Annals of Pharmacotherapy最新文献

Objective: To evaluate the pharmacology, efficacy, safety, and clinical use of datopotamab deruxtecan (Dato-DXd), a recently approved trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC), in the treatment of advanced solid tumors.

Data sources: A comprehensive English-language literature search was conducted on PubMed and ClinicalTrials.gov from January 2010 through September 2025 using the search terms datopotamab, datroway, breast cancer, or nonsmall cell lung cancer.

Study selection and data extraction: Evidence was gathered from clinical trials, relevant articles, guidelines, abstracts, and package inserts.

Data synthesis: Dato-DXd received accelerated approval by the Food and Drug Administration (FDA) in 2025 for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, and epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC). In the TROPION-Breast01 trial, Dato-DXd demonstrated superior efficacy with a response rate of 36.4% versus 22.9% for chemotherapy and median progression-free survival of 6.9 versus 4.9 months. In NSCLC, TROPION-Lung01 showed a response rate of 26.4% with Dato-DXd compared with 12.8% with docetaxel. For the approved EGFR-mutant NSCLC indication, the TROPION-Lung05 trial demonstrated a response rate of 35.8% with Dato-DXd. Treatment-related adverse events included stomatitis, nausea, alopecia, and ocular events, with interstitial lung disease/pneumonitis representing the most clinically significant safety concern.

Relevance to patient care and clinical practice: The TROP2-directed ADC appears to be a viable therapeutic alternative for select patients with previously treated HR+/HER2- breast cancer or EGFR-mutant NSCLC after progression on targeted therapy.

Conclusions: Dato-DXd offers a promising treatment option for heavily pretreated patients with HR+/HER2- breast cancer and EGFR-mutant NSCLC, providing meaningful clinical benefit with a manageable safety profile. Optimal sequencing and positioning within the rapidly shifting ADC landscape requires further investigation.

Background: The 2021 Surviving Sepsis guidelines recommend which vasopressor to initiate first; however, there is a paucity of data to guide the order of vasopressor discontinuation. Retrospective studies have demonstrated an increased risk of hypotension within 24 hours if vasopressin is discontinued first; however, using a shorter timeframe may be of higher clinical relevance and more reflective of vasopressor pharmacokinetic properties.

Objective: The purpose of this study was to evaluate differences in the incidence of rebound hypotension within the first 6 hours following norepinephrine or vasopressin discontinuation in patients with septic shock.

Methods: This was a single-center, retrospective analysis of adult patients with septic shock admitted to an intensive care unit (ICU) who had either vasopressin (AVP1) or norepinephrine (NE1) discontinued first between January 1, 2021 and December 31, 2021. The major outcome was the incidence of hypotension within 6 hours of first discontinued agent. A Kaplan-Meier curve evaluated time to hypotension. Notable minor outcomes included incidence of hypotension within 12 and 24 hours, ICU length of stay (LOS), ICU mortality, and time to shock resolution.

Results: During the study period, 580 patients were evaluated for inclusion, of which 209 were included: 150 in the NE1 group and 59 in the AVP1 group. There was no difference in incidence of hypotension within 6 (54% vs 61%), 6-12 (14.7% vs 10.2%), or 12-24 (6.7% vs 10.2%) hours, ICU LOS, ICU mortality, and shock resolution between groups. The Kaplan-Meier curve showed no differences between groups in time to hypotension within 6 hours of vasopressor discontinuation (p = 0.1)Conclusion and Relevance:This is the first study to evaluate the impact of vasopressor discontinuation order in septic shock within 6 hours, finding no differences in hypotension regardless of discontinuation order. Application of this data gives reassurance the order of vasopressor discontinuation may not impact clinical outcomes.

Objective: To review the pharmacology, usage, efficacy, and safety of fenfluramine in treating seizures in pediatric patients with Lennox-Gastaut syndrome or Dravet syndrome.

Data sources: The PubMed database was searched for studies using the search terms "Lennox-Gastaut Syndrome," "Dravet Syndrome," "fenfluramine," and "Fintepla©."

Study selection and data extraction: Articles were selected based on the following criteria: published in English, published between January 1950 and September 2025, and included clinical relevancy for pharmacology, efficacy, and adverse events.

Data synthesis: In a phase 3 trial, patients with Lennox-Gastaut syndrome experienced a median 26.5% decrease in frequency of drop seizures when taking the 0.7 mg/kg/d dose. In a 2-part phase 2 trial, 54% of patients with Dravet syndrome concurrently taking stiripentol experienced a >50% decrease in monthly seizures at a dosage of 0.4 mg/kg/d; 72.9% of patients with Dravet syndrome not concurrently taking stiripentol experienced a >50% decrease in monthly seizures at a dosage of 0.7 mg/kg/d. Most common adverse effects in both trials included lethargy, decreased weight, and decreased appetite.

Relevance to patient care and clinical practice: Fenfluramine's dual mechanism of action makes it uniquely suited to reduce seizure activity after previous failures in treatment. Some providers are hesitant to prescribe fenfluramine due to its historical association with severe cardiovascular risks. However, proper dosage and titration, as well as adherence to the Risk Evaluation and Mitigation Strategy program can sufficiently mitigate risk for the outcome of seizure reduction and increased quality of life.

Conclusions: As seen through the results of multiple clinical trials, fenfluramine can provide significant seizure reduction for Lennox-Gastaut and Dravet patients with treatment-resistant seizures. Risks can be mitigated through adherence to proper programs and schedules, and can provide enough benefits to outweigh risks in patients with particularly resistant epilepsies.

Background: Remdesivir has demonstrated effect in reducing COVID-19 mortality and disease progression, while conflicting associations have been reported between remdesivir and renal outcomes.

Objective: This study leverages an advanced causal inference tool and real-world data to address this question in hospitalized COVID-19 patients without severe renal impairment.

Methods: A retrospective cohort study was conducted using linked electronic health records and claims data from Optum's deidentified Clinformatics^® Data Mart Database. Each hospitalized COVID-19 patient without severe renal impairment who used remdesivir was matched to up to 4 nonusers based on hospitalization time. The primary outcome was acute kidney injury (AKI) within 14 days, while the secondary outcome, renal adverse events (RAEs), included AKI, renal replacement therapy, and death within 14 days. Marginal structural models were used to estimate cumulative risk differences and differences in restricted mean survival time comparing 10 consecutive days of remdesivir use to nonuse.

Results: The matched cohort included 2768 remdesivir users and 3835 nonusers. No significant differences were found in the risk of AKI (risk difference: -2.44%, 95% confidence interval CI -8.06% to 3.13%) or RAEs (risk difference: -0.71%, 95% CI -7.34% to 5.79%). Restricted mean survival time also showed no significant differences between remdesivir users and nonusers for AKI (0.23 days, 95% CI -0.22 to 0.68) or RAEs (0.13 days, 95% CI -0.40 to 0.67).

Conclusion and relevance: Remdesivir use was not associated with increased or reduced risk of RAEs in hospitalized COVID-19 patients without severe renal impairment, thereby supporting its continued clinical use as a safe antiviral without offering additional renal benefit.

Objective: To assess the efficacy and safety of pitolisant, a selective histamine H₃ receptor antagonist/inverse agonist, for excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA).

Data sources: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched through August 2025 for randomized placebo-controlled trials (RCTs).

Study selection and data extraction: Eligible RCTs reported Epworth Sleepiness Scale (ESS) or Pediatric Daytime Sleepiness Scale (PDSS), mean sleep latency, EQ-5D, or global impression outcomes. Two reviewers independently screened studies, extracted data, and assessed bias using Cochrane RoB 2.0. Publication bias was evaluated using funnel plots and Egger's test; certainty of evidence was rated with GRADE.

Data synthesis: Six RCTs (n = 1149) met the inclusion criteria. Compared with placebo, pitolisant significantly reduced Sleepiness Scale scores (SSS) (mean difference [MD] = -2.97; 95% confidence interval [CI] -3.62 to -2.33), increased mean sleep latency (MD = 3.06; 95% CI 2.12-3.99), and improved EQ-5D scores (MD = 2.68; P = 0.009). Patient global opinion (risk ratio [RR] = 1.40) and clinical global impression of change (CGI-C) (RR = 1.41) also favored pitolisant. Rates of treatment-emergent adverse events, serious adverse events, and withdrawals were comparable with placebo, and common adverse effects, such as headache, insomnia, nausea, and anxiety, were infrequent and not significantly increased.

Relevance to patient care and clinical practice: Pitolisant provides an effective, nonstimulant option for EDS in narcolepsy and OSA, including residual symptoms despite continuous positive airway pressure (CPAP). Its distinct mechanism and tolerability profile make it a valuable alternative or adjunct to existing therapies, supporting personalized care and enhanced daily functioning.

Conclusion and relevance: Pitolisant significantly improves subjective and objective wakefulness and quality of life in EDS due to narcolepsy or OSA, with robust evidence for ESS benefit and a favorable safety profile.

Background: Glucagon-like peptide-1 receptor agonist (GLP-1 RA) and glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptor agonist (GLP-1/GIP RA) use has become increasingly popular, leading to a rise in exposure calls to poison centers.

Objective: To characterize the clinical effects and outcomes following GLP-1 and GLP-1/GIP RA exposures managed in the emergency department and identify factors prevalent among asymptomatic and symptomatic patients.

Methods: This was a retrospective cohort study of patients exposed to a GLP-1 or GLP-1/GIP RA across 3 poison centers between 2005 and 2023. Patients were included if they were managed at a healthcare facility and excluded if they coingested a medication that may cause significant hypoglycemia, the exposure was for suicidal intent, or the exposure was not followed to a known clinical outcome.

Results: ToxSentryWeb identified 186 potential cases; 152 met the study criteria (130 symptomatic and 22 asymptomatic patients). Nausea (92%) and vomiting (76%) were the most reported clinical effects in the symptomatic group. Hypoglycemia occurred in 9% of patients. Most of the clinical effects lasted 8 to 24 hours. These effects were managed primarily with intravenous fluids (56%) and/or antiemetics (51%). Notably, a higher proportion of patients in the asymptomatic group were exposed to dulaglutide, and a higher proportion of patients in the symptomatic group were exposed to semaglutide.

Conclusion and relevance: This study reveals a critical gap in understanding the clinical outcomes of GLP-1 and GLP-1/GIP RA exposures. Most patients experience mild gastrointestinal symptoms, which typically resolve within 8 to 24 hours with short-term observation. However, hypoglycemia was observed at a higher rate than previously reported despite the absence of concomitant hypoglycemic agents, underscoring the need for close monitoring. These findings suggest that providers should tailor observation times based on symptom severity, while emphasizing patient education on proper administration to prevent misuse and ensure optimal therapeutic outcomes.

Background: Critically ill patients receiving continuous renal replacement therapy (CRRT) commonly experience hypotension necessitating fluids, ultrafiltration (UF) adjustment, or vasopressors. There is limited evidence evaluating 25% albumin on vasopressor requirements in this population.

Objective: To evaluate the impact of 25% albumin on vasopressor requirements for critically ill patients requiring CRRT.

Methods: This single-center, retrospective, intrapatient comparator study included adults admitted to the Cardiothoracic Surgery Intensive Care Unit (CTICU) who received 25% albumin intravenously every 6 or 8 hours for ≥2 consecutive doses while on CRRT and vasopressors. The primary endpoint was the absolute change in average vasopressor dosage from 48 hours before to 48 hours after the first albumin administration in norepinephrine equivalents (NEE, mcg/kg/min). A multivariable interrupted time series model was conducted. Notable secondary endpoints included absolute change in UF rate and 48-hour fluid balance.

Results: Of 252 patients reviewed, 60 were included. The median absolute change in average vasopressor dosage from 48 hours prealbumin to 48 hours postalbumin was -0.005 mcg/kg/min (Q1: -0.035, Q3: 0.021, P = 0.24), with a median percentage change in average dosage of -9.5% (Q1: -33.2, Q3: 34.4). The multivariable regression analysis reported a 0.0038 mcg/kg/min increase in vasopressor dosage (P = 0.02) and a 0.0044 mcg/kg/min decrease in vasopressor dosage (P = 0.001) for every 4-hour increase in time in the 48 hours before and after albumin, respectively. From 48 hours prealbumin to 48 hours postalbumin, UF rate increased numerically (10.6 mL/hr [interquartile range (IQR) -24.0, 49.8]), and 48-hour fluid balance decreased numerically (-467.4 mL/48 hr [IQR -3124.5, 1306.3]).

Conclusion and relevance: In CTICU patients receiving CRRT and vasopressors, 25% albumin resulted in no statistically significant difference in average vasopressor requirements in the 48 hours prealbumin compared to the 48 hours postalbumin in the unadjusted model. However, multivariable regression demonstrated a significant association between albumin administration and reduced vasopressors during the 48-hour period following albumin.

Recent rhetoric in the media and from the United States Federal Government has called into question the effectiveness of antidepressants, namely selective serotonin reuptake inhibitors (SSRIs), among other psychiatric pharmacotherapies. Selective serotonin reuptake inhibitors have also been mentioned as potentially addictive similar to illicit narcotics and a potential threat to patients despite their status as first-line medications in treating depression. The purpose of this commentary is to review the potentially damaging effects such actions and language could have on patient perceptions of their conditions and medications, adherence, and in patients seeking mental healthcare secondary to the reinforcement of damaging stigma.