Pharmacotherapy [JOURNAL]
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200 papers
Prescription Sequence Symmetry Analysis for Detection of Chronic Opioid Use Adverse Event Signals Using Administrative Claims Data.
Polychronopoulou E, Raji MA, Kuo YF
Pharmacotherapy · 2025 Dec · PMID 41246890 · Full text
INTRODUCTION: Opioids are commonly used to manage chronic pain in older adults, despite their well-documented adverse events (AEs) and the potential for additional less well-known risks. Post-marketing surveillance metho...
INTRODUCTION: Opioids are commonly used to manage chronic pain in older adults, despite their well-documented adverse events (AEs) and the potential for additional less well-known risks. Post-marketing surveillance methods applied in real-world settings are essential to monitor AEs. Prescription Sequence Symmetry Analysis (PSSA) is a method that compares medication initiation patterns within individuals and can detect signals of prescribing cascades and drug AEs. This study applied PSSA to Medicare claims data to explore potential AEs following the initiation of long-term opioid therapy (LOT). METHODS: We used Texas-Medicare data to identify adults who initiated LOT (≥ 90 consecutive days) in 2016-2019. Prescription sequence symmetry analysis (PSSA) was performed to explore associations between opioids and related adverse events treated by marker drugs. The observation period for sequences of incident marker drug prescriptions was limited to 12 months before and after opioid initiation. Marker drugs were categorized based on the Anatomical Therapeutic Chemical (ATC) Classification System. Adjusted sequence symmetry ratios (aSSR) and 95% confidence intervals were calculated to account for prescribing trend changes. RESULTS: Among 11,233 incident opioid users, we identified incident marker drugs belonging to 145 distinct ATC classes, 36 of which had statistically significant aSSRs. We found signals of increased post-opioid prescriptions related to known opioid AEs (e.g., propulsives, antiemetics, laxatives, naltrexone) and less well-documented associations (antimicrobials, hormones, antiarrhythmics, and antipsychotics). CONCLUSIONS: PSSA applied to administrative claims data effectively identified both expected and potentially underrecognized adverse effects of long-term opioid use. This approach can enhance post-marketing surveillance by uncovering real-world prescribing cascades in older adults.
External Validation of the Fraser Equation for Estimation of Free Valproate Concentrations in Critically Ill Adults.
Webb AJ, Brown CS, Liu J … +5 more , Riker RR, Lopez ND, Rosenthal ES, Zafar SF, Gagnon DJ
Pharmacotherapy · 2025 Dec · PMID 41246825 · Full text
BACKGROUND: Critically ill patients may be overexposed to valproate because altered protein binding leads to a disproportionate free valproate fraction. The Fraser equation was derived and internally validated to estimat...
BACKGROUND: Critically ill patients may be overexposed to valproate because altered protein binding leads to a disproportionate free valproate fraction. The Fraser equation was derived and internally validated to estimate critically ill patients' free valproate concentrations, but it requires external validation. METHODS: Adult intensive care unit (ICU) patients at two academic centers with concurrently measured free and total valproate concentrations were included. Free valproate concentrations were estimated using the Fraser equation which includes total valproate, albumin and BUN concentration, and whether the patient received propofol or aspirin. The primary outcome was Fraser equation performance, assessed using Bland-Altman methods. Comparative performance against estimates from the Doré equation (an alternative predictive equation), therapeutic concordance using a target free valproate range of 5-15 mg/L, and equation improvements were explored. RESULTS: Overall, 315 patients and 556 free-total valproate concentration pairs were included. The mean (±SD) age was 58 (±17) years and 90 (29%) patients were on valproate prior to hospital admission. The Fraser equation estimated free valproate concentrations were correlated with measured concentrations (r = 0.728) with a negative bias (mean bias -2.77 mg/L, 95% LOA -18.9, 13.4). The Fraser equation increasingly underestimated measured concentrations as measured concentrations increased. 71% of Fraser equation estimates were therapeutically concordant (e.g., estimate and measured both within reference range) compared to 61.9% of Doré estimates (p = 0.001). Fraser equation modifications led to minor performance improvements but did not overcome worsening underestimation with higher measured free valproate concentrations. CONCLUSION: The Fraser equation was moderately accurate and corresponded with an appropriate interpretation for 71% of free valproate concentrations. Worse underestimation with higher measured free valproate concentrations suggests direct measurement of free valproate concentrations is warranted. While the Fraser equation could complement therapeutic decision making at centers where direct free valproate measurements are unavailable or slow to return, its accuracy is currently insufficient to replace direct measurement.
Thromboembolic Risk of Thrombopoietin Receptor Agonists for Adult Primary Immune Thrombocytopenia: A Systematic Review and Meta-Analysis Integrating Randomized Controlled Trials and Prospective Evidence.
Dai MF, Chong GW, Xin WX … +12 more , Kong SS, Zhu JF, Zhong LK, Xu GQ, Jin XY, He CN, Wang TT, Mi XF, Luo L, Song ZJ, Ding HY, Fang L
Pharmacotherapy · 2025 Nov · PMID 41224244 · Publisher ↗
BACKGROUND: Although randomized controlled trials (RCTs) have established evidence regarding thromboembolic risks of thrombopoietin receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP) during short-term follow-up...
BACKGROUND: Although randomized controlled trials (RCTs) have established evidence regarding thromboembolic risks of thrombopoietin receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP) during short-term follow-up, the long-term risks remain uncertain. This meta-analysis integrates data from prospective studies and RCTs to provide a comprehensive evaluation of thromboembolic risks associated with TPO-RA therapy. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to January 23, 2025 for RCTs and prospective studies reporting thromboembolic events in patients treated with TPO-RAs. The primary outcome was the risk of any thromboembolism. Subgroup analyses separately assessed the incidence of venous and arterial thrombosis. Short-term (≤ 6 months) evidence was derived from RCTs, while long-term (6-12 months and > 12 months) evidence was supplemented by prospective studies. Data from RCTs were analyzed using the Peto odds ratio (OR) with 95% confidence intervals (CIs), and data from prospective studies were pooled to calculate the incidence of thromboembolic events. RESULTS: The analysis included 12 RCTs (involving 1530 patients) and 11 prospective studies (involving 1820 patients). TPO-RAs significantly increased thromboembolic risk compared to placebo in the short-term (0.72% vs. 0.23%, Peto OR = 3.25, 95% CI = 1.11-9.51, p = 0.03). Pooled results from prospective studies demonstrated thromboembolism incidence of 3.84% at 6 to 12 months and 5.59% beyond 12 months of treatment with TPO-RAs. The reported incidence of arterial thrombosis increased from 0.14% (≤ 6 months) to 1.51% (6-12 months), and further to 4.2% (> 12 months). Whereas the reported incidence of venous thrombosis increased from 0.18% (≤ 6 months) to 2.50% (6-12 months), and plateaued at 2.55% beyond 12 months. CONCLUSION: This analysis demonstrates that TPO-RAs therapy increases the risk of thromboembolism, with the risk of arterial events becoming particularly pronounced during long-term use. These findings highlight the need for individualized risk assessment and vigilant monitoring in patients receiving TPO-RAs.
Oritavancin for Treatment of Osteomyelitis: A Systematic Review and Meta-Analysis of Observational Studies.
Krsak M, Klimpl D, Mueller SW … +7 more , Morrisette T, Grimshaw AA, Chastain D, Steuber T, Sah R, Henao-Martinez AF, Molina KC
Pharmacotherapy · 2025 Nov · PMID 41224240 · Publisher ↗
BACKGROUND: Osteomyelitis (OM) is a complex inflammatory bone infection typically requiring prolonged antibiotic therapy. Oritavancin (ORI), a long-acting lipoglycopeptide with activity against biofilm-embedded pathogens...
BACKGROUND: Osteomyelitis (OM) is a complex inflammatory bone infection typically requiring prolonged antibiotic therapy. Oritavancin (ORI), a long-acting lipoglycopeptide with activity against biofilm-embedded pathogens, has emerged as a potential treatment option despite previous US Food and Drug Administration (FDA) warnings against its use in OM. METHODS: We conducted a systematic review and meta-analysis of observational studies in seven databases through August 8, 2024 (PROSPERO registration: CRD42025635473) to evaluate the available evidence on ORI's efficacy and safety in OM. Clinical success was defined as the improvement or resolution of infection without requiring additional gram-positive antibiotics, surgical debridement, or amputation. Study quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Our systematic review included nine observational studies comprising 316 patients with OM treated with ORI. Quality assessment using the Newcastle-Ottawa Scale revealed scores ranging from 5/9 to 8/9, with most studies demonstrating adequate outcome assessment but limitations in cohort selection and comparability. Meta-analysis demonstrated a pooled clinical success rate of 81% (95% CI: 76%-85%). Comparative analysis of two studies yielded an odds ratio of 2.99 (95% CI: 0.86-10.36) favoring ORI over comparators (daptomycin and dalbavancin), though with substantial heterogeneity (I = 80.2%, p = 0.0247). CONCLUSIONS: Despite previous warnings, we found no evidence of ineffectiveness with ORI for OM. ORI's infrequent dosing schedule may provide convenience over daily parenteral therapy, particularly for difficult-to-treat pathogens like MRSA and VRE. Further research is needed to optimize dosing strategies based on pathogen susceptibility and establish appropriate therapeutic drug monitoring protocols.
Comparison of Subcutaneous Versus Intravenous Filgrastim in Autologous Hematopoietic Stem Cell Transplantation: A Retrospective Study.
Chang G, Nguyen J, Sampson E … +1 more , Pon D
Pharmacotherapy · 2025 Nov · PMID 41218615 · Publisher ↗
PURPOSE: Filgrastim is administered to shorten the duration of chemotherapy-induced neutropenia. Filgrastim can be administered intravenously or subcutaneously, but different routes of administration may result in differ...
PURPOSE: Filgrastim is administered to shorten the duration of chemotherapy-induced neutropenia. Filgrastim can be administered intravenously or subcutaneously, but different routes of administration may result in different pharmacokinetic properties, which may affect efficacy. The primary objective of this study was to determine if subcutaneous (SQ) filgrastim would be associated with a shorter time to neutrophil recovery in patients with myeloma undergoing autologous hematopoietic stem cell transplantation (autoHSCT) when compared to intravenous piggyback (IVPB) filgrastim. METHODS: This was a single-center, retrospective cohort study of patients undergoing autoHSCT for myeloma admitted and discharged between 2018 and 2019. The primary outcome was the mean number of days from transplant day 0 to absolute neutrophil count (ANC) greater than 500 cells/μL. Secondary outcomes were the incidence of and mean number of days of gram-negative antibiotic treatment and 30-day mortality. RESULTS: A total of 196 patients with myeloma met the inclusion criteria. No significant differences in time to neutrophil recovery between IVPB and SQ filgrastim were observed (11.0 ± 0.7 days vs. 10.8 ± 0.8 days, p = 0.15, respectively). No significant differences were observed in any of the secondary outcomes between IVPB and SQ filgrastim. CONCLUSION: In patients with myeloma undergoing autoHSCT, no differences in time to neutrophil recovery, incidence of or duration of gram-negative antibiotic treatment, or 30-day mortality were observed between IVPB and SQ routes of filgrastim administration.
Utilizing Machine Learning to Identify Predictors of Corticosteroid Discontinuation 1-Year After Adult Heart Transplant.
Chen C, Jedeon Z, Jaiswal A … +3 more , Baran DA, Etts K, Baker WL
Pharmacotherapy · 2026 Jan · PMID 41218614 · Publisher ↗
OBJECTIVE: To use machine learning methods to identify factors associated with corticosteroid (CS) discontinuation 1 year after adult heart transplantation (HT). DESIGN: Retrospective, observational, cohort study. DATA S...
OBJECTIVE: To use machine learning methods to identify factors associated with corticosteroid (CS) discontinuation 1 year after adult heart transplantation (HT). DESIGN: Retrospective, observational, cohort study. DATA SOURCE: This study used data from the United Network for Organ Sharing (UNOS) database. PATIENTS: We included adults (age ≥ 18 years) who underwent their first HT between January 2000 and December 2023 in the UNOS database with follow-up through December 2024, who were discharged on a CS. MEASUREMENTS: We divided the cohort into those with or without CS at 1-year post-transplant follow-up. We used the eXtreme Gradient Boosting (XGBoost) algorithm to build a model predicting CS discontinuation at 1 year. Relevant recipient, donor, and transplant variables were included to train the model, with Shapley Additive Explanations (SHAP) used to identify and interpret the most important and predictive features. RESULTS: We identified 72,730 HT recipients; 13,017 (17.9%) had CS discontinued within the first year. Compared with the CS cessation group, those who continued CS were more likely to have had a lower BMI, lower ischemic etiology of cardiomyopathy, lower intra-aortic balloon pump (IABP) and left ventricular assist device (LVAD) use before HT, better renal function, and sustained longer donor ischemic time. Model performance was strong, with an area under the curve of 0.854 (95% confidence interval: 0.848-0.861). Lower average transplant center volume (number of transplants per year), shorter donor ischemic time, and LVAD use at transplant predicted CS discontinuation. CONCLUSIONS: In a large national database, utilizing novel ML modeling techniques, we identified annual transplant center volume, donor ischemia time, and LVAD use at the time of HT as the best predictors of CS discontinuation 1 year after HT.
Impact of Gabapentin as a Benzodiazepine-Sparing Medication During Acute Alcohol Withdrawal.
Cordell WG, Surbaugh LA, Inman K … +3 more , Grauer D, Stewart M, Knutson J
Pharmacotherapy · 2025 Nov · PMID 41218601 · Publisher ↗
BACKGROUND: Abrupt cessation of alcohol consumption after prolonged periods of use leaves patients at risk for experiencing withdrawal symptoms. Alcohol is a central nervous system depressant that increases the activity...
BACKGROUND: Abrupt cessation of alcohol consumption after prolonged periods of use leaves patients at risk for experiencing withdrawal symptoms. Alcohol is a central nervous system depressant that increases the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and suppresses the activity of the excitatory neurotransmitter glutamate. Stopping consumption of alcohol reduces this inhibitory response and leads to a net excitatory state and symptoms of withdrawal, including anxiety, tremors, and even seizures. Benzodiazepines have traditionally been the treatment of choice for patients with alcohol withdrawal. Gabapentin has recently been studied as an adjunctive agent for the treatment and prevention of alcohol withdrawal, given its structural similarity to GABA and lower risk for dependence compared with benzodiazepines. OBJECTIVE: The primary objective of this study was to determine if a gabapentin-based regimen is benzodiazepine-sparing in patients experiencing alcohol withdrawal. METHODS: This was a retrospective, single center, pre- and post-implementation analysis of a gabapentin taper-based alcohol withdrawal protocol in place of a traditional benzodiazepine-based protocol used in patients admitted to a large, urban academic medical center in the Midwest for alcohol withdrawal between January 1, 2017, and January 1, 2023. The primary outcome was a comparison of cumulative benzodiazepine dose (in lorazepam equivalents) received throughout admission between groups. RESULTS: This study included 200 patients with 100 patients in each of the pre- and post-implementation groups. Baseline characteristics were similar between groups except for baseline serum alcohol level, which was higher in the pre-implementation group. Patients in the post-implementation group on average were exposed to 9.7-mg lorazepam equivalents during admission compared with 22.8-mg lorazepam equivalents in the pre-implementation group (p = 0.001). Patients between groups had similar symptom progression as characterized by average daily alcohol withdrawal assessment scale (AWAS) scores and length of stay. CONCLUSION: Utilization of a gabapentin taper resulted in significantly lower cumulative exposure to benzodiazepines and similar clinical outcomes in patients admitted for acute alcohol withdrawal.
Pharmacokinetics of Ceftolozane/Tazobactam in Patients With Partial- and Full-Thickness Skin Burns.
Hall RG, Hooper L, Dissanaike S … +5 more , Griswold JA, Kallem RR, Subramaniyan I, Putnam WC, Pai MP
Pharmacotherapy · 2025 Nov · PMID 41212678 · Publisher ↗
INTRODUCTION: Patients with burns are at an increased risk of multidrug-resistant pathogens including Pseudomonas aeruginosa and may need specialized dosing regimens due to alterations in physiology due to their injuries...
INTRODUCTION: Patients with burns are at an increased risk of multidrug-resistant pathogens including Pseudomonas aeruginosa and may need specialized dosing regimens due to alterations in physiology due to their injuries. METHODS: Therefore, we conducted a single-dose, open-label, pharmacokinetic study of ceftolozane (2 g)/tazobactam (1 g) infused over 60 min in six patients with partial- or full-thickness burns and central line access. Serial blood samples were obtained at the following time points: 0 (predose) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 h following the start of infusion for determination of plasma drug concentrations. RESULTS: Similar estimates of clearance (CL) were observed between the groups, and as a consequence the half-life (T1/2) was longer in the six patients with burns in the current study compared to previous studies of healthy volunteers on average. Although these mean comparisons suggest similarity in exposure based on area under the curve (AUC) and maximum concentration (Cmax), it is important to recognize that the interindividual variability is approximately 2- to 5-fold higher in patients with burns compared to healthy volunteers. CONCLUSIONS: We did not find sufficient deviations in the concentrations of ceftolozane/tazobactam to recommend an empiric dose adjustment for patients with burns. However, this finding is limited by our small sample size and lack of clinical outcome data. Therefore, we also provide a conditional recommendation to conduct therapeutic drug monitoring to adjust ceftolozane/tazobactam dosing or to switch to a continuous infusion approach in cases of a suboptimal clinical response.
Developing New Drugs for the COVID-19 Emergency: Anatomy of the U.S. Response.
Moore TJ, Socal MP, Anderson G
Pharmacotherapy · 2025 Nov · PMID 41123220 · Full text
CONTEXT: To meet the need for effective treatments during the COVID-19 Public Health Emergency, the U.S. government sought to accelerate the discovery and development of new antiviral treatments-a process that normally t...
CONTEXT: To meet the need for effective treatments during the COVID-19 Public Health Emergency, the U.S. government sought to accelerate the discovery and development of new antiviral treatments-a process that normally took 4-12 years. The government changed many features of the established system, selecting the investigational drugs, sponsoring or conducting the clinical testing, and purchasing and managing the distribution of the successful products. METHODS: We focused on novel therapeutic agents for COVID-19 that were funded, clinically tested, and/or received Emergency Use Authorization during the Public Health Emergency from January 2020 to May 2023. The primary sources were the public records of the National Institutes of Health, the U.S. Food and Drug Administration, and the Biomedical Advanced Research and Development Authority. Excluded were vaccines, devices, diagnostic tests, and new indications for approved drugs. RESULTS: In less than 24 months, the emergency program developed, tested, approved, and distributed eight new therapeutic products, including six monoclonal antibodies and two new oral antivirals. In addition, 11 other investigational agents were funded or tested under the emergency program but did not receive Emergency Use Authorization. More than 30 million courses of treatment were distributed at a cost of $29 billion or $881 per patient. By the end of the emergency, viral mutations and rapidly growing population immunity rendered the new products ineffective in almost all patients. CONCLUSIONS: The emergency program was dramatically effective in finding and testing new drug treatments using a variety of clinically relevant endpoints and serving varied patient populations. Planning for future pandemics should include a global network of clinical testing centers that were key to a rapid response. Research is needed to discover more durable antiviral treatments, especially in settings where mutation and population immunity are subject to rapid change.
High-Throughput Screening for Prescribing Cascades Among Real-World Angiotensin-II Receptor Blockers (ARBs) Initiators.
Ndai AM, Smith K, Keshwani S … +9 more , Choi J, Luvera M, Beachy T, Calvet M, Pepine CJ, Schmidt S, Vouri SM, Morris EJ, Smith SM
Pharmacotherapy · 2025 Nov · PMID 41117512 · Full text
OBJECTIVE: Angiotensin-II Receptor Blockers (ARBs) are commonly prescribed; however, their adverse events may prompt new drug prescriptions, known as prescribing cascade (PC). We aimed to identify potential ARB-induced P...
OBJECTIVE: Angiotensin-II Receptor Blockers (ARBs) are commonly prescribed; however, their adverse events may prompt new drug prescriptions, known as prescribing cascade (PC). We aimed to identify potential ARB-induced PCs using high-throughput sequence symmetry analysis. METHODS: Using claims data from a national sample of Medicare beneficiaries (2011-2020), we identified new ARB users aged ≥ 66 years with continuous enrollment ≥ 360 days before and ≥ 180 days after ARB initiation. We screened for initiation of 446 other (non-antihypertensive) "marker" drug classes within ±90 days of ARB initiation. Sequence ratios (SRs) with 95% confidence intervals (CIs) were calculated as the ratio of the number of ARB users initiating the marker class after versus before ARB initiation. Adjusted SRs (aSRs) accounted for prescribing trends over time, and for significant aSRs, we calculated the naturalistic number needed to harm (NNTH); significant signals were reviewed by clinical experts for plausibility. RESULTS: We identified 320,663 ARB initiators, age (mean ± standard deviation) 76.0 ± 7.2 years; 62.5% female; and 91.5% with hypertension. Of the 446 marker classes evaluated, 17 signals were significant, and three (18%) were classified as potential PCs after clinical review. The strongest signals ranked by the lowest NNTH included benzodiazepine derivatives (NNTH 2130, 95% CI 1437-4525), adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (NNTH 2656, 95% CI 1585-10,074), and other antianemic preparations (NNTH 9416, 95% CI 6606-23,784). The strongest signals ranked by highest aSR included other antianemic preparations (aSR 1.7, 95% CI 1.19-2.41), benzodiazepine derivatives (aSR 1.18, 95% CI 1.08-1.3), and adrenergics in combination with anticholinergics, including triple combinations with corticosteroids (aSR 1.12, 95% CI 1.03-1.22). CONCLUSION: The identified PC signals reflected known and possibly under-recognized ARB adverse events in this Medicare cohort. These hypothesis-generating findings require further investigation to determine the extent and impact of these PCs on patient outcomes.
In Search of Big Beautiful Biomarkers.
DeVane CL
Pharmacotherapy · 2025 Oct · PMID 41099492 · Publisher ↗
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Kidney Damage Biomarkers: A Missing Piece of the Diagnostic and Management Puzzle for Acute Drug-Related Kidney Diseases.
Kane-Gill SL
Pharmacotherapy · 2025 Nov · PMID 41090380 · Publisher ↗
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Identifying Pediatric Drug Safety Knowledge Gaps: An Integrated Approach Leveraging Real-World Data, a Biomedical Knowledge Base, and Postmarketing Surveillance Data.
Rahurkar S, Ouyang J, Jonnalagadda P … +6 more , Liu X, Zhang S, Chiang CW, Wang L, Shendre A, Li L
Pharmacotherapy · 2025 Oct · PMID 41031721 · Full text
BACKGROUND: Drug safety has historically been understudied in pediatric populations, rendering them "therapeutic orphans." Pediatric drug indications and dosages are often inferred by extrapolating safety, efficacy, and...
BACKGROUND: Drug safety has historically been understudied in pediatric populations, rendering them "therapeutic orphans." Pediatric drug indications and dosages are often inferred by extrapolating safety, efficacy, and dosing data from adult studies, leading to widespread off-label use. However, this approach fails to account for age-specific differences in disease pathophysiology and developmental pharmacokinetics (PK). Despite evidence that adverse drug events (ADEs) manifest with greater severity in pediatric populations than in adults, fewer than 50% of drugs have been systematically studied for pediatric use. The lack of robust drug safety data may result in suboptimal or harmful treatment strategies. METHODS: We used a data-driven approach that integrated three databases -including Merative MarketScan claims, the Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledgebase (including 670,185 pediatric pharmacoepidemiology, PK, and clinical trial publications on 5062 drugs), the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, a postmarketing safety surveillance database), and FDA drug label data- to identify high-impact target. High-impact targets were defined as drugs that have a high prescription volume, limited safety evidence and high risk of serious ADEs. RESULTS: With 229,550 prescriptions in MarketScan, only 9 studies, and almost 50 high risk serious ADEs benzonatate was identified as a high-impact drug of concern. Serious ADEs included seizure, death, and arrhythmia with proportional reportion ratios (PRRs) ranging from 4.3 to 477.8. CONCLUSION: Approved in 1958, Benzonatate, a nonnarcotic antitussive agent has a limited safety evidence with only nine PE/PK publications in six decades. Moreover, it is frequently prescribed off-label for cough relief despite questionable effectiveness, and high-risk of serious ADEs. Our findings reveal a disconnect between clinical practice and suppporting safety evidence. As such, there is critical need to study the safety of this drug using emerging real-world data for real-world evidence. In summary, this study presents an approach that is systematic, objective, reproducible, and data driven to identify and prioritize drug-ADE combinations with limited evidence.
Acute Pharmacodynamic Effects of Oral Levodopa on Blood Pressure in Parkinson's Disease.
Longardner K, Liu C, Momper J … +5 more , Mahato K, Moonla C, Ghodsi H, Wang J, Litvan I
Pharmacotherapy · 2025 Nov · PMID 41031701 · Full text
BACKGROUND: Levodopa decreases blood pressure (BP) in persons with Parkinson's disease (PwP), but no pharmacodynamic studies integrating systemic levodopa concentration measurements have characterized its hypotensive eff...
BACKGROUND: Levodopa decreases blood pressure (BP) in persons with Parkinson's disease (PwP), but no pharmacodynamic studies integrating systemic levodopa concentration measurements have characterized its hypotensive effects. Understanding this relationship is clinically relevant for guiding therapeutic decisions, such as how aggressively to treat hypotension before initiating or increasing levodopa. In this pilot study, we aimed to determine the acute pharmacodynamic effects of oral immediate-release carbidopa/levodopa on BP in PwP. METHODS: PwP taking chronic oral carbidopa/levodopa with baseline BP ≥ 90/60 mmHg were recruited. Participants withheld antiparkinsonian medications overnight prior to the study visit and received carbidopa/levodopa immediate-release tablets at time 0. Capillary blood levodopa levels, seated BP measurements, and motor symptom assessments were performed at baseline and repeated every 10 min for 70-100 min. Non-compartmental pharmacokinetic parameters of levodopa were determined, including the area under the curve up to the last time point (AUC), maximum concentration (C), and time to maximum concentration (T). RESULTS: Fourteen PwP were enrolled (mean age 69.5 ± 7.6 years, six females). Two participants had orthostatic hypotension at baseline (defined as a sustained drop in systolic BP ≥ 20 mmHg or diastolic BP ≥ 10 mmHg within 3 min of standing), and six were taking antihypertensive medications. Mean arterial pressure (MAP) declined during the study from an average of 105 ± 13.1 mmHg at baseline to a nadir of 84 ± 15.8 mmHg. The maximum MAP drop occurred at 100 min post-dose. Cumulative levodopa AUC negatively correlated with MAP (Pearson's r = -0.30; p = 0.00036). CONCLUSIONS: Oral levodopa is associated with acute hypotension in PwP, and levodopa exposure is inversely correlated with MAP. These effects should be considered when adjusting levodopa dosing, particularly in patients with hypotension, to improve safety outcomes.
Nephrocast-V: A Deep Learning Model for the Prediction of Vancomycin Trough Concentration Using Electronic Health Record Data.
Ghanbari G, Stevens C, Aronoff-Spencer E … +3 more , Malhotra A, Nemati S, Yousif Z
Pharmacotherapy · 2026 Jan · PMID 41025800 · Full text
INTRODUCTION: Vancomycin is a critical antibiotic for treating methicillin-resistant Staphylococcus aureus and other gram-positive bacterial infections, but achieving and maintaining therapeutic trough concentrations is...
INTRODUCTION: Vancomycin is a critical antibiotic for treating methicillin-resistant Staphylococcus aureus and other gram-positive bacterial infections, but achieving and maintaining therapeutic trough concentrations is challenging. OBJECTIVES: We hypothesized that a deep learning model could accurately predict vancomycin trough concentrations 2 days in advance in critically ill patients and provide recommendations for optimal dosing adjustments to achieve target drug concentrations. METHODS: We trained and validated the model using electronic health record (EHR) data from adults admitted to the University of California San Diego Health system intensive care units (ICUs) from January 1, 2016, to June 30, 2024. Features included patient demographics, comorbidities, vital signs, laboratory measurements, medications, and vancomycin dosing information. The model architecture combined Long Short-Term Memory and Multi-Head Attention layers, supplemented with skip connections to incorporate past dosage information at the final layer of the deep learning model. Model performance was evaluated using mean absolute error (MAE) and root mean square error (RMSE) metrics. RESULTS: A total of 2205 encounters met the eligibility criteria. The median age was 57 years, and the median ICU length of stay was 4.9 days. The model achieved an MAE of 3.15 mg/L and an RMSE of 4.17 mg/L, comparable to that of a critical care pharmacist aided by a Bayesian dosing software. Additionally, deviations from patient-specific model-based dose recommendations were generally associated with nontherapeutic vancomycin levels. CONCLUSION: This study demonstrates the potential to leverage deep learning to individualize and support vancomycin therapeutic drug monitoring in critically ill patients.
Focusing on an EEG Biomarker, the Photoparoxysmal Response (PPR), to Identify Promising Investigational Anti-Seizure Medications (ASMs) and Differentiate the Efficacy of Existing ASMs.
Reed RC, Kasteleijn-Nolst Trenite DGA
Pharmacotherapy · 2025 Oct · PMID 41024690 · Full text
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Lithium Augmentation in Treatment-Resistant Depression: A Qualitative Review of the Literature.
Acero-González A, Guzman Y, Proaños NJ … +6 more , Bustos RH, Aconcha M, Guerrero I, Martinez LA, Berk M, Dodd S
Pharmacotherapy · 2025 Oct · PMID 40985502 · Full text
Depression is the leading cause of disability worldwide, affecting people of all ages. Both pharmacological and non-pharmacological therapies are available for its treatment. However, some patients do not respond to firs...
Depression is the leading cause of disability worldwide, affecting people of all ages. Both pharmacological and non-pharmacological therapies are available for its treatment. However, some patients do not respond to first-line pharmacological interventions, referred to as treatment-resistant depression (TRD). Individuals with TRD face a significantly higher risk of mortality, including an increased risk of suicide. Additionally, TRD poses a substantial economic burden on health care systems. Various treatment options have been explored for TRD, including augmentation of an antidepressant through the use of an additional agent. Lithium salts have shown promising benefits in the TRD. Lithium requires close therapeutic monitoring due to its narrow therapeutic range, with well-defined thresholds for efficacy and toxicity, in addition to its pharmacokinetic characteristics. Furthermore, lithium has been associated with a reduced risk of mortality by lowering aggression, impulsivity, and suicide rates. Compared with other agents used in the management of TRD-such as atypical antidepressants, second-generation antipsychotics (SGAs), ketamine, and thyroid hormones-lithium is considered a cost-effective augmentation option, alongside other evidence-based strategies, and has a well-established efficacy profile. This literature review examines the role of lithium as an augmentation agent in TRD, with a focus on its pharmacological and clinical properties, as well as the current evidence supporting its use.
Synthetic Data-Driven Early Prediction Framework for Acute Kidney Injury in Patients Receiving Vancomycin and Ceftazidime/Avibactam.
Ramazani M, Brothers T, Ahmed I … +1 more , Al-Mamun MA
Pharmacotherapy · 2026 Jan · PMID 40985484 · Publisher ↗
BACKGROUND: The nephrotoxic risks of combining ceftazidime/avibactam (AVI) with vancomycin (VAN) remain underexplored, despite both agents independently being linked to acute kidney injury (AKI). This study assessed the...
BACKGROUND: The nephrotoxic risks of combining ceftazidime/avibactam (AVI) with vancomycin (VAN) remain underexplored, despite both agents independently being linked to acute kidney injury (AKI). This study assessed the risk of AKI associated with concurrent VAN and ceftazidime/avibactam (VAN-AVI) therapy and developed synthetic data models to enable early prediction of AKI. METHODS: We conducted a retrospective analysis using electronic health record data from hospitalized adults between 2015 and 2022. The incidence of AKI was compared among patients receiving VAN-AVI or VAN in combination with piperacillin/tazobactam (VAN-TPZ) versus VAN monotherapy. AKI was defined as a composite of de novo and recurrent AKI (i.e., patients had a prior diagnosis of AKI within the preceding 6 months and experienced a new AKI event after 7 days of VAN-AVI initiation). To address sample size imbalance, we applied inverse probability of treatment weighting (IPTW) and generated synthetic datasets using Conditional Tabular Generative Adversarial Networks (CTGAN) and Tabular Variational Autoencoders (TVAE). These synthetic datasets were subsequently used to augment machine learning (ML) models aimed at the early prediction of AKI in patients treated with VAN-AVI combination therapy. RESULTS: Among the 92 patients receiving VAN-AVI combination therapy, only four (4.3%) patients experienced new-onset AKI, and 66 (71.7%) patients had a recurrent AKI. After applying IPTW, VAN-AVI was associated with a higher risk of AKI Hazard Ratio (HR) = 3.47; 95% Confidence Interval (CI): 1.97-6.11, followed by VAN-TPZ (HR = 1.96; 95% CI: 1.37-2.81), compared to VAN alone. Synthetic data analyses conducted over 1000 iterations supported these findings, with mean HRs for VAN-AVI of 3.80 using TVAE and 4.45 using CTGAN. ML models augmented with synthetic data outperformed those using original data alone. For 30-day AKI prediction, F1-scores improved across all models, with the highest performance observed in the augmented XGBoost and logistic regression classifier (F1 = 0.80). CONCLUSION: This study introduces a novel approach that integrates IPTW with synthetic data generation to evaluate drug-associated AKI risk in small-sample cohorts. Although our findings demonstrate a lower incidence of de novo AKI in the VAN-AVI group, the use of synthetic data and augmented ML models significantly improved early AKI prediction. These findings support the potential utility of synthetic data frameworks for scalable drug safety evaluations, although further validation is warranted.
Association of Omeprazole-Related Myopathy With Drug-Drug and Drug-Gene Interactions Involving CYP2C19 and CYP3A4: A Nested Case-Control Study.
Jeong E, Shendre A, Su Y … +3 more , Guo X, Li L, Chen Y
Pharmacotherapy · 2025 Oct · PMID 40916919 · Full text
BACKGROUND: Omeprazole, a widely used proton pump inhibitor, has been associated with rare but serious adverse events such as myopathy. Previous research suggests that concurrent use of omeprazole with fluconazole, a pot...
BACKGROUND: Omeprazole, a widely used proton pump inhibitor, has been associated with rare but serious adverse events such as myopathy. Previous research suggests that concurrent use of omeprazole with fluconazole, a potent cytochrome P450 (CYP) 2C19/3A4 inhibitor, may increase the risk of myopathy. However, the contribution of genetic polymorphisms in CYP enzymes remains unclear. AIMS: This study leveraged electronic health record (EHR) and biobank data to validate an interaction between omeprazole and fluconazole and to explore drug-gene interactions (DGIs) between omeprazole and polymorphisms in CYP enzymes. MATERIALS AND METHODS: A nested case-control design with incidence-density matching was used. Cases were defined as patients who developed myopathy during ongoing omeprazole therapy. For each case, up to four controls were selected from patients who had not developed myopathy by the time the case was diagnosed. Conditional logistic regression models, adjusting for relevant covariates, evaluated (i) the association between concomitant fluconazole use and myopathy and (ii) genotype-stratified myopathy risk. RESULTS: Among 902 cases and 3608 controls, the combined use of omeprazole and fluconazole was linked to an increased risk of myopathy (adjusted odds ratio [AOR] = 1.75, 95% confidence interval [CI]: 1.17-2.63, p = 0.007). In the DGI analysis, which included 862 cases and 3448 controls, individuals classified as CYP2C19 poor metabolizers paired with CYP3A4 extensive metabolizers showed a significantly higher myopathy risk (AOR = 1.62, 95% CI: 1.03-2.55, p = 0.036); those with CYP2C19 poor metabolizer/CYP3A4 intermediate metabolizer had an even greater risk (AOR = 4.77, 95% CI: 1.74-13.1, p = 0.002). DISCUSSION: These findings not only confirm previously reported drug-drug interactions (DDIs) between omeprazole and fluconazole but also reveal the emerging clinical implications of DGIs. CONCLUSION: By integrating EHR and genetic data, the study showcases how informatics tools can translate DDI findings into DGI hypotheses, effectively bridging genetic insights and clinical outcomes.
The Use of Plasma Exchange for Clozapine Intoxication: A Case Report.
Peters BJ, Sullivan LY, Lange RL … +2 more , Jones KW, Baqir M
Pharmacotherapy · 2025 Oct · PMID 40916481 · Publisher ↗
We describe a case of a 56-year-old male who developed severe, refractory hypotension after an intentional ingestion of clozapine and who became hemodynamically stable after one session of therapeutic plasma exchange (TP...
We describe a case of a 56-year-old male who developed severe, refractory hypotension after an intentional ingestion of clozapine and who became hemodynamically stable after one session of therapeutic plasma exchange (TPE). The patient, who presented after an ingestion of clozapine, was found to have altered mental status and hypotension in the emergency department. Escalating catecholamine vasoactive agents were necessary to maintain adequate hemodynamics. Angiotensin II was added and rapidly up titrated in efforts to maintain adequate blood pressure. Due to persistent hemodynamic instability despite four vasoactive agents, TPE was attempted to enhance the elimination of the highly protein bound medication. Within 2 h of completing TPE, the catecholamines and vasopressin were stopped, and angiotensin II dosing was significantly decreased. This is the first report of utilizing TPE as a method of enhanced elimination of a toxic clozapine ingestion resulting in severe hemodynamic compromise. Further study is necessary to determine if TPE should be incorporated into the care of patients experiencing clozapine toxicity.
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