Annals of Pharmacotherapy

Webster, Rachel E.; Belfer, Julie J.; Schmidt, Kyle J.

doi: 10.1177/10600280231197255pmid: 37700565

Background:There is limited evidence evaluating the impact of insulin treatment strategies on glucose variability in critically ill patients without preexisting diabetes.Objective:Compare basal plus insulin (BPI) and sliding scale insulin (SSI) impact on glycemic control outcomes in critically ill patients without preexisting diabetes experiencing hyperglycemia.Methods:This multicenter, retrospective review analyzed critically ill patients with hyperglycemia who received either BPI or SSI. Patients with a hemoglobin A1C >6.5% during the admission of interest or in the previous 3 months, or a diagnosis of diabetes at the time of discharge were excluded. The primary outcome was glucose variability during the intensive care unit (ICU) admission. Secondary outcomes included hypoglycemia frequency, frequency of goal glucose levels, mortality, and length of stay.Results:The analysis included 228 patients (39 in BPI, 189 in SSI). Average glucose variability was higher in the BPI group compared with the SSI group (85.8 mg/dL ± 33.1 vs 70.2 mg/dL ± 30.7; P = 0.009), which remained when controlling for baseline confounding (−12.1 [5.6], 95% CI −23.2 to −0.99; P = 0.033). Hypoglycemia incidence was similar between groups. BPI patients had a lower incidence of glucose values within goal range than SSI patients (P = 0.046). There was no difference in length of stay or hospital mortality.Conclusions and Relevance:The use of SSI compared with a BPI regimen may result in reduced glycemic variability in critically ill patients without preexisting diabetes. Future prospective studies, with a larger sample size, are warranted to confirm our exploratory findings and characterize clinically significant benefits.

Campbell, Ashley M.; Pae, Elizabeth; Lee, Eunice; Jacisin, Timothy; Price, Alina; DeAngelo, Jessica

doi: 10.1177/10600280231199137pmid: 37712551

Background:Apixaban is commonly used to prevent stroke in older adults with nonvalvular atrial fibrillation (AF). Although its package insert has specific dose reduction criteria, providers may dose reduce outside of these parameters based on clinical scenarios.Objective:The primary objective was to determine the incidence of apixaban off-label reduced dosing, while secondarily determining the safety and efficacy outcomes associated with such dosing.Methods:A retrospective analysis of patients aged 65 and older with orders for apixaban for AF was institutional review board (IRB)-approved and conducted across 3 academic medical centers. Patients receiving off-label reduced-dose apixaban (ie, “underdosed”) were matched to a cohort of patients dosed according to the package insert at the standard dosing (5 mg twice daily) using stratified random sampling. Secondary outcomes included 1-year incidence of major bleeding, clinically relevant non-major bleeding (CRNMB), stroke or transient ischemic attack (TIA), and mortality. The Fisher exact tests were used to compare between-group differences.Results:Of the 1172 patients meeting initial inclusion criteria, 201 (17%) were dosed off-label, with 175 (15%) “underdosed.” The 147 “underdosed” patients with documented follow-up were matched with 139 patients receiving standard Food and Drug Administration (FDA)-labeled dosing. There were no significant differences in incidence of stroke (2.7% vs 2.2%), major bleeding (0% vs 0.7%), and CRNMB (2.7% vs 1.4%) in the off-label reduced dosing versus standard dosing groups. All-cause mortality was higher in the off-label reduced-dose group (16 [10.9%] vs 2 [1.4%], P < 0.05).Conclusion and Relevance:Older adults with nonvalvular AF are commonly prescribed lower-than-recommended doses of apixaban. However, no significant association was found between empiric off-label reduced dosing and stroke or bleeding outcomes.

Ng, Tsz Hin; Zhao, Jing J.; Gumbleton, Ryan; Olson, Shannon; Smith, Stephanie; Scipione, Marco R.

doi: 10.1177/10600280231201953pmid: 37752788

Background:Carbapenem-resistant (Car-R) Pseudomonas aeruginosa is an urgent threat. These isolates may remain susceptible to traditional noncarbapenem antipseudomonal β-lactams, but it is unclear if carbapenem resistance impacts the effectiveness of these agents.Objective:The purpose of this study was to compare clinical outcomes in Car-R and cephalosporin-susceptible (Ceph-S) P. aeruginosa pneumonia treated with cefepime versus other susceptible agents.Methods:This retrospective cohort study evaluated patients diagnosed with hospital-acquired or ventilator-associated pneumonia who had a respiratory isolate of Car-R Ceph-S P. aeruginosa. Patients were excluded if they had polymicrobial respiratory cultures, other concomitant infections, empyema, death within 3 days of index culture, or received less than 3 days of susceptible therapy. Patients treated with cefepime were compared to other susceptible therapies. The primary endpoint was 30-day in-hospital mortality.Results:Eighty-seven patients were included: cefepime, n = 61; other susceptible therapies, n = 26. There were no differences in 30-day in-hospital mortality between cefepime and other susceptible therapies (19.6% vs. 19.2%, p value = 0.719). In addition, there were no differences between clinical cure rates (cefepime 65.6% vs. other therapies 72 %, p value = 0.47). In multivariate logistic regression, treatment with cefepime (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.11-2.52) was not independently associated with 30-day in-hospital mortality.Conclusion and Relevance:For the treatment of Car-R Ceph-S P. aeruginosa pneumonia, cefepime showed similar rates of 30-day in-hospital mortality and clinical outcomes when compared to other susceptible therapies. Cefepime may be utilized to conserve novel β-lactam and β-lactamase inhibitors.

Duong, Amy; Heacock, Samantha; Amering, Sarah; Brennan, Lillian; Venci, Jineane; Acquisto, Nicole M.

doi: 10.1177/10600280231199852pmid: 37743669

Background:Limited real-world data on the benefits and risks associated with 3 and 4.5 mg doses of dulaglutide currently exists, making it difficult to determine the impact of dose titration for patients currently managed with dulaglutide 1.5 mg weekly.Objective:To determine the impact of dulaglutide 3 and 4.5 mg doses on weight and hemoglobin A1c (HbA1c) in patients with type 2 diabetes mellitus (T2DM), in clinical practice.Methods:Retrospective, observational study of adult T2DM patients receiving dulaglutide 3 or 4.5 mg weekly within a large, university-affiliated, primary care network. The primary outcome was change in weight and HbA1c from baseline to 24 weeks. Secondary outcomes included incremental changes in weight and HbA1c, and describing trends related to dose reductions.Results:Ninety-five patients were included, 62 in the dulaglutide 3 mg group and 33 in the dulaglutide 4.5 mg group. After 24 weeks, the mean changes in weight and HbA1c from baseline were −1.8 kg (P < 0.01) and −0.4% (P < 0.01) in the 3 mg group, and −4.2 kg (P < 0.01) and −0.4% (P = 0.119) in the 4.5 mg group. Incremental change in weight and HbA1c among patients who were titrated from dulaglutide 3 to 4.5 mg weekly were −2.6 kg (P < 0.01) and −0.2% (P = 0.04), respectively.Conclusion and Relevance:Titration from dulaglutide 1.5 to 3 mg resulted in significant reductions in weight and HbA1c after 24 weeks. Additional, statistically significant, reductions in weight and HbA1c were seen when patients were further titrated to dulaglutide 4.5 mg weekly.

Sathienluckana, Thanompong; Jansing, Thaksin; Srisuriyakamon, Supakan; thonkhunthod, Aunchalee; Sangsuwanto, Parsiri; Losatiankij, Pholphat; Supanya, Suttha

doi: 10.1177/10600280231201708pmid: 37743679

Background:Clozapine is the most effective antipsychotic with respect to the incidence of discontinuation and is indicated for treatment-resistant schizophrenia. Although the recommendation for clozapine administration is divided dosing, once-daily dosing of clozapine is commonly prescribed in many countries. However, there is currently no clinical data comparing all-cause discontinuation between the 2 methods of administration of clozapine.Objectives:To compare the all-cause discontinuation and safety of clozapine administration between once-daily and divided dosing regimens.Methods:This was a retrospective cohort study. Participants were patients with treatment-resistant schizophrenia who had received 300 to 600 mg/day of clozapine for at least 3 months. Data were collected from outpatient medical records at Somdet Chaopraya Institute of Psychiatry. Eligible patients were classified into 2 groups: once-daily dosing and divided dosing. The primary outcome was the all-cause discontinuation rate between groups. The duration of the study was 2 years.Results:One hundred eighteen patients were included and analyzed in this study (once-daily dosing group: n = 58; divided dosing group: n = 60). There was no significant difference in all-cause discontinuation between the 2 groups (odds ratio 1.03; 95% confidence interval: [0.28, 3.79]: P = 1.00), or adverse events between groups.Conclusion and Relevance:In patients with treatment-resistant schizophrenia, there were no significant differences in effectiveness or safety between once-daily and divided dosing of clozapine. Further prospective studies with larger sample sizes are required to confirm these findings.

Zhang, Yundi; Du, Yue; Ren, Shuyu; Li, Yue; Zhang, Xiaoming; Cao, Xiaohong; Liu, Fengxi; Zong, Huiying; Li, Yan

doi: 10.1177/10600280231197399pmid: 37702380

Background:The effect of drug-drug interaction (DDI) between tacrolimus and voriconazole on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies.Objective:The objective of this study was to investigate whether CYP3A5 genotype could influence tacrolimus-voriconazole DDI in Chinese kidney transplant patients.Methods:All kidney transplant patients were divided into combination and non-combination groups based on whether tacrolimus was combined with or without voriconazole. Each group was subdivided into CYP3A5 expresser (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 nonexpresser (CYP3A5*3/*3). A retrospective analysis compared tacrolimus dose (D)-corrected trough concentrations (C0) (C0/D) between combination and non-combination groups, respectively. Tacrolimus C0/D was also compared between CYP3A5 expresser and nonexpresser in both groups.Results:The C0/D values of tacrolimus were significantly different between CYP3A5 expresser and nonexpresser in combination group (378.20 [219.38, 633.48] ng/mL/[mg/kg/d] vs 720.00 [595.35, 1681.50] ng/mL/[mg/kg/d], P = 0.0010). Either in CYP3A5 expresser or nonexpresser, we found a statistically significant difference in tacrolimus C0/D between combination and non-combination group (P < 0.0001). The increase in CYP3A5 nonexpresser was 1.38 times higher than that in CYP3A5 expresser (320.93% vs 232.19%).Conclusion and Relevance:The median C0/D values were 90.38% higher in kidney transplant recipients with CYP3A5*3/*3 genotype than in those with CYP3A5*1/*1 or CYP3A5*1/*3 genotype when treated with both tacrolimus and voriconazole. A CYP3A5 genotype-dependent DDI was found between tacrolimus and voriconazole. Therefore, personalized therapy accounting for CYP3A5 genotype detection and therapeutic drug monitoring is necessary for kidney transplant patients when treating with tacrolimus and voriconazole.

Jerousek, Cole R.; Reinert, Justin P.

doi: 10.1177/10600280231194708pmid: 37608463

Objective:The objective was to evaluate the efficacy and safety of dexmedetomidine in the treatment and prophylaxis of paroxysmal sympathetic hyperactivity (PSH).Data Sources:A review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria and queried Embase, MEDLINE (PubMed), Cochrane CENTRAL, Web of Science, SciELO, Korean Journal Index (Clarivate), Global Index Medicus, and CINAHL Plus for results through June 2023.Study Selection and Data Extraction:Studies providing efficacy or safety data associated with dexmedetomidine with a reported diagnosis of PSH were included. Exclusion of studies in pediatric populations, without quantitative and qualitative outcome data, and not readily translatable to English was adhered to.Data Synthesis:Thirteen observational studies of 178 patients were included in the qualitative analysis. Reductions in PSH frequency or symptom severity were reported in 44 of 48 patients who received dexmedetomidine for acute treatment. Prophylactic use of dexmedetomidine was associated with reductions in PSH-Assessment Measure (PSH-AM) scores in postsurgical patients with traumatic brain injuries (TBIs). Adverse events associated with dexmedetomidine were either absent or reported as none.Relevance to Patient Care and Clinical Practice:This review supports the safe and effective use of dexmedetomidine in the treatment and prophylaxis of PSH. Further investigation is required to determine optimal dosing strategies and the extent to which PSH etiology correlated to the efficacy of dexmedetomidine.Conclusions:The use of dexmedetomidine appears to be both efficacious and safe for the treatment and prevention of PSH in patients experiencing a TBI. Additional research is needed to elucidate dosing strategies, titration parameters, and duration of therapy.

Mausey, Natalie; Halford, Zachery

doi: 10.1177/10600280231197459pmid: 37700573

Objective:To evaluate the safety and efficacy of the novel KRAS-targeting agents, sotorasib and adagrasib, in treating KRAS G12C-mutated non–small cell lung cancer (NSCLC).Data Sources:A comprehensive English-based literature search of PubMed and Clinicaltrials.gov between January 2000 and July 2023 was conducted using the terms sotorasib, Lumakras, AMG 510, adagrasib, Krazati, and MRTX849.Study Selection and Data Extraction:Relevant prescribing information, clinical trials, and treatment guidelines were evaluated.Data Synthesis:Sotorasib and adagrasib received accelerated US Food and Drug Administration (FDA) approval following pivotal phase I/II clinical trials. Sotorasib, a first-in-class KRAS inhibitor, demonstrated an overall response rate (ORR) of 41% and a progression-free survival (PFS) of 6.3 months. In a phase III confirmatory trial, sotorasib showed significantly longer PFS compared with docetaxel (5.6 vs. 4.5 months; P = 0.0017). Adagrasib produced an ORR of 42.9% and a PFS of 6.5 months. Both drugs present unique safety profiles, with common toxicities, including diarrhea, musculoskeletal pain, fatigue, and hepatotoxicity.Relevance to Patient Care and Clinical Practice:With KRAS mutations being among the most common oncogenic alterations in NSCLC, sotorasib and adagrasib offer new therapeutic avenues for this previously “undruggable” target. Current treatment guidelines list sotorasib and adagrasib as second-line options in patients with confirmed KRAS G12C-mutated NSCLC. Additional studies are required to further differentiate the safety and efficacy profiles of these 2 agents and identify their optimal place in therapy.Conclusion:Sotorasib and adagrasib demonstrated promising outcomes in targeting the constitutively active KRAS G12C oncogenic driver, underscoring the need for further research to optimize their therapeutic application in this high-risk population.

Lanier, Cameron; Melton, Tyler C.

doi: 10.1177/10600280231195649pmid: 37650387

Objective:The objective of the study is to describe and analyze the pharmacodynamics and pharmacokinetics of oteseconazole as well as the clinical evidence supporting the efficacy of oteseconazole in treating recurrent vulvovaginal candidiasis (RVVC).Data Sources:A literature search was conducted using MEDLINE and EMBASE databases (2015-June 2023). Search terms included “oteseconazole” OR “VT-1161” or “VIVJOA” AND “RVVC” or “recurrent vulvovaginal candidiasis” or “vulvovaginal candidiasis.” Conference abstracts, bibliographies, clinical trials, and drug monographs were included for review.Study Selection and Data Extraction:Relevant studies in English and clinical trials conducted in humans were reviewed.Data Synthesis:Oteseconazole is approved for the treatment of RVVC. In 2 identical phase III studies, oteseconazole was superior to placebo through 48 weeks for preventing recurrence of RVVC (6.7% vs 42.8%, P < 0.001 and 3.9% vs 39.4%, P < 0.001). In the only phase III trial comparing oteseconazole against active drug, oteseconazole was well tolerated and exhibited noninferiority to fluconazole in acute treatment and superiority to placebo for prevention maintenance through 50 weeks (5.1% vs 42.2%, P < 0.001).Relevance to Patient Care and Clinical Practice in Comparison to Existing Agents:This review describes the use of oteseconazole for the treatment of RVVC as compared with fluconazole. Oteseconazole is an effective treatment option for common pathogens causing vulvovaginal candidiasis, including Candida and fluconazole-resistant Candida.Conclusions:Oteseconazole is an effective and safe treatment option for the management of RVVC though current research lacks comparison with established maintenance regimens. Additional research is needed to ascertain the placement of oteseconazole in the treatment of RVVC.

Chiu, Ada W.; Bredenkamp, Nina

doi: 10.1177/10600280231198925pmid: 37706310

Objective:To provide an overview of the guidelines on the management of immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), review the evidence for sparsentan, and discuss its place in therapy.Data Sources:A literature search was conducted using MEDLINE, EMBASE, and clinicaltrials.gov using the search terms “sparsentan” and “RE-021” up to the end of Jun 2023.Study Selection and Data Extraction:English studies were included if they evaluated the pharmacology, pharmacokinetics, efficacy, and safety of sparsentan in human subjects. Information from the Food and Drug Administration (FDA) and manufacturer’s monograph were also extracted.Data Synthesis:In comparison with irbesartan, sparsentan reduced urine protein-to-creatinine ratio (UPCR) in both IgAN (−49.8% vs −15.1% at interim 36 weeks) and FSGS (−44.8% vs −18.5% at 8 weeks). Hypotension and edema were the most common adverse events in the sparsentan groups. Hepatotoxicity appears to be comparable between sparsentan and irbesartan in short-term results.Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs:Sparsentan provides a new option for patients with IgAN who are otherwise at high risk of progressive kidney disease. Continued FDA approval is dependent on long-term study results on renal function decline and safety.Conclusion:Sparsentan reduces proteinuria in IgAN and FSGS, and has expedited approval by the FDA for IgAN in patients at risk of rapid disease progression, generally at urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g. Interim results from PROTECT and results from DUET showed promise for improving proteinuria in IgAN and FSGS. Long-term renal function benefit and safety data are pending.