Centanni N, Garvey K, Mullany E
… +1 more, Nichols S
Pharmacotherapy
· 2025 Mar · PMID 39835595
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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 p...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.
Roberts MZ, Durham SH, Pinner NA
… +1 more, Starr JA
Pharmacotherapy
· 2025 Feb · PMID 39831680
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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 cert...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.
Pharmacotherapy
· 2025 Mar · PMID 39831652
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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 ex...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.
Jones J, Morrisette T, Hamby A
… +2 more, Hornback KM, Burgoon R
Pharmacotherapy
· 2025 Feb · PMID 39797412
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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 isol...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.
Karanam A, Pennell PB, Meador KJ
… +2 more, Long Y, Birnbaum AK
Pharmacotherapy
· 2025 Jan · PMID 39764656
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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 pharmacokinetic...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) 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.
Henry K, Deng S, Chen X
… +9 more, Zhang T, Devlin JW, Murphy DJ, Smith SE, Murray B, Kamaleswaran R, Most A, Sikora A, MRC‐ICU Investigator Team
Pharmacotherapy
· 2025 Feb · PMID 39749877
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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 evalu...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.
Møller AE, Bech-Drewes A, Rasmussen L
… +2 more, Friis S, Schmidt M
Pharmacotherapy
· 2025 Feb · PMID 39744765
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AIMS: With the growing evidence of cardiovascular risks associated with diclofenac use, regulatory measures governing its application and sales have intensified since 2008. We evaluated the association between central re...AIMS: With the growing evidence of cardiovascular risks associated with diclofenac use, regulatory measures governing its application and sales have intensified since 2008. We evaluated the association between central regulatory actions and trends in diclofenac use in Denmark from 1999 to 2023, according to different dosage forms and routes of administration. METHODS AND RESULTS: Data on diclofenac sales in Denmark from 1999 to 2023 were retrieved from the publicly available web database MEDSTAT, based on the Danish Register of Medicinal Products Statistics. The annual sales of various diclofenac dosage forms, including systemic (tablets, modified-release dosage forms, and suppositories) and topical (nonspecific and ophthalmic) dosage forms, were calculated and displayed by sales unit. From 1999 to 2008, sales of all systemically administered diclofenac forms increased: tablets by 51% (2000-2008), modified-release dosage forms by 40% (2003-2007), and suppositories by 44% (1999-2008). Thereafter, sales of tablets declined by 86% and modified-release dosage forms by 90% through 2023. The sales of suppositories declined somewhat lesser, by 34%, during 2008 to 2018 and then increased by 67% through 2023. Sales of nonspecific topical diclofenac increased by several thousandfold from 2005, although with brief periods of decline. CONCLUSION: Sales of systemically administered diclofenac dosage forms, particularly tablets and modified-release drugs, declined by approximately 90% from about 2008 to 2023, indicating compliance with Danish and international regulatory actions. Conversely, sales of topically administered diclofenac increased heavily from 2005 to 2023, denoting a policy-driven shift toward these lower risk dosage forms.
Harris RD, Taylor OA, Gramatges MM
… +22 more, Hughes AE, Zobeck M, Pruitt S, Bernhardt MB, Chavana A, Huynh V, Ludwig K, Klesse L, Heym K, Griffin T, Erana R, Bernini JC, Choi A, Ohno Y, Richard MA, Morrison AC, Chen H, Yu B, Lupo PJ, Rabin K, Scheurer ME, Brown AL
Pharmacotherapy
· 2025 Jan · PMID 39734275
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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 susce...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.
Tian X, Esmaeili H, Minich D
… +9 more, Seitz F, Roessner PM, Wind S, Grempler R, Gan G, Chan TS, Mahmoudi M, Sadrolhefazi B, Müller F
Pharmacotherapy
· 2025 Feb · PMID 39727284
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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 oxidativ...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, AUC) and maximum measured plasma concentration (C). 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 and AUC of zongertinib were both reduced to 36.5% (90% CI: 32.0%-41.6% for AUC and 31.9%-41.7% for AUC). The C 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.
Rose NR, Bailey J, Anderson JD
… +4 more, Chalamalla AR, Ryan KJ, Acosta EP, Guimbellot JS
Pharmacotherapy
· 2024 Dec · PMID 39716404
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BACKGROUND: Nutritional support for people with cystic fibrosis (PwCF) after the implementation of novel drug therapies is shifting from managing malnutrition through a high-fat, high-calorie diet to managing emerging in...BACKGROUND: Nutritional support for people with cystic fibrosis (PwCF) after the implementation of novel drug therapies is shifting from managing malnutrition through a high-fat, high-calorie diet to managing emerging incidences of obesity in this population. Additionally, dietary recommendations prescribed with elexacaftor/tezacaftor/ivacaftor (ETI) recommend taking this drug with a fat-containing meal, which is variably interpreted by patients. This pilot and feasibility study was conducted to assess dietary fat intake and body composition on ETI plasma concentrations. METHODS: Ten participants were enrolled in a 1:1 crossover design by dietary recommendations. To mimic recommendations made during routine clinical care, participants were instructed to consume either a general healthful diet (no more than 30% calories from fat) or a high-fat diet (>40% calories from fat) for a week before crossing over to the alternative diet. RESULTS: This pilot study was acceptable to and feasible for study participants. Most participants increased fat intake calories when following a high-fat diet. Body composition measurements showed a trending correlation between lean mass and fat-free mass with ETI plasma concentrations. ETI compounds were quantified in plasma at 0 h (prior to the ETI morning dose) and 6 h after ingestion, and consuming a high-fat diet did not significantly impact ETI concentrations. CONCLUSIONS: Consuming a higher-fat diet did not significantly impact ETI plasma concentrations, and all participants were in range for clinical effectiveness of ETI regardless of fat intake. This work provides vital pilot data to design larger studies to clarify dietary composition for optimal ETI exposure for PwCF on this therapy.
Hellenbart EL, Ipema HJ, Rodriguez-Ziccardi MC
… +2 more, Krishna H, DiDomenico RJ
Pharmacotherapy
· 2025 Feb · PMID 39714070
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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 a...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.
Nelson NR, Quinn NJ, Bills S
… +6 more, Dellabella A, Gregar SE, Lear A, Marsolek L, Mounce C, Tobin M
Pharmacotherapy
· 2024 Dec · PMID 39702906
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The objective of this scoping review was to answer the question, "What has been published describing drug dosing in sustained low-efficiency dialysis (SLED)?" PubMed, Embase, and Scopus were searched on November 18, 2022...The objective of this scoping review was to answer the question, "What has been published describing drug dosing in sustained low-efficiency dialysis (SLED)?" PubMed, Embase, and Scopus were searched on November 18, 2022. Methodology followed the Arksey and O'Malley framework for scoping reviews and Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Two investigators independently screened abstracts and full-texts of citations identified related to drug dosing and SLED. Exclusion criteria included case reports, conference abstracts, pediatrics, treatment dialysis, and non-human subjects. A standardized data extraction sheet was used to collate and summarize data. The quality of evidence was evaluated by two investigators using the Mixed Methods Appraisal Tool. A total of 230 citations were identified for screening. Of these, 29 studies met criteria for inclusion after full-text review. Four drug groups including beta-lactam antibiotics, non-beta-lactam antibiotics, antifungals, and levetiracetam were identified. Dialysate rates, dialysis durations, and medication doses used varied widely across studies. Outcomes and pharmacokinetic parameters that were assessed were also heterogenous. Drug dosing in SLED is challenging and there is minimal evidence available to guide appropriate dosing. Larger studies are needed to more accurately determine how to appropriately dose medications in SLED. Therapeutic drug monitoring should be used in all patients on SLED when available.
Garwood CL, Cabral KP, Brown R
… +1 more, Dixon DL
Pharmacotherapy
· 2025 Jan · PMID 39679827
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Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Lowering low-density lipoprotein cholesterol (LDL-C) levels is a primary strategy to reduce ASCVD risk. Although statin therapy...Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Lowering low-density lipoprotein cholesterol (LDL-C) levels is a primary strategy to reduce ASCVD risk. Although statin therapy remains the initial therapy of choice to reduce LDL-C and ASCVD risk, statin intolerance and suboptimal LDL-C lowering response prompts the need for additional non-statin therapies. Ezetimibe and bempedoic acid are reasonable options but they modestly reduce LDL-C levels (15% to 25%). Therapies directed at the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, however, reduce LDL-C levels by 50%-60% when added to background statin therapy. PCSK9 is an enzyme synthesized by the liver that facilitates the degradation of LDL receptors and prevents their recycling to the hepatocyte surface to remove LDL-C from circulation. Approaches to inhibit this effect have centered on monoclonal antibodies (mAbs) (alirocumab, evolocumab) targeting PCSK9 functionality and small interfering RNA (siRNA) therapies (inclisiran) targeting the hepatic synthesis of PCSK9. Randomized controlled trials have demonstrated beneficial cardiovascular outcomes of PCSK9 mAbs, but such evidence is not yet available for inclisiran. Current clinical practice guidelines generally recommend PCSK9-directed therapies for higher-risk patients with established ASCVD and those with familial hypercholesterolemia. This approach is, in part, due to their cost and uncertain economic value, but also because these therapies require subcutaneous administration, which is not preferred by some patients. Oral therapies targeting PCSK9 are, however, in development. This scoping review covers the development of current and emerging PCSK9-directed therapies, their efficacy, safety, and role in clinical practice.
Kim S, Welch L, Santos BL
… +3 more, Radwański PB, Munger MA, Kim K
Pharmacotherapy
· 2025 Jan · PMID 39673065
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BACKGROUND: Drug-induced atrial fibrillation (AF) is recognized as an important causal association. Lamotrigine (LTG) is a widely prescribed neurological agent with Class IB antiarrhythmic properties at therapeutically r...BACKGROUND: Drug-induced atrial fibrillation (AF) is recognized as an important causal association. Lamotrigine (LTG) is a widely prescribed neurological agent with Class IB antiarrhythmic properties at therapeutically relevant concentrations. The United States Food and Drug Administration has issued a warning for a higher risk of LTG proarrhythmic events in patients with structural heart disease (SHD) and/or myocardial ischemia. This study evaluated the incidence of AF with LTG use. METHODS: A retrospective observational study was performed using a large healthcare claims database of adult participants analyzing 2 years AF incidence. The analytic cohort included adult participants with bipolar I disorder (BPD), partial seizures (PSZ), or generalized tonic-clonic seizures (GTSZ). Exposure to LTG was compared with commonly prescribed alternative agents as the control comparators (CTR). Participants were free from supraventricular or ventricular arrhythmias during the 6 months baseline period prior to the index LTG or CTR date. Kaplan-Meier estimator calculated 2 years cumulative AF incidence, with participants censored at last enrollment, treatment switching, or discontinuation. The AF association hazard ratios (HR) for LTG versus CTR were adjusted for baseline characteristics. RESULTS: The analytic cohort with BPD, PSZ, and GTSZ consisted, respectively, of 150,470 LTG versus 204,704 CTR, 9565 LTG versus 21,595 CTR, and 5505 LTG versus 15,513 CTR patients. In a predominantly middle-aged female population at baseline, the prevalence of cardiovascular conditions was low. The 12 months cumulative incidence of AF for LTG versus CTR was 0.764% versus 0.642% among BPD, 0.833% versus 0.646% among PSZ, and 0.585% versus 0.338% among GTSZ, respectively. The adjusted 365-day HR [95% confidence interval CI] of AF for LTG versus CTR in the BPD, PSZ, and CTSZ groups was 1.257 [1.088-1.453], 1.651 [1.104-2.468], and 1.451 [0.770-2.734], respectively. CONCLUSIONS: In adult AF-naïve participants, LTG has a strong association with increased AF risk compared with commonly prescribed alternatives.
Finch NA, Granillo A, Pouya N
… +3 more, Bhimraj A, Miller WR, Tam VH
Pharmacotherapy
· 2025 Jan · PMID 39629915
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OBJECTIVE: Cefiderocol is a novel antibiotic used to treat multidrug-resistant bacterial infections. However, there is limited data on its effectiveness for ventriculitis. The objective of this study was to evaluate cefi...OBJECTIVE: Cefiderocol is a novel antibiotic used to treat multidrug-resistant bacterial infections. However, there is limited data on its effectiveness for ventriculitis. The objective of this study was to evaluate cefiderocol concentrations in both serum and cerebrospinal fluid (CSF) during the treatment of ventriculitis. METHOD: A 54-year-old patient with carbapenem-resistant Acinetobacter baumannii ventriculitis was given cefiderocol intravenously 2 g every 6 h (each dose administered over 3 h). Serial samples were obtained over a dosing interval at steady state, and cefiderocol concentrations in serum and CSF were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cefiderocol serum concentration-time profile was characterized by a one-compartment model with zero-order input. Penetration into CSF was estimated as the CSF AUC/unbound serum AUC ratio. RESULTS: Observed total serum concentrations ranged between 24.6 and 76.7 mg/L, while CSF concentrations were approximately 10.0 mg/L. The AUC of the free drug in serum and CSF were 181.6 and 60.2 mg h/L, respectively. CONCLUSION: We observed minimal fluctuation of cefiderocol concentrations in CSF, questioning the conventional reliance on CSF/serum area under the curve (AUC) ratio as a measure of CNS penetration. Our experience suggests that a single CSF concentration (random or trough) could be directly compared to the minimum inhibitory concentration, offering a potentially simpler approach to evaluate dosing adequacy.