PURPOSE: Lacosamide is well known for its additional anti-seizure activity, especially during pregnancy when monotherapy of lamotrigine or levetiracetam fails in people with focal seizures. Pharmacokinetics change during...PURPOSE: Lacosamide is well known for its additional anti-seizure activity, especially during pregnancy when monotherapy of lamotrigine or levetiracetam fails in people with focal seizures. Pharmacokinetics change during pregnancy and limited results of changes in lacosamide plasma concentrations are available. METHODS: In this case series, 6 women were retrospectively studied in change of concentration dose ratios (C/D ratios) during pregnancy. RESULTS: We found that C/D ratios changed during the trimesters of pregnancy between 48% and 146% compared to baseline values. We couldn’t find a relationship between CD ratios (B=-36, 95%CI= -81-8.5, p-value = 0.10) or RTCs (B = -0.37, 95%CI = -1.3-0.54; p-value = 0.40) during pregnancy and the change in seizure frequency. In future larger datasets are necessary for further recommendations. CONCLUSION: We found that lacosamide concentrations changes during pregnancy, however in this small sample set variations were too high to draw firm conclusions.
OBJECTIVES: This study aims to assess the applicability of published polymyxin B population pharmacokinetics (PopPK) models in critically ill patients using an external dataset, with the goal of establishing an evidence-...OBJECTIVES: This study aims to assess the applicability of published polymyxin B population pharmacokinetics (PopPK) models in critically ill patients using an external dataset, with the goal of establishing an evidence-based framework to guide optimal model selection for precision dosing in clinical critical care practice. METHODS: Nine published PopPK models of polymyxin B were reconstructed. A validation dataset was compiled from data of critically ill patients receiving intravenous polymyxin B. The predictive performance was assessed based on predicted and simulated diagnosis and Bayesian forecasting. RESULTS: The data from 132 samples of 72 critically ill patients were collected as the validation dataset. In prediction-based diagnostics, none of the nine PopPK models met the criteria. In simulation-based diagnostics, although no model achieved full adequacy in the tests, four models showed acceptable normality in normalized prediction distribution error plots. Bayesian forecasting significantly improved the predictive performance across all models, particularly when ≥ 2 prior observations were available. Collectively, one model demonstrated good prediction performance. CONCLUSIONS: The integration of PopPK model with Bayesian forecasting provides a valuable approach for model-informed precision dosing of polymyxin B, facilitating the individualization of dosing regimens in critically ill patients.
INTRODUCTION: Spontaneous reporting systems are essential for post-marketing pharmacovigilance, enabling the identification of new adverse drug reactions (ADRs). However, differences in report origin, structure and compl...INTRODUCTION: Spontaneous reporting systems are essential for post-marketing pharmacovigilance, enabling the identification of new adverse drug reactions (ADRs). However, differences in report origin, structure and completeness may affect the effectiveness of signal detection. OBJECTIVE: To analyse the characteristics of ADR reports submitted in Spain between 2019 and 2023, comparing cases reported directly to the Spanish Pharmacovigilance System (SEFV) with those submitted via marketing authorisation holders (MAHs), and to identify areas for improvement in spontaneous reporting practices. METHODS: This was a retrospective analysis of individual case safety reports (ICSRs) included in the national database FEDRA. Reports were classified according to their origin (SEFV or MAH), seriousness, report type (spontaneous or study), reporter qualification, suspected ADR (MedDRA HLT level), and suspected drug (ATC classification and substance level). Additional approach was also carried out in SEFV cases, with the variables qualification reporter, seriousness and unknown adverse reactions. RESULTS: A total of 145,498 ICSRs were analysed, 62.4% submitted by MAHs and 38.1% by SEFV. Only 31% of MAH reports were serious compared to 45.9% of SEFV reports. Nearly half of MAH reports were from studies. The main reporter in MAH cases was the consumer, while physicians predominated in SEFV reports. Notably, 12.6% of serious SEFV reports submitted by consumers included unknown ADRs. CONCLUSION: Direct reporting to SEFV should be actively encouraged, as these reports show higher completeness and greater clinical relevance. This is particularly important for newly authorised medicines, which are predominantly reported via MAHs. Strengthening direct reporting pathways would improve signal detection.
Solhaug V, Waade RB, Jansrud L
… +4 more, Molden E, Størset E, Høiseth G, Tveito M
Eur J Clin Pharmacol
· 2025 Dec · PMID 41420713
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PURPOSE: While antipsychotic monotherapy is generally recommended in treatment of psychotic disorders, polytherapy is frequently observed in clinical practice. We aimed to investigate the total antipsychotic load among p...PURPOSE: While antipsychotic monotherapy is generally recommended in treatment of psychotic disorders, polytherapy is frequently observed in clinical practice. We aimed to investigate the total antipsychotic load among patients treated with olanzapine in monotherapy vs. polytherapy, and how the antipsychotic load changed in relation to age. METHODS: Patients with serum concentration measurements of olanzapine alone (monotherapy) or in combination with other antipsychotics (polytherapy) were retrospectively included from a therapeutic drug monitoring service. The antipsychotic load was measured as olanzapine dose and concentration equivalents. Patients were categorised into three age groups (18–49 years, 50–74 years and ≥ 75 years of age). RESULTS: In total, 10 190 patients (54% males) were included, whereof 8 759 (86%) received olanzapine in monotherapy and 1 431 (14%) in polytherapy. The mean olanzapine dose equivalent was significantly higher in the polytherapy group compared to the monotherapy group (23.0 vs. 11.1 mg, p < 0.001). Likewise, the mean concentration equivalent was higher in the polytherapy group than in the monotherapy group (179 vs. 89.1 nmol/L, p < 0.001). When comparing patients ≥ 75 years with patients 18–49 years, the mean dose equivalents were 43% and 41% lower in the monotherapy and polytherapy group, respectively (both p < 0.001), whereas the respective concentration equivalents were only 11% (p < 0.001) and 10% (p = 0.141) lower. CONCLUSION: Patients receiving olanzapine in antipsychotic polytherapy had twice as high antipsychotic load compared to patients using olanzapine monotherapy, both in terms of olanzapine dose and concentration equivalents. Although the antipsychotic doses were reduced by age, the concentration levels remained similar.
BACKGROUND: The relationship between early post-transplantation cyclosporine A (CsA) trough concentrations and the occurrence of acute graft-versus-host disease (aGVHD) was explored in 185 pediatric patients diagnosed wi...BACKGROUND: The relationship between early post-transplantation cyclosporine A (CsA) trough concentrations and the occurrence of acute graft-versus-host disease (aGVHD) was explored in 185 pediatric patients diagnosed with severe β-Thalassemia who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The time-weighted average (TWA) method was utilized to calculate the average of all CsA trough concentrations taken before aGVHD or within 30 days post-transplantation. RESULTS: It was found that TWA CsA trough exposure early post-transplantation was associated with grade II-IV aGVHD and grade III-IV aGVHD in univariate analysis and the Kaplan-Meier curves. After adjusting for potential confounders, multivariate analysis indicated that TWA CsA ≥ 150 µg/L was correlated with a reduced risk of grade II-IV aGVHD (P = 0.003; HR = 0.338; 95%CI, 0.167–0.685) and grade III-IV aGVHD (P = 0.012; HR = 0.203; 95%CI, 0.058–0.708). Notably, the optimal threshold concentration of CsA for preventing the onset of aGVHD in pediatric patients, was found TWA CsA ≥ 131 µg/L was associated with a lower risk of grade II-IV aGVHD (P < 0.001; HR = 0.271; 95%CI, 0.145–0.507, while a TWA CsA ≥ 135 µg/L was correlated with a lower risk of grade III-IV aGVHD (P = 0.002; HR = 0.190; 95%CI, 0.066–0.545). Upon comparing models with different thresholds, no significant improvement in performance was observed for models that incorporated relatively higher thresholds. CONCLUSIONS: This research indicates the initial CsA trough concentration post-transplantation significantly influences the development of aGVHD and children with severe β-Thalassemia undergoing allo-HSCT may not require CsA trough threshold concentrations as high as those required for adults.
Almås G, Stangebye M, Slørdal L
… +1 more, Spigset O
Eur J Clin Pharmacol
· 2025 Dec · PMID 41413334
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PURPOSE: Previous studies have questioned the integrity of drug promotional material from the pharmaceutical industry to medical professionals. Herein, we present the result of repeated monitoring of adherence to legal r...PURPOSE: Previous studies have questioned the integrity of drug promotional material from the pharmaceutical industry to medical professionals. Herein, we present the result of repeated monitoring of adherence to legal requirements regulating marketing mailings from pharmaceutical companies to Norwegian general practitioners over three separate time periods in 2004, 2012 and 2023-24. METHODS: The claims made in the mailings were compared to the sources cited and evaluated in accordance with the governmental regulations. Pertinent information about conflicts of interest was registered and considered. RESULTS: A considerable decline in the number of mailings acquired over time was noted. The proportion of claims defined as correct and clinically relevant according to the legal definition was 48%, 56% and 78% in 2004, 2012 and 2023-24, respectively (p < 0.001 for trend). The most common deviations were claims with unclear or no clinical relevance, information extrapolated beyond the actual content of the referenced material, claims not covered in the cited reference, and general claims not providing any meaningful information about the drug. In some cases, the citation of sources was incomplete, or the reference unobtainable. The percentage of references with declared conflicts of interest was relatively stable at about 60% over the entire period. CONCLUSION: Concomitant with a decline in the number of drug mailings aimed at general practitioners, there has been an increase in compliance with legislative measures regulating this activity. Nevertheless, there are still significant instances of deviations from the legal requirements, warranting skepticism.
Kaşkal M, Bucci T, Alobaida M
… +7 more, Lam SHM, Rossi M, Tartaglia E, Askarinejad A, Rigutini AG, Lip GYH, Burton RAB
Eur J Clin Pharmacol
· 2025 Dec · PMID 41407975
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BACKGROUND: Chronic pericarditis is associated with significant cardiovascular morbidity, including atrial fibrillation (AF), heart failure (HF), and stroke. Colchicine is widely used in pericarditis management for its a...BACKGROUND: Chronic pericarditis is associated with significant cardiovascular morbidity, including atrial fibrillation (AF), heart failure (HF), and stroke. Colchicine is widely used in pericarditis management for its anti-inflammatory effects, but its impact on arrhythmias and other cardiovascular outcomes remains uncertain. METHODS: We conducted a retrospective observational cohort study using the TriNetX global federated research network to assess the association between colchicine use and cardiovascular outcomes in in-patients with chronic pericarditis. Patients diagnosed with chronic adhesive and constrictive pericarditis with or without colchicine use between 2010 and 2024 were included. Propensity score matching (PSM) (1:1) was used to balance baseline characteristics. The primary outcome was 1-year incidence of AF. Secondary outcomes included all-cause mortality, ischemic stroke, acute myocardial infarction (AMI), acute HF, cardiac arrest, ventricular arrhythmias, and a composite cardiovascular outcome. RESULTS: Of 8,120 patients hospitalized with chronic pericarditis, 1,064 received colchicine. 1,061 patients were matched in each group after PSM. The 1-year incidence of AF was similar between colchicine users and non-users (HR: 0.90, 95% CI: 0.76–1.06) after PSM. Colchicine use was associated with significantly lower risk of all-cause mortality (HR: 0.67, 95% CI: 0.54–0.84) and ischemic stroke (HR: 0.45, 95% CI: 0.29–0.67) after PSM. No significant differences were observed for AMI, cardiac arrest, HF, or ventricular arrhythmias. CONCLUSION: In this real-world cohort of patients with chronic pericarditis, colchicine did not increase the risk of AF. Colchicine was linked to significantly lower risks of all-cause mortality and ischemic stroke in hospitalized chronic pericarditis patients, suggesting potential systemic cardiovascular benefits.
OBJECTIVE: to evaluate the impact of beta-blocker (BB) initiation, continuation, and withdrawal on in-hospital mortality in patients with severe acute decompensated heart failure (ADHF), particularly those presenting wit...OBJECTIVE: to evaluate the impact of beta-blocker (BB) initiation, continuation, and withdrawal on in-hospital mortality in patients with severe acute decompensated heart failure (ADHF), particularly those presenting with cardiogenic shock (CS). DESIGN: systematic review and meta-analysis. SETTING: cohort studies and randomized controlled trials (RCTs) published through December 31, 2024. PATIENTS OR PARTICIPANTS: adult patients with ADHF and CS. INTERVENTIONS: parenteral beta-blocker. MAIN VARIABLES OF INTEREST: in-hospital mortality. RESULTS: Sixteen studies (12 cohorts and 4 RCTs) comprising 23,947 patients were included. Among them, 3,215 presented with CS, and 1,246 died. Of the total population, 12,952 received BBs and 10,549 did not. Initiation of BBs in previously untreated patients with CS was not associated with a reduction in mortality (RR: 0.82; 95% CI: 0.64–1.04). Continuation of BBs in patients already receiving them at admission significantly reduced mortality by 49% (RR: 0.51; 95% CI: 0.43–0.61). In contrast, BB withdrawal was not associated with increased mortality risk (RR: 1.92; 95% CI: 0.37–10.09). CONCLUSIONS: In adult patients with ADHF and CS, continuing BB therapy appears to improve survival, while discontinuation may be harmful. Initiation of BBs in previously untreated patients might also offer benefits, although the evidence is inconclusive. These findings highlight the importance of individualized BB strategies in critically ill HF patients, though they should be interpreted with caution due to study heterogeneity.
PURPOSE: Deprescribing antihypertensive medications in older adults can prevent potentially serious adverse effects, especially in those who are frail. However, explicit clinical criteria to guide healthcare providers in...PURPOSE: Deprescribing antihypertensive medications in older adults can prevent potentially serious adverse effects, especially in those who are frail. However, explicit clinical criteria to guide healthcare providers in making such complex decisions are lacking. The aim of this study was to validate a set of proposed explicit clinical criteria for supporting the deprescribing of antihypertensive medications in older adults. METHODS: The modified Delphi consensus technique was employed in two stages using questionnaires to systematically gather and analyse expert opinions on explicit antihypertensive deprescribing criteria. RESULTS: Eight experts completed the first round of the Delphi technique and seven completed the second round. A strong consensus among the expert panel was achieved for most of the proposed clinical criteria. No consensus was reached on criteria involving target blood pressure levels for individuals aged 75 years and older, the presence of asymptomatic orthostatic hypotension, and the use of calcium channel blockers in cases of chronic constipation. CONCLUSION: The criteria validated in this study can be considered a decision support tool to avoid aggressive treatment and symptoms of hypotension in older adults.
Shang H, Mao H, Wang J
… +3 more, Tian X, Zheng K, Wang J
Eur J Clin Pharmacol
· 2025 Dec · PMID 41057541
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PURPOSE: This narrative review evaluates the clinical value of key globally marketed potassium-competitive acid blockers (P-CABs) for acid-related diseases (ARDs) based on current evidence-based medical research to infor...PURPOSE: This narrative review evaluates the clinical value of key globally marketed potassium-competitive acid blockers (P-CABs) for acid-related diseases (ARDs) based on current evidence-based medical research to inform clinical practice. METHODS: We compare P-CABs and proton pump inhibitors (PPIs) in terms of their mechanisms of acid suppression, speed of onset, metabolic pathways, and long-term safety. We present a detailed comparison of the clinical efficacy of individual P-CABs and PPIs for gastroesophageal reflux disease (GERD), peptic ulcers, and Helicobacter pylori (H. pylori) eradication, synthesizing findings from recent clinical trials and meta-analyses. RESULTS: This highlights the advantages of P-CABs, such as rapid acid control and the achievement of maximal efficacy with the first dose, as well as their reduced susceptibility to CYP2C19 polymorphisms. Evidence suggests that P-CABs have potential advantages in the initial and maintenance treatment of erosive esophagitis (EE). P-CABs demonstrate non-inferiority to PPIs in ulcer healing. For H. pylori eradication, P-CABs are comparable to PPIs in standard regimens; however, P-CAB-based dual therapy (e.g., P-CAB + high-dose amoxicillin) is emerging as a promising first-line treatment option. CONCLUSION: This review emphasizes the evolving role of P-CABs in optimizing management strategies for ARDs.
PURPOSE: Imatinib is the first-line therapy for gastrointestinal stromal tumor (GIST), significantly enhancing patient prognosis. However, its clinical efficacy and safety are highly dependent on plasma concentration, wh...PURPOSE: Imatinib is the first-line therapy for gastrointestinal stromal tumor (GIST), significantly enhancing patient prognosis. However, its clinical efficacy and safety are highly dependent on plasma concentration, which exhibits considerable interindividual variability. The purpose of this study is to determine the optimal monitoring time for imatinib concentration in postoperative patients with GIST, analyze single nucleotide polymorphisms affecting plasma concentration, and investigate their correlation with efficacy and adverse drug reactions (ADRs), offering valuable insights for personalized therapy. METHODS: This study was conducted on 116 postoperative patients with GIST treated with imatinib in China between 2014 and 2018. Imatinib peak and trough concentrations (C and C) were measured in 608 samples using liquid chromatography-tandem mass spectrometry to determine the optimal monitoring time for steady-state concentration. DNA was extracted from 60 patients' peripheral blood to Genotype 22 single nucleotide polymorphisms in genes such as CYP3A4, CYP3A5, ABCB1, SLC22A1, and SLC22A5 (OCTN2). Therapeutic efficacy was evaluated based on recurrence-free survival (RFS), and ADRs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Statistical analyses were performed using SPSS 26.0, with p < 0.05 considered statistically significant. RESULTS: The C and C of imatinib and its metabolite N-desmethyl imatinib reached their highest levels within the first month of treatment, and were stabilized by the third month. Genetic polymorphisms in ABCG2 (rs2231137), SLC22A1 (rs628031, rs3605065), and SLC22A5 (OCTN2) (rs2631372) were significantly associated with variations in imatinib C. Genetic polymorphisms in CYP3A5 (rs776746), ABCG2 (rs2231137), and SLC22A1 (rs755828176) influenced imatinib C. Patients carrying the CG and CC genotypes of SLC22A5 (OCTN2) (rs2631372) exhibited longer RFS and lower disease progression risk compared to those with the GG genotype (p < 0.05). Additionally, there was no significant correlation between the occurrence of ADRs and the studied genetic polymorphisms. CONCLUSIONS: Imatinib plasma concentration was stabilized by the third month in postoperative patients with GIST. Genetic polymorphisms in ABCG2, SLC22A1, and SLC22A5 (OCTN2) were associated with imatinib plasma concentration, while SLC22A5 (OCTN2) also influenced recurrence rates. These results provide a reference for personalized therapy and concentration monitoring.
Zhou S, Lian Q, Luo H
… +5 more, Xie H, Guan Y, He J, Wei L, Ju C
Eur J Clin Pharmacol
· 2025 Dec · PMID 40983806
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PURPOSE: This study aimed to establish a population pharmacokinetic model and optimise tacrolimus dosing regimens in Chinese lung transplant recipients. METHODS: A total of 988 tacrolimus trough concentrations and clinic...PURPOSE: This study aimed to establish a population pharmacokinetic model and optimise tacrolimus dosing regimens in Chinese lung transplant recipients. METHODS: A total of 988 tacrolimus trough concentrations and clinical data of 142 adult lung transplant recipients were collected. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. A Monte Carlo simulation was conducted to determine the optimal dosing regimen. RESULTS: The pharmacokinetics of tacrolimus could be best described by a one-compartment model with first-order absorption and elimination. The typical population parameter estimates of apparent clearance and apparent volume of distribution were 7.58 L·h and 701.39 L, respectively. The clearance of tacrolimus in rapid and intermediate metabolisers of CYP3A5 was 2.72-fold and 1.87-fold higher, respectively, than in poor metabolisers of CYP3A5. The concurrent use of voriconazole, posaconazole, and itraconazole led to a reduction in tacrolimus clearance by 38.21%, 26.30%, and 57.98%, respectively. Recommended dose regimens were obtained by Monte Carlo simulation based on the established model. CONCLUSION: Recipients with the CYP3A5*3/*3 genotype, elevated haematocrit levels, short postoperative days, and concurrent administration of azole antifungal drugs needed a reduced maintenance dose to reach the therapeutic window, which provided a reference for the formulation of individualised tacrolimus regimen during the early post-transplantation phase.
BACKGROUND AND OBJECTIVE: While current clinical guidelines generally advocate for beta-blocker therapy following acute myocardial infarction (AMI), conflicting findings have surfaced through large-scale observational st...BACKGROUND AND OBJECTIVE: While current clinical guidelines generally advocate for beta-blocker therapy following acute myocardial infarction (AMI), conflicting findings have surfaced through large-scale observational studies and meta-analyses. We conducted this systematic review and meta-analysis of published observational studies to quantify the long-term therapeutic impact of beta-blocker across heterogeneous AMI populations. METHODS: We conducted comprehensive searches of the PubMed, Embase, Cochrane, and Web of Science databases for articles published from 2000 to 2025 that examine the link between beta-blocker therapy and clinical outcomes (last search update: March 1, 2025). We used the odds ratio (OR) with its 95% confidence interval (95% CI) to evaluate the effect of beta-blocker therapy on all-cause mortality, cardiac death, or major adverse cardiac events (MACE) in AMI patients. Our analysis stratified these effects by study type, ejection fraction (EF), sample size, follow-up duration, and patient characteristics including primary coronary revascularization, ST-segment elevation status, and comorbidities. RESULTS: This meta-analysis incorporated 34 observational studies covering 233,303 AMI patients. Our results showed beta-blockers reduced all-cause (OR = 0.73, 95% CI = 0.64-0.82) and cardiac mortality (OR = 0.79, 95% CI = 0.70-0.89) in post-AMI patients, with no significant effect on MACE. In these patients, post-PCI and STEMI patients, beta-blockers lowered all-cause mortality but not MACE risk. Subgroup analysis revealed that beta-blockers decreased all-cause death in post-AMI patients with diabetes and COPD, but not in those with hypertension and AF. Stratified by EF, beta-blockers were beneficial for all-cause death (OR = 0.75, 95% CI = 0.60-0.93), cardiac death (OR = 0.72, 95% CI = 0.56-0.92), and MACE (OR = 0.85, 95% CI = 0.76-0.96) in post-AMI patients with reduced EF and only decreased all-cause death in those with preserved EF. CONCLUSIONS: Our meta-analysis suggests beta-blockers may offer long-term clinical benefits to AMI patients, particularly those with reduced EF. However, this is not conclusive for AMI patients with comorbidities or preserved EF.