 [1.01-1.05] and 0.98 [0.97-1.00] in the non-AF group, respectively. The favorable prognostic associations of β-blocker use were observed regardless of AF in patients across a broad spectrum of HF in a superaged society.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646231","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}
Jieni Li, George J Hutton, Tyler J Varisco, Ying Lin, Ekere J Essien, Rajender R Aparasu
In patients with multiple sclerosis (MS), infections represent a significant concern, particularly given the immunomodulatory effects of disease-modifying agents (DMAs). High-efficacy DMAs (heDMAs) play a pivotal role in delaying MS progression, yet their use also raises concerns regarding the risk of infection. This study aimed to compare the infection risk with the use of heDMA and moderate-efficacy disease-modifying agents (meDMAs) in MS patients. This retrospective cohort study involved adult (18-64 years) MS patients with incident DMA use based on the 2015-2019 MarketScan Commercial Claims and Encounters Database. Patients initiating heDMAs (natalizumab, alemtuzumab, and ocrelizumab) or meDMAs (interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and glatiramer acetate) were included. The outcomes of interest were comparative risk of overall infection, serious infection, and frequently reported types of infection. Adjusted hazard ratios (aHR) were estimated in inverse probability treatment weighting (IPTW) based on Cox proportional hazard models. Among 10,003 eligible incident DMA users, 22.92% of patients initiated heDMAs. The IPTW-CPH model revealed that patients with heDMAs were associated with a higher risk of serious infection (aHR: 1.24, 95% confidence interval (CI): 1.06-1.44) and urinary tract infection (UTI; aHR: 1.21, 95% CI: 1.14-1.30). Sensitivity analyses with different follow-up periods yielded consistent findings with the main analyses. In MS, heDMAs were associated with a greater risk of serious infection and UTI compared with meDMAs. These findings suggest the need to carefully monitor and manage the infection risk to optimize the use of heDMAs in MS.
{"title":"Infection Risk Associated with High-Efficacy Disease-Modifying Agents in Multiple Sclerosis: A Retrospective Cohort Study.","authors":"Jieni Li, George J Hutton, Tyler J Varisco, Ying Lin, Ekere J Essien, Rajender R Aparasu","doi":"10.1002/cpt.3492","DOIUrl":"https://doi.org/10.1002/cpt.3492","url":null,"abstract":"<p><p>In patients with multiple sclerosis (MS), infections represent a significant concern, particularly given the immunomodulatory effects of disease-modifying agents (DMAs). High-efficacy DMAs (heDMAs) play a pivotal role in delaying MS progression, yet their use also raises concerns regarding the risk of infection. This study aimed to compare the infection risk with the use of heDMA and moderate-efficacy disease-modifying agents (meDMAs) in MS patients. This retrospective cohort study involved adult (18-64 years) MS patients with incident DMA use based on the 2015-2019 MarketScan Commercial Claims and Encounters Database. Patients initiating heDMAs (natalizumab, alemtuzumab, and ocrelizumab) or meDMAs (interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and glatiramer acetate) were included. The outcomes of interest were comparative risk of overall infection, serious infection, and frequently reported types of infection. Adjusted hazard ratios (aHR) were estimated in inverse probability treatment weighting (IPTW) based on Cox proportional hazard models. Among 10,003 eligible incident DMA users, 22.92% of patients initiated heDMAs. The IPTW-CPH model revealed that patients with heDMAs were associated with a higher risk of serious infection (aHR: 1.24, 95% confidence interval (CI): 1.06-1.44) and urinary tract infection (UTI; aHR: 1.21, 95% CI: 1.14-1.30). Sensitivity analyses with different follow-up periods yielded consistent findings with the main analyses. In MS, heDMAs were associated with a greater risk of serious infection and UTI compared with meDMAs. These findings suggest the need to carefully monitor and manage the infection risk to optimize the use of heDMAs in MS.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions.","authors":"","doi":"10.1002/cpt.3453","DOIUrl":"https://doi.org/10.1002/cpt.3453","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637963","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}
Abhishek G Sathe, Paul M Diderichsen, Floris Fauchet, See-Chun Phan, Sandhya Girish, Ahmed A Othman
Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in metastatic setting). Exposure-response (E-R) relationships between SG exposure and efficacy and safety outcomes were characterized in 277 patients with mTNBC using data from the phase I/II IMMU-132-01 and phase III ASCENT (IMMU-132-05) studies. Evaluated endpoints included complete response (CR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety endpoints (individual first worst grade of select adverse events (AEs)). E-R analyses were also conducted for time to first dose reduction or delay. Patients received SG at 8 or 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle. Average SG-related serum exposure over the treatment duration (until the event) was consistently the most significant exposure metric correlated with efficacy and safety endpoints. Higher average concentration over the treatment duration for SG (CAVGSG) was the best predictor of CR and ORR. The model-predicted proportions of patients with CR and ORR at 10 mg/kg were 4.26% and 32.6%, respectively. Higher CAVG for total antibody was the best predictor of OS and PFS. The model-predicted probability of OS at 12 months at median lactate dehydrogenase (227 IU/L) was 53%. The probability of grade ≥1 evaluated AEs and the risk of dose reductions and delays significantly increased with increasing CAVGSG. The model-predicted proportions of patients with any-grade AEs were 35.9%, 67.4%, 64.7%, and 67.1% for vomiting, diarrhea, nausea, and neutropenia, respectively (10 mg/kg dose group). Neutropenia was the only evaluated AE for which CAVGSG was significantly associated with grade ≥3 events. The clinically meaningful efficacy and manageable safety achieved with SG 10 mg/kg on days 1 and 8 of every 21-day cycle dosing regimen supports the appropriateness of this clinical dosage in patients with mTNBC.
{"title":"Exposure-Response Analyses of Sacituzumab Govitecan Efficacy and Safety in Patients With Metastatic Triple-Negative Breast Cancer.","authors":"Abhishek G Sathe, Paul M Diderichsen, Floris Fauchet, See-Chun Phan, Sandhya Girish, Ahmed A Othman","doi":"10.1002/cpt.3495","DOIUrl":"10.1002/cpt.3495","url":null,"abstract":"<p><p>Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in metastatic setting). Exposure-response (E-R) relationships between SG exposure and efficacy and safety outcomes were characterized in 277 patients with mTNBC using data from the phase I/II IMMU-132-01 and phase III ASCENT (IMMU-132-05) studies. Evaluated endpoints included complete response (CR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety endpoints (individual first worst grade of select adverse events (AEs)). E-R analyses were also conducted for time to first dose reduction or delay. Patients received SG at 8 or 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle. Average SG-related serum exposure over the treatment duration (until the event) was consistently the most significant exposure metric correlated with efficacy and safety endpoints. Higher average concentration over the treatment duration for SG (CAVG<sub>SG</sub>) was the best predictor of CR and ORR. The model-predicted proportions of patients with CR and ORR at 10 mg/kg were 4.26% and 32.6%, respectively. Higher CAVG for total antibody was the best predictor of OS and PFS. The model-predicted probability of OS at 12 months at median lactate dehydrogenase (227 IU/L) was 53%. The probability of grade ≥1 evaluated AEs and the risk of dose reductions and delays significantly increased with increasing CAVG<sub>SG</sub>. The model-predicted proportions of patients with any-grade AEs were 35.9%, 67.4%, 64.7%, and 67.1% for vomiting, diarrhea, nausea, and neutropenia, respectively (10 mg/kg dose group). Neutropenia was the only evaluated AE for which CAVG<sub>SG</sub> was significantly associated with grade ≥3 events. The clinically meaningful efficacy and manageable safety achieved with SG 10 mg/kg on days 1 and 8 of every 21-day cycle dosing regimen supports the appropriateness of this clinical dosage in patients with mTNBC.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612726","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}
Anuradha Ramamoorthy, Islam Younis, Ya-Feng Wen, Mai Mehanna, Kathleen M. Giacomini, Piet H. van der Graaf
<p>Rare disease (a disease that affects fewer than 1 in about 2,000 people<span><sup>1</sup></span>) and neglected disease (an infectious disease that is present in lower income countries) have very limited therapeutic options and can be considered as “therapeutic orphans.” Collectively, rare and neglected diseases are estimated to affect nearly 2 billion people worldwide – about 300 million people are estimated to be affected by rare diseases and 1.7 billion by neglected tropical diseases.<span><sup>2, 3</sup></span> However, it is reported that only <5% of rare diseases and a limited number of neglected diseases have therapeutic options available.<span><sup>4, 5</sup></span> That is, even though one in four people globally are affected by these diseases, very limited therapeutic options exist for these patients. In this special issue, we focus on rare diseases to highlight challenges and opportunities in developing therapies for these diseases and showcase the current and future role of clinical pharmacology and translational sciences in addressing the challenges and taking advantage of the opportunities. Additionally, the American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2024 Annual Meeting Award and State-of-Art lectures summarized in this issue also highlight the challenges and opportunities in developing effective therapies for the neglected diseases (e.g., tropical diseases including tuberculosis) and neglected populations (e.g., pregnant women or breastfeeding mothers). Our intention for this special issue of <i>Clinical Pharmacology & Therapeutics</i> (<i>CPT</i>) is that we can all collectively learn from these examples and experiences to accelerate drug development for these therapeutic orphans (<b>Figure</b> 1).</p><p>There are a number of challenges in developing therapies for rare diseases. Because each rare disease afflicts only a small number of patients, the market size is relatively limited, and consequently, developing drugs for many of these diseases may not be considered as being commercially attractive. Additionally, most rare diseases are poorly understood because limited longitudinal natural history data are available, and consequently, more information on disease etiology, pathogenesis, genotype-to-phenotype correlation, disease progression, and outcome is needed. Furthermore, the small patient population size can lead to difficulties in enrolling sufficient numbers of patients in clinical trials and in generating adequate data to determine the benefit–risk profile of the drug. Compounding these challenges, there may be a lack of well-established biomarkers or animal models that can be leveraged during drug development. In sum, insufficient commercial interest and inadequate scientific research make it challenging to develop effective therapeutics for rare diseases.</p><p>Recognizing some of these challenges and limitations, several regulatory agencies and public-private partnerships have focuse
{"title":"Therapeutic Orphan No More: Role for Clinical Pharmacology and Translational Science in Developing Therapeutics for Rare and Neglected Diseases","authors":"Anuradha Ramamoorthy, Islam Younis, Ya-Feng Wen, Mai Mehanna, Kathleen M. Giacomini, Piet H. van der Graaf","doi":"10.1002/cpt.3474","DOIUrl":"10.1002/cpt.3474","url":null,"abstract":"<p>Rare disease (a disease that affects fewer than 1 in about 2,000 people<span><sup>1</sup></span>) and neglected disease (an infectious disease that is present in lower income countries) have very limited therapeutic options and can be considered as “therapeutic orphans.” Collectively, rare and neglected diseases are estimated to affect nearly 2 billion people worldwide – about 300 million people are estimated to be affected by rare diseases and 1.7 billion by neglected tropical diseases.<span><sup>2, 3</sup></span> However, it is reported that only <5% of rare diseases and a limited number of neglected diseases have therapeutic options available.<span><sup>4, 5</sup></span> That is, even though one in four people globally are affected by these diseases, very limited therapeutic options exist for these patients. In this special issue, we focus on rare diseases to highlight challenges and opportunities in developing therapies for these diseases and showcase the current and future role of clinical pharmacology and translational sciences in addressing the challenges and taking advantage of the opportunities. Additionally, the American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2024 Annual Meeting Award and State-of-Art lectures summarized in this issue also highlight the challenges and opportunities in developing effective therapies for the neglected diseases (e.g., tropical diseases including tuberculosis) and neglected populations (e.g., pregnant women or breastfeeding mothers). Our intention for this special issue of <i>Clinical Pharmacology & Therapeutics</i> (<i>CPT</i>) is that we can all collectively learn from these examples and experiences to accelerate drug development for these therapeutic orphans (<b>Figure</b> 1).</p><p>There are a number of challenges in developing therapies for rare diseases. Because each rare disease afflicts only a small number of patients, the market size is relatively limited, and consequently, developing drugs for many of these diseases may not be considered as being commercially attractive. Additionally, most rare diseases are poorly understood because limited longitudinal natural history data are available, and consequently, more information on disease etiology, pathogenesis, genotype-to-phenotype correlation, disease progression, and outcome is needed. Furthermore, the small patient population size can lead to difficulties in enrolling sufficient numbers of patients in clinical trials and in generating adequate data to determine the benefit–risk profile of the drug. Compounding these challenges, there may be a lack of well-established biomarkers or animal models that can be leveraged during drug development. In sum, insufficient commercial interest and inadequate scientific research make it challenging to develop effective therapeutics for rare diseases.</p><p>Recognizing some of these challenges and limitations, several regulatory agencies and public-private partnerships have focuse","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"116 6","pages":"1363-1368"},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3474","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612878","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}
Huan Mo, Yamna Channa, Tracey M Ferrara, Bennett J Waxse, David J Schlueter, Tam C Tran, Anas H Awan, Slavina B Goleva, Ariel Williams, Anav Babbar, Onajia Stubblefield, Jacob M Keaton, Eric A Larson, Russell A Wilke, Joshua C Denny
Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.
选择性血清素再摄取抑制剂(SSRI)、血清素-去甲肾上腺素再摄取抑制剂(SNRI)和去甲肾上腺素-多巴胺再摄取抑制剂(NRI)类抗抑郁药可通过抗利尿激素分泌不当综合征(SIADH)引起低钠血症。本研究以 "我们所有人研究计划"(All of Us Research Program)中的一项回顾性观察队列研究为参照,评估了与常用处方 SSRIs(氟西汀、帕罗西汀、舍曲林、西酞普兰、艾司西酞普兰)、SNRIs(度洛西汀、文拉法辛)和 NRIs(安非他酮)以及奥美拉唑相关的低钠血症的不同风险。研究对象包括接受过八种常见抗抑郁药中任何一种单药治疗的患者,每种药物都被视为一个独立的治疗组,并以开始日期为索引。事件定义为首次出现低血浆钠测量值或低钠血症或 SIADH 的临床诊断记录。未发生事件的患者在最后一次测量血浆钠时被剔除。共有 17,439 人接受了八种抗抑郁药中的一种作为单一疗法。在抗抑郁药物治疗组中,低钠血症的总发生率在头30天为0.87%,头3年为10.5%。与舍曲林相比,度洛西汀(危险比 [HR] = 1.37 [1.19-1.58])和艾司西酞普兰(HR = 1.16 [1.01-1.33])的低钠血症总风险最高,而安非他酮(HR = 0.83 [0.73-0.94])和帕罗西汀(HR = 0.78 [0.65-0.93])的风险最低。在对合并症和多重用药进行调整后,风险保持不变。这些信息有助于指导医疗服务提供者管理患者及其服用普通抗抑郁药时发生低钠血症的风险。
{"title":"Hyponatremia Associated with the Use of Common Antidepressants in the All of Us Research Program.","authors":"Huan Mo, Yamna Channa, Tracey M Ferrara, Bennett J Waxse, David J Schlueter, Tam C Tran, Anas H Awan, Slavina B Goleva, Ariel Williams, Anav Babbar, Onajia Stubblefield, Jacob M Keaton, Eric A Larson, Russell A Wilke, Joshua C Denny","doi":"10.1002/cpt.3484","DOIUrl":"https://doi.org/10.1002/cpt.3484","url":null,"abstract":"<p><p>Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612857","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}
Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen-dependent COVID-19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P-glycoprotein (P-gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P-gp, such as direct oral anticoagulants (DOAC). Currently, there is limited robust evidence to support a clinically significant interaction between DEX and DOAC. Using physiologically based pharmacokinetic modeling (PBPK), we investigated the impact of DEX administered in the context of SARS-CoV-2 infection on the pharmacokinetics of apixaban (APX) and rivaroxaban (RVX). After validating the induction effect of the DEX compound on two CYP3A4 substrates using the limited available studies, we optimized the compound in a COVID-19 patient population, where significantly higher DEX plasma concentrations were observed compared to healthy volunteers. Our PBPK-based PK simulations showed a 20% decrease in the AUC of APX and RVX in a worst-case scenario and when DEX was administered at 6 mg PO for 10 days. This finding confirms the limited clinical data currently available and supports the use of APX and RVX with DEX in COVID-19 patients at low-risk for thrombo-embolism. In addition, our results suggest that prednisone (PRED), when used at an equipotent dose, could serve as a viable alternative to DEX, given its less pronounced induction effect on APX and RVX. Further research is needed to validate these findings and to explore the clinical implications of using PRED in place of DEX in such scenarios.
{"title":"The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID-19 Patients: A Physiologically Based Pharmacokinetic Modeling Study.","authors":"Jean Terrier, Kenza Abouir, Frederic Gaspar, Youssef Daali, Caroline Flora Samer","doi":"10.1002/cpt.3491","DOIUrl":"https://doi.org/10.1002/cpt.3491","url":null,"abstract":"<p><p>Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen-dependent COVID-19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P-glycoprotein (P-gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P-gp, such as direct oral anticoagulants (DOAC). Currently, there is limited robust evidence to support a clinically significant interaction between DEX and DOAC. Using physiologically based pharmacokinetic modeling (PBPK), we investigated the impact of DEX administered in the context of SARS-CoV-2 infection on the pharmacokinetics of apixaban (APX) and rivaroxaban (RVX). After validating the induction effect of the DEX compound on two CYP3A4 substrates using the limited available studies, we optimized the compound in a COVID-19 patient population, where significantly higher DEX plasma concentrations were observed compared to healthy volunteers. Our PBPK-based PK simulations showed a 20% decrease in the AUC of APX and RVX in a worst-case scenario and when DEX was administered at 6 mg PO for 10 days. This finding confirms the limited clinical data currently available and supports the use of APX and RVX with DEX in COVID-19 patients at low-risk for thrombo-embolism. In addition, our results suggest that prednisone (PRED), when used at an equipotent dose, could serve as a viable alternative to DEX, given its less pronounced induction effect on APX and RVX. Further research is needed to validate these findings and to explore the clinical implications of using PRED in place of DEX in such scenarios.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612871","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}
Britney A Stottlemyer, Tiffany Tran, Kangho Suh, Sandra L Kane-Gill
There is a scarcity of information related to the financial impact of acute kidney injury (AKI), and even more so the economics of drug-associated AKI (D-AKI). Our goal was to provide a comprehensive summary of the economic burden of D-AKI by evaluating the costs of D-AKI compared to not developing AKI and cost savings associated with nephrotoxin stewardship approaches. Following the PRISMA guidelines, a literature search was conducted using PubMed to identify articles from database inception through November 2023. The main outcomes included AKI incidence, resource use, and cost of nephrotoxin stewardship programs/D-AKI event or no event. Key findings were summarized based on whether the study compared the cost of D-AKI vs. no AKI or identified potential cost savings associated with a nephrotoxin stewardship method to prevent D-AKI or worsening D-AKI. All costs were adjusted to USD2023. Twenty-five studies met the inclusion criteria. Eight studies compared the cost of D-AKI to no AKI. Total admission costs of patients who developed D-AKI ranged from $47,696 to $173,569. Nineteen studies implemented nephrotoxin stewardship with 12 substituting a less nephrotoxic drug; five using therapeutic drug monitoring and two altering drug dosing to limit exposure. Overall, these prevention strategies ranged from $5,171 to $364,973 in total medical cost savings and $17 to $942 in total cost savings per patient-day. The in-hospital economic impact of D-AKI is substantial. Implementing nephrotoxin stewardship strategies to reduce D-AKI is associated with cost savings. Institutions should adopt strategic and efficient nephrotoxin stewardship programs to optimize patient care and reduce costs.
{"title":"A Systematic Review of the Costs of Drug-Associated Acute Kidney Injury and Potential Cost Savings with Nephrotoxin Stewardship Prevention Strategies.","authors":"Britney A Stottlemyer, Tiffany Tran, Kangho Suh, Sandra L Kane-Gill","doi":"10.1002/cpt.3493","DOIUrl":"https://doi.org/10.1002/cpt.3493","url":null,"abstract":"<p><p>There is a scarcity of information related to the financial impact of acute kidney injury (AKI), and even more so the economics of drug-associated AKI (D-AKI). Our goal was to provide a comprehensive summary of the economic burden of D-AKI by evaluating the costs of D-AKI compared to not developing AKI and cost savings associated with nephrotoxin stewardship approaches. Following the PRISMA guidelines, a literature search was conducted using PubMed to identify articles from database inception through November 2023. The main outcomes included AKI incidence, resource use, and cost of nephrotoxin stewardship programs/D-AKI event or no event. Key findings were summarized based on whether the study compared the cost of D-AKI vs. no AKI or identified potential cost savings associated with a nephrotoxin stewardship method to prevent D-AKI or worsening D-AKI. All costs were adjusted to USD2023. Twenty-five studies met the inclusion criteria. Eight studies compared the cost of D-AKI to no AKI. Total admission costs of patients who developed D-AKI ranged from $47,696 to $173,569. Nineteen studies implemented nephrotoxin stewardship with 12 substituting a less nephrotoxic drug; five using therapeutic drug monitoring and two altering drug dosing to limit exposure. Overall, these prevention strategies ranged from $5,171 to $364,973 in total medical cost savings and $17 to $942 in total cost savings per patient-day. The in-hospital economic impact of D-AKI is substantial. Implementing nephrotoxin stewardship strategies to reduce D-AKI is associated with cost savings. Institutions should adopt strategic and efficient nephrotoxin stewardship programs to optimize patient care and reduce costs.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612719","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}