Pharmacotherapy最新文献

Transthyretin amyloidosis (ATTR) is a rare disease that results in amyloid fibril misfolding and deposition in multiple organs, including the heart, leading to the development of ATTR cardiomyopathy (ATTR-CM), which is associated with poor outcomes. In the last decade, several disease-modifying medications are in advanced stages of clinical development or have been approved to treat ATTR-CM. The purpose of this review is to critically evaluate clinical trial data investigating the use of approved and investigational medications for the treatment of ATTR-CM. We performed a comprehensive literature search via PubMed and EMBASE to identify randomized controlled trials evaluating medications for the treatment of ATTR-CM published through August 2024. This narrative review describes the pathophysiology of ATTR-CM, highlights important screening and diagnostic work-up, and summarizes the existing clinical evidence resulting from our literature search. Several classes of disease-modifying medications are in development for ATTR-CM. The tetramer stabilizers and transthyretin silencers have proven to be the most effective therapies to date. Tafamidis and acoramidis are currently approved for ATTR-CM while vutrisiran approval for ATTR-CM may be forthcoming. Other disease-modifying medication classes in development include antisense oligonucleotides, gene editing therapies, and monoclonal antibodies. However, several unmet needs exist including the lack of cost-effectiveness due to the extremely high acquisition costs of these medications. Disease-modifying medications approved and in development to treat ATTR-CM offer hope for patients with this disease, but their lack of affordability is the biggest barrier to their use.

Background: Infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) are increasing in the United States. Although many risk factor scoring tools exist, many are specific to bloodstream isolates and may not represent all patient populations. The purpose of this study was to create and validate an institution-specific scoring tool for select ESBL-E of non-urinary origin based on previously identified risk factors.

Methods: This retrospective, case-control analysis included inpatient adults at an academic medical center from July 2021 through August 2023 with a documented ESBL-E or non-ESBL-E infection of non-urinary origin. Patients with ESBL-E isolates were matched in a 1:1 ratio to non-ESBL-E isolates by organism and specimen type. Points for each risk factor were assigned by dividing their respective regression coefficient by half of the smallest regression coefficient and rounding to the nearest integer (prior ESBL-E within the past 12 months: 6 points, urinary catheter: 3 points, central venous catheter: 2 points, cirrhosis: 2 points). Sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) were calculated for each score, and discriminatory power was assessed via the receiver operating characteristic (ROC)-area under the curve (AUC).

Results: Of the 1139 identified cultures, 140 patients met the criteria for inclusion into the ESBL-E case arm, thus 140 patients with non-ESBL-E cultures were matched as controls. Baseline characteristics were relatively similar between the groups. A score of 0 was associated with low risk of ESBL-E (PPV 0.31, NPV 0.36), whereas scores between 2 and 5 were considered moderate risk (PPV 0.56, NPV 0.55), and scores ≥6 were associated with high risk (PPV 0.91, NPV 0.56). The ROC curve AUC was 0.705.

Conclusions: The majority of ESBL-E risk factor scoring tools are specific to isolates causing bloodstream infections. This institution-specific scoring tool may be used to tailor empiric antimicrobial regimens and decrease unnecessary exposure to carbapenems in non-ESBL-E infections of non-urinary origin.

Introduction: Zongertinib (BI 1810631) is a potent, selective, and epidermal growth factor receptor (EGFR) wild-type sparing human epidermal growth factor receptor 2 (HER2) inhibitor. Based on in vitro data, the oxidative hepatic metabolism of zongertinib is principally driven by cytochrome P450 (CYP) 3A4/5. Therefore, zongertinib may be affected by strong CYP3A inducers, like carbamazepine.

Objective: This study aimed to investigate the effect of multiple oral doses of carbamazepine on the pharmacokinetics of a single oral dose of zongertinib in healthy male subjects.

Methods: This open-label, two-period, fixed-sequence clinical drug-drug interaction study examined the pharmacokinetics of a single 60-mg oral dose of zongertinib in the absence or presence of multiple oral doses of carbamazepine. The extent of drug-drug interaction was estimated using the adjusted geometric mean ratios (and 90% confidence intervals [CIs]) for the test treatment (zongertinib in the presence of carbamazepine) versus the reference treatment (zongertinib alone) for areas under the plasma concentration-time curve from time 0 to infinity and to the last quantifiable time point (AUC_0-∞, AUC_0-tz) and maximum measured plasma concentration (C_max).

Results: Sixteen subjects (all Caucasian males) received zongertinib alone in Study Period 1, and 15 of them received both zongertinib and carbamazepine in Study Period 2. Upon co-administration with carbamazepine in Study Period 2, AUC_0-∞ and AUC_0-tz of zongertinib were both reduced to 36.5% (90% CI: 32.0%-41.6% for AUC_0-∞ and 31.9%-41.7% for AUC_0-tz). The C_max of zongertinib was reduced to 56.4% (90% CI: 45.1%-70.6%).

Conclusion: Zongertinib exposure was reduced by 63.5% when coadministered with the strong CYP3A inducer, carbamazepine.

Background: Fluid overload (FO) in the intensive care unit (ICU) is common, serious, and may be preventable. Intravenous medications (including administered volume) are a primary cause for FO but are challenging to evaluate as a FO predictor given the high frequency and time-dependency of their use and other factors affecting FO. We sought to employ unsupervised machine learning methods to uncover medication administration patterns correlating with FO.

Methods: This retrospective cohort study included 927 adults admitted to an ICU for ≥72 h. FO was defined as a positive fluid balance ≥7% of admission body weight. After reviewing medication administration record data in 3-h periods, medication exposure was categorized into clusters using principal component analysis (PCA) and Restricted Boltzmann Machine (RBM). Medication regimens of patients with and without FO were compared within clusters to assess their temporal association with FO.

Results: FO occurred in 127 (13.7%) of 927 included patients. Patients received a median (interquartile range) of 31(13-65) discrete intravenous medication administrations over the 72-h period. Across all 47,803 intravenous medication administrations, 10 unique medication clusters, containing 121 to 130 medications per cluster, were identified. The mean number of Cluster 7 medications administered was significantly greater in the FO cohort compared with patients without FO (25.6 vs.10.9, p < 0.0001). A total of 51 (40.2%) of 127 unique Cluster 7 medications were administered in more than five different 3-h periods during the 72-h study window. The most common Cluster 7 medications included continuous infusions, antibiotics, and sedatives/analgesics. Addition of Cluster 7 medications to an FO prediction model including the Acute Physiologic and Chronic Health Evaluation (APACHE) II score and receipt of diuretics improved model predictiveness from an Area Under the Receiver Operation Characteristic (AUROC) curve of 0.719 to 0.741 (p = 0.027).

Conclusions: Using machine learning approaches, a unique medication cluster was strongly associated with FO. Incorporation of this cluster improved the ability to predict FO compared to traditional prediction models. Integration of this approach into real-time clinical applications may improve early detection of FO to facilitate timely intervention.

Recent guidelines for acute ischemic stroke (AIS) indicate administration of intravenous thrombolysis (IVT) in patients receiving direct oral anticoagulants (DOAC) is not firmly established and may be harmful unless certain potential parameters are met. This systematic review and meta-analysis explores safety outcomes and other clinical parameters from the growing number of publications describing patients taking a DOAC who experience an AIS that is treated acutely with IVT alone. Embase, International Pharmaceutical Abstracts, and PubMed were searched up to January 9, 2024 for studies including adult patients taking a DOAC who experienced an AIS treated with IVT and did not undergo endovascular therapy (EVT), regardless of the use of an anticoagulation reversal agent. Primary safety outcomes evaluated included symptomatic intracranial hemorrhage (sICH), any intracranial hemorrhage, and in-hospital mortality. A total of 873 patients from 78 studies, primarily case reports or case series of patients receiving dabigatran with or without idarucizumab reversal (n = 340), were included in the review. The rate of sICH during the index hospitalization was 3.3%. Seven high-quality studies with low risk of bias included outcomes for patients on DOAC and comparator groups of either patients not taking an oral anticoagulant (no OAC) or patients taking a vitamin K antagonist (VKA) with INR primarily <1.7 at the time of AIS. No significant difference was observed in the incidence of sICH among patients receiving DOAC vs. no OAC (odds ratio [OR] 0.8, 95% confidence interval [CI]: 0.48-1.33) or among patients receiving DOAC vs. VKA (OR 1.02, 95% CI 0.59-1.75). Similar findings of no difference were observed for other safety outcomes. Findings from this study suggest that utilization of IVT as sole recanalization therapy for AIS may be safe in patients taking a DOAC; however, further studies are needed to elucidate specific parameters that differentiate timepoints and variables to ensure safe, optimal treatment.

Introduction: Clozapine and risperidone are second-generation antipsychotics used in the treatment of schizophrenia. There are no guidelines on cross-titration of antipsychotics and, additionally, there is a paucity of published data to support the potential utility of using serum drug levels to guide dosing in these situations.

Case report: A 68-year-old female patient with a history of schizophrenia, taking risperidone and fluoxetine, and a recent diagnosis of Parkinson's disease was admitted to the hospital after a fall at home. During the patient's hospital stay, utilizing serum clozapine levels as guidance, the patient was cross-titrated from risperidone 12 mg daily to a final dose of clozapine 75 mg daily over the span of 17 days, in the setting of multiple possible drug-drug interactions.

Discussion: There is no evidence-based guidance on transitioning patients from one antipsychotic to another especially in the setting of drug-drug interactions. In this case, the patient was successfully transitioned from risperidone to clozapine using serum clozapine levels and clinical status to guide decision-making.

Conclusions: Utilizing serum clozapine levels may be helpful in guiding dose changes during antipsychotic cross-titration, especially when multiple drug interactions are involved.

Introduction: Heart failure (HF) affects more than 6 million adults in the United States, contributing to substantial morbidity, mortality, and health care costs. Despite advances in medical care, many medications can exacerbate HF, yet their prevalence of use remains unknown. This study examined the national use of prescription medications that could exacerbate HF in adults with self-reported HF.

Methods: We analyzed data from US adults with self-reported HF in the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020. Medications known to exacerbate HF, identified from HF guidelines, were documented through pill bottle reviews. Weighted estimates were used to calculate prevalence overall and by sex, race and ethnicity, and level of evidence for avoidance. Multivariable logistic regression models calculated adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for the use of these high-risk medications by sex and race and ethnicity.

Results: A total of 687 participants, representing 5.2 million U.S. adults with HF after applying sampling weights, were included (mean age, 66.1 [95% CI 64.9, 67.4] years; 50.4% female [95% CI 45.9%, 55.0%]). Overall, 14.5% (95% CI 10.4%, 19.5%; n = 92) of adults with HF were prescribed at least one medication known to exacerbate HF, with the most common being diltiazem, meloxicam, and ibuprofen. Use of these medications was not significantly different by sex nor by race and ethnicity. Of these medications, 21.7% (95% CI 10.7%, 38.8%) had level A evidence warning against use, and 78.3% (95% CI 61.2%, 89.3%) had B level evidence.

Conclusion: Over one-seventh of U.S. adults with HF were likely to have been prescribed medications that could exacerbate the condition, underscoring the need to optimize care. Reducing high-risk medication use may mitigate HF exacerbations and improve outcomes in this vulnerable population.

Background: Lamotrigine clearance can change drastically in pregnant women with epilepsy (PWWE) making it difficult to assess the need for dosing adjustments. Our objective was to characterize lamotrigine pharmacokinetics in PWWE during pregnancy and postpartum along with a control group of nonpregnant women with epilepsy (NPWWE).

Methods: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study was a prospective, observational, 20 site, cohort study conducted in the United States (December 2012 and February 2016). Inclusion criteria included patients aged 14-45 years, gestational age <20 weeks at the time of recruitment, IQ >70 points, and receiving lamotrigine. PWWE participated throughout pregnancy and 18 months postpartum with NPWWE having matched visit intervals. Plasma drug and hormone concentrations were measured at each of the seven visits. A population mixed-effects modeling approach was used to describe lamotrigine clearance change.

Results: 221 (170 PWWE, 51 NPWWE) women were included. Baseline apparent clearance (clearance for NPWWE and when not pregnant for PWWE) was identical between the two groups (2.79 L/hour. with 36% between-subject variability). Two subpopulations were identified in PWWE: ~91% of PWWE had a maximum increase to 275% of baseline clearance with 50% of the maximum increase reached at 12 weeks gestational age and ~9% had no significant change in clearance during gestation. Following delivery, a first-order mono-exponential decline (1.27 weeks^-1) in clearance as a function of postpartum week described a return of clearance to baseline. The use of estrogen-based medication and enzyme-inducing antiseizure medications increased nonpregnant clearance by a further 0.33-fold and 0.84-fold, respectively.

Discussion: During pregnancy, 91% of PWWE experience a 275% change from nonpregnant baseline in lamotrigine clearance whereas the remaining PWWE experience little to no change. Nonpregnant baseline lamotrigine clearance was higher in both PWWE and NPWWE with the administration of oral estrogen-containing medications. Our results are of clinical importance as they indicate a subpopulation without the need for substantial dose changes during pregnancy and a source of potential difference across nonpregnant individuals.

Background: Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.

Methods: This study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance therapy were independently reviewed by at least two pediatric oncologists. Germline DNA was genotyped and 97 methotrexate pharmacogenomic variants of interest with at least grade 3 evidence were identified using the Pharmacogenomics Knowledge Base. Associations between variants and neurotoxicity were assessed by logistic regression. Data were randomly split (80/20) and random forest was constructed to estimate the ability of the variants to correctly classify neurotoxicity.

Results: Of the 763 patients included in the study, 8.2% (n = 63) developed methotrexate-associated neurotoxicity. In logistic models, none of the 97 available pharmacogenomic variants reached adjusted statistical significance. However, two variants, rs17222723 (odds ratio [OR] = 2.83 [ref. = T allele], 95% confidence interval [CI]: 1.20-6.15) in ABCC2 and rs1045642 (OR = 0.66 [ref. = minor A allele], 95% CI: 0.44-0.98) in ABCB1, were nominally associated (p-value < 0.05) with neurotoxicity susceptibility. The addition of pharmacogenomic variants did not improve the predictive performance of random forest model (AUC = 0.73) compared to clinical information alone (AUC = 0.74).

Conclusion: Overall, our results suggest that associations between neurotoxicity susceptibility and methotrexate pharmacogenomic variants are generally modest and these variants do not significantly improve neurotoxicity risk stratification among children with ALL.