Clinical therapeutics最新文献

{"title":"Antimicrobial Stewardship: A Creative Outlet for Clinicians","authors":"","doi":"10.1016/j.clinthera.2024.05.009","DOIUrl":"10.1016/j.clinthera.2024.05.009","url":null,"abstract":"","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0149291824001164/pdfft?md5=8293912809296189f5ae49c0ad517ca5&pid=1-s2.0-S0149291824001164-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy","authors":"","doi":"10.1016/j.clinthera.2024.04.004","DOIUrl":"10.1016/j.clinthera.2024.04.004","url":null,"abstract":"<div><h3>Purpose</h3><p>This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy.</p></div><div><h3>Methods</h3><p>Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to &lt;180 mmHg and mean sitting diastolic BP &lt;110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography.</p></div><div><h3>Findings</h3><p>In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were −14.78 (12.35) mmHg, −21.47 (12.78) mmHg, and −8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were −13.30 (12.47) mmHg and −7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (<em>P</em> &lt; 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study.</p></div><div><h3>Implications</h3><p>The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability.</p></div><div><h3>Clinical Trial Registration</h3><p>ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0149291824000845/pdfft?md5=67d08dc341de5531751c0da962047c91&pid=1-s2.0-S0149291824000845-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Impact of Vancomycin MIC on Outcomes in Patients With Coagulase-negative Staphylococcal Bacteremia","authors":"","doi":"10.1016/j.clinthera.2024.01.012","DOIUrl":"10.1016/j.clinthera.2024.01.012","url":null,"abstract":"<div><h3>Purpose</h3><p>Coagulase-negative staphylococci (CoNS) are Gram-positive organisms that are a known component of normal skin flora and the most common cause of nosocomial bacteremia. For CoNS species, the vancomycin MIC breakpoint for susceptibility set by the Clinical and Laboratory Standards Institute is ≤4 µg/mL. There has been published reports of vancomycin heteroresistance in CoNS with vancomycin MICs of 2 to 4 µg/mL. The aim of this retrospective cohort analysis was to assess the clinical impact of vancomycin MICs &lt;2 µg/mL versus ≥2 µg/mL in adult patients with CoNS bloodstream infections.</p></div><div><h3>Methods</h3><p>Adult patients admitted to University Medical Center New Orleans with a blood culture positive for CoNS were assessed. The primary outcome was difference in 30-day mortality. Secondary outcomes were in-hospital, all-cause mortality; duration of bacteremia; hospital length of stay; and percentage of oxacillin-resistant CoNS.</p></div><div><h3>Findings</h3><p>There was no difference in mortality in the vancomycin MIC &lt;2 µg/mL group versus the vancomycin MIC ≥2 µg/mL group at 30 days (15.4% vs 17.4%; <em>P</em> = 1). In-hospital, all-cause mortality was also not different between groups (11.5% vs 13%; <em>P</em> = 1). Hospital length of stay between groups was 28.2 days versus 21 days (<em>P</em> = 0.692). Median duration of bacteremia was 1 day in both groups (<em>P</em> = 0.975), and median scheduled duration of antibiotic therapy was 14.9 days and 19.5 days (<em>P</em> = 0.385). The source and mode of acquisition of CoNS were similar between groups. Of all CoNS isolates, 58.7% (44 of 75) were oxacillin resistant. <em>Staphylococcus epidermidis</em> was the most common CoNS species at 66.7% (50 of 75). Of all isolates, 30.7% (23 of 75) had a vancomycin MIC ≥2 µg/mL, and 87% (20 of 23) of these were <em>S. epidermidis</em>. There was a higher percentage of <em>S. epidermidis</em> in the vancomycin MIC ≥2 µg/mL group than in the MIC &lt;2 µg/mL group (87% vs 57.7%; <em>P</em> = 0.012). CoNS with a vancomycin MIC ≥2 µg/mL were also more likely to be oxacillin resistant (78.3% vs 50%; <em>P</em> = 0.005).</p></div><div><h3>Implications</h3><p>There was no difference in clinical outcomes in adult patients with a CoNS bloodstream infection with a vancomycin MIC &lt;2 µg/mL versus ≥2 µg/mL. At present, vancomycin remains appropriate empiric therapy for CoNS bloodstream infection. Further research is needed to determine if there is a true clinical impact of a vancomycin MIC ≥2 µg/mL in CoNS infections.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0149291824000213/pdfft?md5=9a48dda6d5d0f8e46b9bba3ac3e7e2e2&pid=1-s2.0-S0149291824000213-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140139990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiretroviral Stewardship: Top 10 Questions Encountered by Stewardship Teams and Solutions to Optimize Therapy","authors":"","doi":"10.1016/j.clinthera.2024.04.002","DOIUrl":"10.1016/j.clinthera.2024.04.002","url":null,"abstract":"<div><h3>Purpose</h3><p>Infectious disease pharmacists and physicians overseeing antimicrobial stewardship programs possess expertise and often advanced certification in management of antiretrovirals to treat HIV. Stewardship programs are responsible for managing facility formularies and must stay up to date with the latest antiretrovirals, including once daily formulations and depot injectables. Furthermore, stewardship program members need to understand drug-interactions, short-, and long-term toxicities of these regimens, including dyslipidemia and cardiovascular effects. Patients receiving chronic antiretroviral therapy may present to the acute care, ambulatory care, and long-term care settings. Like other antimicrobials, audit-and-feedback, drug monitoring, and dose-optimization are often required to prevent antiretroviral associated medication errors and minimize resistance.</p></div><div><h3>Methods</h3><p>A narrative review was conducted on antiretroviral stewardship, addressing common clinical questions encountered by stewardship teams and best practices to optimize antiretroviral therapy and reduce the risk for treatment interruptions, resistance, drug interactions, long term toxicities, and other adverse effects.</p></div><div><h3>Findings</h3><p>People living with HIV are often hospitalized and treated by medical teams without formal HIV training. For this reason, these patients are at greater risk for medication errors during hospitalization and between transitions of care. Many opportunities are present for antiretroviral stewardship to mitigate these errors. Frequent updates to simplify HIV regimen, maintain select patients on fixed-dose combination tablets, and strategies to minimize drug interactions make it difficult for even the seasoned clinician to keep up regularly.</p></div><div><h3>Implications</h3><p>Despite the availability of free online HIV resources and progress made in HIV management, significant opportunities for antiretroviral stewardship remain. Implementing electronic order entry updates, formulary upgrades, and formal pharmacy renal dose adjustments to optimize antiretroviral therapy will help clinicians harness these opportunities. Dedicated time and expertise for antiretroviral stewardship as part of local antimicrobial stewardship programs are needed.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S014929182400081X/pdfft?md5=38841adbbc97a211771510147f40a48c&pid=1-s2.0-S014929182400081X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140862476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of Enzyme- and Transporter-mediated Drug Interactions With Drugs Approved by the US Food and Drug Administration in 2022: A Detailed Analysis of In Vitro and Clinical Data Available in New Drug Application Reviews","authors":"","doi":"10.1016/j.clinthera.2024.04.008","DOIUrl":"10.1016/j.clinthera.2024.04.008","url":null,"abstract":"<div><h3>Purpose</h3><p>This analysis aimed to provide mechanistic understanding and clinical relevance of pharmacokinetic drug-drug interactions (DDIs) associated with drugs approved by the Food and Drug Administration in 2022.</p></div><div><h3>Methods</h3><p>Drug metabolism, transport, and DDI data available in New Drug Applications (NDAs) of small molecular drugs approved (n = 22) was analyzed. The mechanism and clinical magnitude of these interactions were characterized based on in vitro, in silico, and clinical data.</p></div><div><h3>Findings</h3><p>As victims, 10 drugs were identified as clinical substrates. Of these, 7 drugs were substrates of CYP3A, including the sensitive substrates daridorexant and mitapivat. As perpetrators, 3 drugs (adagrasib, lenacapavir, and vonoprazan) were clinical inhibitors of CYP enzymes, and 2 drugs (mavacamten and mitapivat) showed induction. Regarding transporter data, abrocitinib and deucravacitinib were found to be substrates of OAT3 and P-gp/BCRP, respectively, and 4 drugs (abrocitinib, adagrasib, lenacapavir, and oteseconazole) were found to inhibit P-gp and/or BCRP. As expected, all clinical DDIs with AUC changes ≥ 2-fold triggered label recommendations. Over half of DDIs with an AUC change &lt; 2 also had label recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Overall, CYP3A played a major role in the drug disposition of the drugs approved in 2022, mediating all strong drug interactions.</p></div><div><h3>Implications</h3><p>The mechanistic information obtained from studying these new therapeutics with marker compounds can be extrapolated to common concomitant medications sharing the same pharmacokinetic properties, enhancing the safe and effective administration of these products in situations of polytherapy.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Importance of Ongoing Surveillance, Education, and Due Diligence for Antimicrobial Stewardship","authors":"","doi":"10.1016/j.clinthera.2024.05.008","DOIUrl":"10.1016/j.clinthera.2024.05.008","url":null,"abstract":"","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overview of the Participation of Nurses in Antimicrobial Stewardship Activities","authors":"","doi":"10.1016/j.clinthera.2024.05.002","DOIUrl":"10.1016/j.clinthera.2024.05.002","url":null,"abstract":"<div><p><strong>A</strong>ntibiotic resistance is a planetary threat demanding maximum attention from health and social care services worldwide due to the clinical, economic, and human costs. Interventions to address resistance—antimicrobial stewardship (AMS) programs—are multipronged and require the close collaboration of all health care workers involved in antimicrobial decisions and use. Nurses have traditionally been absent from such engagement. This Commentary highlights existing evidence of the need for, and impact of, nursing involvement and leadership in AMS. In addition, four barriers (ie, foundational, ownership, education, and leadership) to the increased involvement of nurses in AMS are discussed, with implications and potential solutions.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0149291824001097/pdfft?md5=3eef705400b44944b9e7810d76211a06&pid=1-s2.0-S0149291824001097-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of Cefazolin and Ceftriaxone Enterobacterales Susceptibilities for Inpatient Treatment of Urinary Tract Infections and Risk of Hospital-onset Clostridioides difficile Infection","authors":"","doi":"10.1016/j.clinthera.2024.02.011","DOIUrl":"10.1016/j.clinthera.2024.02.011","url":null,"abstract":"<div><h3>Purpose</h3><p>Urinary tract infection (UTI) is the second most common indication for antibiotic therapy among inpatients in the United States. Ceftriaxone, a third-generation cephalosporin, is habitually chosen to treat inpatient UTIs due to familiarity, cost, and perceived safety. However, third-generation cephalosporins increase the risk of health care facility–onset <em>Clostridioides difficile</em> infection (HOCDI) more than any other antibiotic group, while no statistical risk exists for first-generation cephalosporins. Recent evidence comparing Enterobacterales susceptibility for first- and third-generation cephalosporins in urinary specimens in the United States is limited. This analysis assessed the comparative activity of cefazolin and ceftriaxone for Enterobacterales urinary isolates and incidence of HOCDI to determine the usefulness of cefazolin as an empirical agent to manage inpatient UTI and limit ceftriaxone collateral damage.</p></div><div><h3>Methods</h3><p>This was a retrospective single-center observational study. Microbiologic susceptibility data were analyzed for <em>Escherichia coli, Klebsiella pneumoniae</em>, and <em>Proteus mirabilis</em> urinary specimens taken from adult inpatients admitted from January 1, 2022, to December 31, 2022. Primary outcome was incidence of <em>E coli, K pneumoniae</em>, and <em>P mirabilis</em> susceptibility to cefazolin in uncomplicated UTI (MIC &lt;16 µg/mL). Secondary outcomes include susceptibility for complicated UTI and HOCDI risk associated with cefazolin and ceftriaxone.</p></div><div><h3>Findings</h3><p>A total of 1150 urine samples were identified as <em>E coli, K pneumoniae</em>, and <em>P mirabilis</em> in 2022. Susceptibility to cefazolin was observed in 1064 (92.5%) of 1150 isolates using the MIC breakpoint for uncomplicated UTI and to ceftriaxone in 1115 (97.0%) of 1150 isolates (<em>P</em> &lt; 0.001). From 2016 to 2022, either cefazolin or ceftriaxone was administered in 26,462 inpatient admissions, with HOCDI diagnoses occurring in 89 admissions. HOCDI developed in 78 admissions (0.40%) with ceftriaxone exposure, and 11 cases (0.15%) developed in cefazolin-exposed admissions (adjusted odds ratio, 2.44; 95% CI, 1.25–4.76; <em>P</em> &lt; 0.001).</p></div><div><h3>Implications</h3><p>Cefazolin exhibits high susceptibility for uropathogens commonly implicated in cases of uncomplicated UTI, the most common UTI diagnosis among inpatients. Although ceftriaxone shows a higher susceptibility rate against these common uropathogens, it more than doubles the risk for HOCDI compared with cefazolin. For institutions evaluating opportunities to reduce ceftriaxone use to limit associated collateral damage such as HOCDI, use of cefazolin for uncomplicated UTI may be evaluated by using local susceptibility data.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0149291824000663/pdfft?md5=d8fdb84e10987d4f8f6a126b3380be20&pid=1-s2.0-S0149291824000663-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Safety of Aztreonam Versus Ceftazidime in Patients Labeled With Penicillin Allergy: A Cohort Study","authors":"","doi":"10.1016/j.clinthera.2024.05.007","DOIUrl":"10.1016/j.clinthera.2024.05.007","url":null,"abstract":"<div><h3>Purpose</h3><p>Penicillin allergy is the most common drug allergy among hospitalized patients. Traditionally, aztreonam is recommended for patients labeled with penicillin allergy (PLWPA) in our institutional empirical antibiotic guidelines. Due to a global aztreonam shortage in December 2022, the antimicrobial stewardship unit recommended ceftazidime as a substitute. There is a paucity of real-world data on the safety profile of ceftazidime in PLWPA. Hence, we evaluated tolerability outcomes of ceftazidime use in PLWPA.</p></div><div><h3>Methods</h3><p>This retrospective cohort study compared PLWPA in Singapore General Hospital who received aztreonam (October 2022–December 2022) or ceftazidime (December 2022–February 2023). Patients were stratified according to their risk of allergic reaction (AR) based on history of penicillin allergy. The severity of AR was based on the Delphi study grading system. The primary outcome was development of AR after initiation of aztreonam or ceftazidime. The secondary tolerability outcomes include hepatotoxicity and neurotoxicity.</p></div><div><h3>Findings</h3><p>There were 168 patients in the study; 69 were men (41.1%) and the median age was 69 years (interquartile range: 59–76 years). Incidence of AR was statistically similar in both arms: 1 of 102 patients (0.98%) in the aztreonam arm vs 2 of 66 patients (3.03%) in the ceftazidime arm (<em>P</em> = 0.33). The patient in the aztreonam arm was deemed at medium risk of having an AR and developed localized rashes (grade 1). Both patients in the ceftazidime arm were deemed at high risk of AR and developed localized skin reaction (grade 1). Hepatotoxicity was observed in 1 patient prescribed aztreonam. No patients in the ceftazidime arm developed adverse events.</p></div><div><h3>Implications</h3><p>Ceftazidime appears to be better tolerated and cheaper compared with aztreonam in PLWPA, and serves as an antimicrobial stewardship strategy to conserve broader-spectrum antibiotics use.</p></div>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venetoclax Clinical Pharmacokinetics After Administration of Crushed, Ground or Whole Tablets.","authors":"Samaneh Alaei, Yamin Wang, Yueli Liu, Julia Schiele, Rong Deng, Danielle Shiller, Patrick Marroum, Rajeev Menon, Ahmed Hamed Salem","doi":"10.1016/j.clinthera.2024.03.012","DOIUrl":"https://doi.org/10.1016/j.clinthera.2024.03.012","url":null,"abstract":"<p><strong>Purpose: </strong>Venetoclax is a potent, orally bioavailable BCL-2 inhibitor used in the treatment of some hematological malignancies. Crushing tablets may be necessary to help with the administration of venetoclax to patients with swallowing difficulties or patients requiring nasogastric tube feeding. The study was conducted to assess the bioavailability of crushed and finely ground venetoclax tablets relative to whole tablets.</p><p><strong>Methods: </strong>An open-label, randomized, 3-way, crossover study in 15 healthy adult females was conducted. Venetoclax tablets were administered orally in a crushed, ground or intact form on Day 1 of each period with water following a high-fat breakfast. Pharmacokinetic samples were collected up to 72 hours postdosing.</p><p><strong>Findings: </strong>The crushed and ground tablets met the bioequivalence criteria (0.80-1.25) relative to the intact tablets with respect to area under the concentration-time curve to time of the last measurable concentration (AUC_t) and to infinite time (AUC_inf) but exhibited a slightly lower maximum plasma concentration (C_max). This was not considered clinically significant as only venetoclax overall exposure (AUC) has been shown to correlate with clinical efficacy. There was no change in the physical appearance and the evaluated physicochemical properties of crushed and ground venetoclax tablets after 72 hours of storage at 25°C/60% relative humidity.</p><p><strong>Implications: </strong>Crushing or grinding venetoclax tablets before administration could be considered as a viable alternative method of administration for patients who have difficulty swallowing whole venetoclax tablets or patients requiring nasogastric tube feeding.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifiers: </strong>NCT05909553, registered June 12, 2023.</p>","PeriodicalId":10699,"journal":{"name":"Clinical therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}