Annals of Pharmacotherapy

Sun, Hong; Bu, Fengjiao; Li, Ling; Zhang, Xiuwen; Xin, Xiu; Yan, Jingchao; Huang, Taomin

doi: 10.1177/10600280231188171pmid: 37488978

BackgroundDifferent clinical trials for recurrent or metastatic nasopharyngeal carcinoma have studied different combinations of immuno-oncology in first-line treatment, but the optimal choice has not been determined.ObjectiveTo systematically examine and compare the efficacy and safety of different immune checkpoint inhibitors (ICIs) combined with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma.MethodsSeveral electronic databases were systematically searched up to February 2023. Articles meeting the inclusion criteria were included.ResultsThree RCTs were eligible in the study. Compared with placebo plus gemcitabine-cisplatin (GP), toripalimab plus GP (HR = 0.59, 95% CI: 0.37-0.95) was significantly associated with a better OS. Tislelizumab plus GP generated best progression-free survival (PFS) benefit (HR = 0.50, 95% CI: 0.37-0.67), greatest improvement in 1-year PFS rate (RR = 3.00, 95% CI: 1.84-5.22), and objective response rate (ORR) (RR = 1.26, 95% CI: 1.04-1.53) over the placebo plus GP. Furthermore, tislelizumab plus GP appeared to be safer than toripalimab plus GP and camrelizumab plus GP in terms of adverse events (AEs)-grade ≥3, treatment-related AEs (TRAEs)-grade ≥3, serious AEs (SAEs), treatment-related SAEs (TRSAEs), and AEs leading to discontinuation of treatment.Conclusion and RelevanceIn recurrent or metastatic nasopharyngeal carcinoma, programmed death 1 (PD-1) inhibitors plus GP as first-line treatment have better survival outcomes than placebo plus GP with comparable toxicity. Toripalimab plus GP shows the best OS benefit over placebo plus GP, while tislelizumab plus GP generates the best PFS, 1-year PFS rate, ORR, and safety. Tislelizumab plus GP could be the best choice among the ICIs combined with chemotherapy regimens as first-line treatment in recurrent or metastatic nasopharyngeal carcinoma.

Kufel, Wesley D.; Zagoria, Zoey; Blaine, Bruce E.; Steele, Jeffrey M.; Mahapatra, Rahul; Paolino, Kristopher M.; Thomas, Stephen J.

doi: 10.1177/10600280231189888pmid: 37542415

Background:The preferred antibiotic salvage regimen for persistent methicillin-susceptible Staphylococcus aureus bacteremia (MSSAB) is unclear. Ertapenem with cefazolin or an antistaphylococcal penicillin has been primarily described, but identifying alternative carbapenem-sparing options may support antibiotic stewardship efforts and decrease the risk of antibiotic-associated Clostridioides difficile infection.Objective:We sought to evaluate the effectiveness and safety of daptomycin plus oxacillin (D/O) for persistent MSSAB.Methods:This was a single-center, retrospective cohort of patients with persistent MSSAB who received D/O between January 1, 2014, and January 1, 2023. Adult patients were included if they had blood cultures positive for MSSA ≥72 hours and received D/O combination for ≥48 hours. Patients were excluded if they were pregnant, incarcerated, or received another antibiotic considered to have excellent activity against MSSA. The primary outcome was time to MSSA bacteremia clearance post-daptomycin initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day all-cause mortality, MSSA bacteremia-related mortality, 90-day readmission for MSSAB, and incidence of antibiotic-associated adverse effects. Time to MSSAB clearance post-D/O initiation was plotted using Kaplan-Meier estimation.Results:Seven unique patient encounters were identified including 4 with endocarditis. Despite a median MSSA bacteremia duration of 7.8 days, median clearance was 2 days post-daptomycin initiation. All achieved microbiological cure, and no adverse effects were reported. Ninety-day all-cause mortality, MSSAB-related mortality, and 90-day readmission for MSSAB occurred in 28.6%, 14.3%, and 14.3% of patients, respectively.Conclusions and Relevance:D/O was an effective, well-tolerated salvage regimen in this cohort and may represent a carbapenem-sparing option for persistent MSSAB.

Sheredy, Shane A.; Stone, Andrew C.; Mostafavifar, Ahmad M.; Mostafavifar, Lisa G.; Smith, Rachel M.; Doepker, Bruce A.

doi: 10.1177/10600280231189488pmid: 37515524

Background:The American Society of Hematology Guidelines for the management of venous thromboembolism recommend against the use of anti-Xa monitoring for assessing enoxaparin dosing based on a low level of evidence associating supratherapeutic levels with an increased risk of bleeding. However, institutions still utilize anti-Xa levels in select patient populations with altered volume of distribution and/or excretion to monitor and adjust therapy.Objective:The primary objective of this study was to identify risk factors associated with supratherapeutic peak anti-Xa levels (≥1.10 IU/mL) for patients receiving therapeutic enoxaparin.Methods:This was a retrospective single-center study performed at an academic tertiary care hospital. Patients who received enoxaparin at 1 mg/kg twice daily and peak anti-Xa monitoring were separated into supratherapeutic and therapeutic/subtherapeutic cohorts.Results:A total of 436 patients were screened, and 215 were included, with a mean age of 62 years. There were 108 in the therapeutic/subtherapeutic cohort and 107 in the supratherapeutic cohort. Acute kidney injury (AKI), body mass index (BMI), weight, female sex, intensive care unit (ICU) service, Sequential Organ Failure Assessment (SOFA) score ≥4, and creatinine clearance at the time of peak anti-Xa level collection were associated with supratherapeutic anti-Xa levels in univariate models. Adjusted logistic regression models were created and identified BMI in the 30 to 34.9 kg/m2 (odds ratio [OR] 4.35; 95% confidence interval [CI] 1.70-11.13, P < 0.005) and ≥35 kg/m2 (OR 6.75; 95% CI 3.05-14.94, P < 0.005) and AKI (OR 2.62; 95% CI 1.04-6.62, P = 0.042) as significant risk factors for supratherapeutic anti-Xa levels.Conclusion and Relevance:Our study identified BMI ≥ 30 kg/m2, AKI, female sex, ICU service, SOFA score ≥4, and creatinine clearance as risk factors for supratherapeutic anti-Xa levels in patients receiving 1 mg/kg twice daily dosing of enoxaparin. Further research should be done to provide evidence for the association between anti-Xa levels and bleeding risk.

Tang, Linlin; Ding, Chuanhua; Li, Hongying; Zhou, Xueheng; Yin, Guoqiang

doi: 10.1177/10600280231189897pmid: 37522435

Background:Drug-induced immune hemolytic anemia (DIIHA) is a rare but potentially life-threatening pharmacogenic hematological adverse effect. Updating the risk of DIIHA among the currently available drugs based on spontaneously reported adverse event data is of great significance.Objective:This study aimed to identify the top 50 drugs associated with immune hemolytic anemia in adults as well as common drugs that could cause immune hemolytic anemia in children based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database.Methods:We extracted adverse events (AE) in the FAERS database from Q1 2004 to Q3 2022 using Open vigil2.1. We use the high-level term “anaemias haemolytic immune” according to the Medical Dictionary for Regulatory Activities (MedDRA) Dictionary (version 24.0). The reported correlation between drugs and DIIHA risk was identified by reported odds ratio (ROR) and proportional reporting ratio (PRR).Results:There were 10500309 AEs in FAERS from 2004Q1 to 2022Q3, of which 2326 (0.02%) were DIIHA cases. The incidence of DIIHA is comparable between males and females. The most common drugs associated with DIIHA in adults and children are summarized according to the number of AE reports. The top 3 categories in terms of quantity of drugs are antineoplastic agents, immunosuppressants, and antibiotics for systemic use. The top 5 drugs in terms of ROR and PRR are alemtuzumab, daclizumab, fludarabine, busulfan, and bendamustine in adults, with entecavir, treosulfan, vinorelbine, pegademase, and alemtuzumab for children.Conclusions:Our study identified the most common drugs that could induce DIIHA in adults and children, as well as the respective ROR and PRR value to discover new drug signals. This study provides references to clinicians for the management of rare DIIHA.

Ahn, Hyun-Young; Jung, Yuju; Kim, Tae Wan; Cho, Yang Hyun; Yang, Jeong Hoon; Chung, Chi Ryang; Min, Myung-Sook; Ko, Ryoung-Eun

doi: 10.1177/10600280231183510pmid: 37401103

Background:Only some studies have directly compared and analyzed the roles of activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in coagulation monitoring during argatroban administration.Objectives:This study aims to assess the correlation of argatroban dose with ACT and aPTT values and to identify the optimal coagulation test for argatroban dose adjustment.Methods:We evaluated 55 patients on extracorporeal membrane oxygenation (ECMO) who received argatroban for more than 72 hours. The correlation between argatroban dose and aPTT and ACT values was evaluated. To compare argatroban dose and bleeding events according to liver dysfunction, the patients were divided into 2 groups based on alanine aminotransferase and total bilirubin.Results:Among the 55 patients, a total of 459 doses and coagulation tests were evaluated. The aPTT and ACT values showed a weak correlation with argatroban dose, with the Pearson correlation coefficients of 0.261 (P < 0.001) and 0.194 (P = 0.001), respectively. The agreement between the target 150 to 180 seconds for ACT and 55 to 75 seconds for aPTT was observed in 140 patients (46.1%). Twenty-four patients (43.6%) had liver dysfunction when they started argatroban. The median argatroban dose was lower in the liver dysfunction group than in the control group (0.094 mcg/kg/min vs 0.169 mcg/kg/min, P = 0.020). Difference was not observed between the 2 groups in the amount of red blood cell (0.47 vs 0.43 pack, P = 0.909) and platelet (0.60 vs 0.08 pack, P = 0.079) transfusion per day.Conclusion and Relevance:A weak correlation was observed between argatroban dose and the aPTT and ACT values. However, the agreement between aPTT and ACT was only 46.1% regarding the scope of target range. Further research is necessary to determine how to assess the optimal argatroban dose for patients administered argatroban while undergoing ECMO at the intensive care unit.

Steuber, Taylor D.; Rosandich, Thomas; Cadwallader, Tiffany; Steil, Lauren; Belk, Madeline; Yendrapalli, Usha; Hassoun, Ali; Edwards, Jonathan

doi: 10.1177/10600280231190401pmid: 37522616

Background:Tocilizumab may reduce the risk of death, length of stay, and time of mechanical ventilation in patients hospitalized with COVID-19. Limited data are available evaluating low-dose subcutaneous administration of tocilizumab in this setting.Objective:To compare outcomes of 2 tocilizumab dosing and administration strategies in patients hospitalized with COVID-19.Methods:A retrospective, observational cohort study was conducted to compare clinical outcomes in patients hospitalized with COVID-19 receiving tocilizumab 400 mg intravenously (400 mg IV) or 162 mg subcutaneously (162 mg SC). Hospitalized patients receiving a single dose of tocilizumab were eligible for inclusion and grouped by dosing and administration strategy. The primary endpoint was ventilator-free days at day 28. Secondary endpoints included length of stay (LOS), intensive care unit (ICU) LOS, mechanical ventilation required after dose, 28-day readmission, 28-day mortality, and change in inflammatory markers.Results:A total of 303 patients were included, with 147 who received tocilizumab 400 mg IV and 156 who received 162 mg SC. There was no significant difference in average ventilator-free days at day 28 in patients receiving 400 mg IV compared with 162 mg SC (26.4 ± 5.3 vs 25.6 ± 6.8 days, respectively; P = 0.812). There was also no difference in LOS (10.4 ± 12.6 vs 10.5 ± 14.0 days; P = 0.637), ICU LOS (3.9 ± 9.0 vs 3.5 ± 8.3 days; P = 0.679), mechanical ventilation after dose (15.6% vs 19.2%; P = 0.412), 28-day readmission (6.1% vs 9.6%; P = 0.268), or 28-day mortality (23.1% vs 25.6%; P = 0.611). Finally, there was no difference regarding change in inflammatory markers at 48 hours (P > 0.05 for all interactions).Conclusion and Relevance:In this retrospective study involving hospitalized patients with COVID-19, there was no difference between tocilizumab 162 mg SC and 400 mg IV in terms of efficacy. The 162 mg SC dose may be a reasonable alternative to traditional doses.

Lobkovich, Alison; Kale-Pradhan, Pramodini; Lipari, Melissa

doi: 10.1177/10600280231190089pmid: 37522468

Objective:This is a narrative review of incretin analogs and their effect on weight management in adult without diabetes.Data Sources:Randomized controlled trials were identified by English language. PubMed/MEDLINE, Scopus, and Embase databases were searched from inception through June 2023 to identify all pertinent trials reporting outcomes on efficacy and safety search using the terms: tirzepatide, semaglutide, liraglutide, and obesity.Study Selection and Data Extraction:Selected studies were included if the study population was composed of adults without diabetes being treated by glucagon-like peptide 1 (GLP-1) receptor agonists or glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 agonists for weight management, and weight loss was assessed as a primary outcome.Data Synthesis:Fifteen studies involving 3 pharmacotherapies (liraglutide, semaglutide, and tirzepatide) were identified. Efficacy data supporting the use of these agents for weight management were promising when compared to placebo and/or other behavioral therapies. Percent weight loss ranged from 5.7% to 11.8%, 14.9% to 17.4%, and 15% to 20.9% for liraglutide, semaglutide, and tirzepatide, respectively. Safety data were relatively similar across all trials and identified gastrointestinal adverse effects as most common.Relevance to Patient Care and Clinical Practice:Glucagon-like peptide 1 agonists are preferred for overweight or obese patients by the American Gastroenterological Association. Future guidelines may address tirzepatides’ place in therapy as new evidence comes forth. Providers should consider patient-specific factors such as cost, adverse effects, drug interactions, and comorbidities when prescribing these agents and provide education regarding the need for concurrent diet and exercise modifications.Conclusions:All incretin analogs in this review are superior to placebo when used for weight management in adults without diabetes.

Bergsma, Emilie J.; Elgawly, Mariam; Mancuso, David; Orr, Roger; Vuskovich, Theresa; Seligson, Nathan D.

doi: 10.1177/10600280231187421pmid: 37466080

ObjectiveThe objective was to review the pharmacology, efficacy, and safety of atezolizumab (Tecentriq) for the treatment of adult and pediatric patients aged 2 years and older with unresectable or metastatic alveolar soft part sarcoma (ASPS).Data SourcesA literature search was conducted using PubMed and MEDLINE databases, published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and May 31, 2023. Keywords included atezolizumab, Tecentriq, MPDL3280, immunotherapy, PD-L1, PD-1, pediatrics, sarcoma, and ASPS.Study selection and data extractionAll English-language studies involving atezolizumab for ASPS were included and discussed.Data synthesisAtezolizumab is an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody designed to block the interaction between PD-L1 and the programmed cell death protein 1 (PD-1) receptor. Atezolizumab was granted approval by the FDA specifically for ASPS based on a phase II clinical trial in adult and pediatric patients (n = 49), which reported an overall response rate of 24% and a durable response rate at 6 and 12 months of 67% and 42%, respectively. Common grade 3/4 adverse reactions include musculoskeletal pain (8%), followed by hypertension (6%), weight gain (6%), headache (4%), and dizziness (4%).Relevance to patient care and clinical practice in comparison with existing drugsAdvanced ASPS is a high-risk disease with limited treatment options. Atezolizumab appears to be a viable treatment option in ASPS demonstrating clinical efficacy and a manageable toxicity profile.ConclusionsWith no other treatments that are FDA approved specifically for ASPS, and few demonstrating efficacy in the advanced setting, the approval of atezolizumab, including the first approval for pediatric patients, represents a landmark improvement to the therapeutic arsenal against this rare disease.

Truong, Thu Minh; Pathak, Gaurav N.; Singal, Amit; Taranto, Viktoriia; Rao, Babar K.

doi: 10.1177/10600280231153863pmid: 37341177

ObjectiveThe objective of this study was to review the safety and efficacy of deucravacitinib, a tyrosine kinase 2 (TYK2) inhibitor for moderate to severe plaque psoriasis.Data SourcesLiterature was reviewed from MEDLINE and Clinicaltrials.gov up to December 2022 using the terms “deucravacitinib” and “BMS-986165.”Study SelectionRelevant articles in English relating to the pharmacodynamics, pharmacokinetics, efficacy, and safety of deucravacitinib were included. A total of 6 trial results were included.Study Selection and Data ExtractionDeucravacitinib showed clinical efficacy across all the phase II and III clinical trials. Excluding the long-term extension study, there were 2248 subjects across all studies, with 63.2% of patients receiving deucravacitinib 6 mg daily. Of these subjects, the average proportion achieving a PASI 75 (a reduction of greater than 75% in the Psoriasis Area and Severity Index) at week 16 was 65.1%. Patients receiving deucravacitinib 6 mg once daily had a higher rate of achieving both PASI 75 response and a Static Physician’s Global Assessment (sPGA) score of 0 or 1, compared with oral apremilast 30 mg twice daily. The safety profile of deucravacitinib includes mild adverse events (AEs), most commonly nasopharyngitis, with serious AEs reported ranging from 1.35% to 9.5%.Relevance to Patient Care and Clinical Practice in Comparison With Existing MedicationsWhile many available therapies for moderate to severe plaque psoriasis rely on an injectable dosage form or extensive monitoring, deucravacitinib can potentially reduce patient medication-related burden. This review summarizes the efficacy and safety of oral deucravacitinib for the treatment of severe plaque psoriasis.ConclusionDeucravacitinib shows a consistent efficacy and safety profile as the first oral TYK2 inhibitor approved for adult patients with moderate to severe plaque psoriasis who are eligible for systemic therapy or phototherapy treatment.

Dao, Diem-Phuong D.; Pixley, Jessica N.; Akkurt, Zeynep M.; Feldman, Steven R.

doi: 10.1177/10600280231182421pmid: 37386842

Objective:This article assesses the efficacy, safety, pharmacology, and clinical applications of topical sirolimus 0.2% gel for the treatment of tuberous sclerosis complex (TSC)–associated facial angiofibromas.Data sources:A review of the literature was conducted using the Medline (PubMed) and EMBASE databases using the keywords topical sirolimus, rapamycin, Hyftor, and tuberous sclerosis.Study selection and data extraction:Articles written in English and relevant to the topic were included.Data synthesis:In the phase 2 trial, the mean improvement factor, a composite measure of improved tumor size and redness, was achieved in all patient groups (P < 0.001) with significant responses among the adult and pediatric subgroups at week 12. There were no serious adverse events recorded. In the phase 3 trial, 60% of participants responded to treatment in the sirolimus group compared with 0% in the placebo group with different response rates between the adult and pediatric subgroups at week 12. Sirolimus gel had no serious adverse events, and dry skin was the most common adverse reaction. Patients who had completed the 12-week trials were then enrolled in a long-term trial; angiofibromas had response rates of 78.2% to 0.2% sirolimus gel.Relevance to patient care and clinical practice in comparison to existing drugs:Topical sirolimus 0.2% is a first-in-class, newly Food and Drug Administration (FDA)–approved, mammalian target of rapamycin (mTOR) inhibitor that is a promising and safe, noninvasive alternative to surgical procedures for TSC-associated angiofibromas.Conclusions:Topical sirolimus 0.2% gel is a moderately effective treatment for TSC-associated facial angiofibromas with an adequate safety profile.