European Journal Of Clinical Pharmacology[JOURNAL]
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200 papers
Immunotherapy checkpoint inhibitor-combination therapy versus chemotherapy alone among Chinese population in cholangiocarcinoma treatment: a systematic review and meta-analysis.
Shi L, Du W, Miao J … +9 more , Peng XY, Li W, Ur-Rehman A, Ge MW, Shen LT, Feng R, Zhong K, Gao SQ, Chen HL
Eur J Clin Pharmacol · 2026 Jan · PMID 41546709 · Publisher ↗
BACKGROUND: The rise in cholangiocarcinoma (CCA) cases and deaths in China necessitates new treatments. This investigation is designed to establish the comparative efficacy between the coupling of immune checkpoint inhib...
BACKGROUND: The rise in cholangiocarcinoma (CCA) cases and deaths in China necessitates new treatments. This investigation is designed to establish the comparative efficacy between the coupling of immune checkpoint inhibitors (ICIs) paired with chemotherapy and chemotherapy alone for Chinese individuals diagnosed with CCA. METHOD: Web of Science, Embase, Scopus, the Cochrane Library and PubMed databases were scanned systematically, spanning their initial establishment through June 2025. Overall survival (OS) and progression-free survival (PFS), the primary outcome measures, were demonstrated by the included studies. Included studies specified objective response rate (ORR), adverse events (AEs), and disease control rate (DCR) as secondary endpoints. Engauge Digitizer 11.3 extracted survival curve data points for studies with sole curve data. Calculated: log (HR) = ln (HR), [Formula: see text],[Formula: see text]. RESULTS: The synthesis of the research incorporated findings from eight studies, which altogether assessed 802 cases of cholangiocarcinoma. Combining ICIs with chemotherapy markedly enhanced survival duration. OS had a hazard ratio of 0.46 (95% CI, 0.30–0.58; P < 0.001). PFS had a HR of 0.56 (95% CI, 0.46–0.67; P < 0.001). Higher ORR and DCR were also noted with combination therapy (ORR: risk ratio [RR], 1.34; 95% CI, 1.22–1.48; P < 0.001; DCR: RR, 2.46; 95% CI, 1.84–3.29; P < 0.001). Combination therapy was found, via Kaplan-Meier curves, to significantly increase OS (HR = 0.46, 95% CI 0.39–0.53; P < 0.001); PFS (HR = 0.38, 95% CI 0.35–0.46; P < 0.001). Sensitivity analysis validated stable, OS: HR = 0.46 (95% CI 0.36–0.58, P < 0.001); PFS: HR = 0.56 (95% CI 0.46–0.67, P < 0.001) for ICIs plus chemotherapy treatment. CONCLUSIONS: Adding ICIs to chemotherapy for advanced CCA in China enhances treatment response and survival, without added adverse effects, offering a beneficial and tolerable therapeutic alternative for advanced and recurrent CCA.
Safety and efficacy of DOACs for non-cirrhotic splanchnic vein thrombosis: a single centre retrospective analysis.
Depietri L, Fabbri FB, Veropalumbo MR … +5 more , Spaggiari E, Corradini S, Leone MC, Casali A, Iotti M
Eur J Clin Pharmacol · 2026 Jan · PMID 41546703 · Publisher ↗
BACKGROUND: In recent years, increasing evidence has emerged regarding the use of direct oral anticoagulants (DOACs) for the treatment of splanchnic vein thrombosis (SVT) in non-cirrhotic patients. However, available dat...
BACKGROUND: In recent years, increasing evidence has emerged regarding the use of direct oral anticoagulants (DOACs) for the treatment of splanchnic vein thrombosis (SVT) in non-cirrhotic patients. However, available data are predominantly retrospective, derived from small and heterogeneous cohorts; consequently, the use of DOACs for this indication remains off-label. METHODS: To further evaluate the safety and efficacy of DOACs in this setting, 21 consecutive patients with acute non-cirrhotic SVT were enrolled and treated with DOACs for a minimum of 6 months. RESULTS: No cases of SVT progression, recurrence, or major bleeding were observed during follow-up. One patient experienced a minor bleeding event. CONCLUSIONS: These findings are consistent with previous reports indicating a favorable safety profile of DOACs, with a low risk of bleeding. However, conclusions regarding efficacy remain uncertain, precluding definitive inferences on their effectiveness in non-cirrhotic SVT. Larger, well-designed prospective studies are required to clarify the true efficacy of DOACs in this clinical setting.
Efficacy and safety of CGRP monoclonal antibodies for migraine prevention in episodic migraine; a network Meta-analysis.
Shakir I, Shahzad F, Shabbir A … +6 more , Shahabuddin S, Shabbir H, Karamat S, Hulou S, Khalid AR, Ahmed SI
Eur J Clin Pharmacol · 2026 Jan · PMID 41546694 · Publisher ↗
BACKGROUND AND PURPOSE: Episodic migraine is a neurological disorder characterized by recurrent, unilateral headaches that significantly impair quality of life. CGRP monoclonal antibodies, targeting calcitonin gene-relat...
BACKGROUND AND PURPOSE: Episodic migraine is a neurological disorder characterized by recurrent, unilateral headaches that significantly impair quality of life. CGRP monoclonal antibodies, targeting calcitonin gene-related peptide (CGRP), have shown efficacy in preventing and treating episodic migraine. METHODS: A systematic search of PubMed, Cochrane, and Embase databases was conducted in September 2024 to identify randomized controlled trials (RCTs) on CGRP monoclonal antibodies for episodic migraine. A network meta-analysis was performed to assess efficacy (change in monthly migraine days) and safety (incidence of adverse events). Odds ratios (ORs) and surface under the cumulative ranking curve (SUCRA) were calculated. RESULTS: 16 studies with 9,123 participants were included. galcanezumab (240 mg) showed the highest efficacy (SMD = 0.5012, p < 0.0001). fremanezumab (225 mg) had the highest odds of ≥ 50% reduction in migraine days (OR = 3.1684, p < 0.0001). erenumab (28 mg) showed the best safety profile (OR = 0.6815, p = 0.2220). fremanezumab ranked highest in both efficacy (SUCRA = 84.6%) and safety (SUCRA = 61.8%). CONCLUSION: fremanezumab offers the best balance of efficacy and safety. Further long-term studies are needed.
Efficacy and safety of esketamine for sedation during colonoscopy: A systematic review and Meta-analysis of randomized controlled trials.
Hussein Z, Taha AM, Abouelmagd AA … +6 more , Elshabrawi MN, Durvesh AK, Nada EA, Abuelazm M, Elnaggar M, Elkhattib I
Eur J Clin Pharmacol · 2026 Jan · PMID 41546692 · Full text
BACKGROUND: Hemodynamic instability during colonoscopy sedation remains a significant clinical concern. Esketamine's sympathomimetic properties may protect against these risks while reducing sedative requirements. Hence,...
BACKGROUND: Hemodynamic instability during colonoscopy sedation remains a significant clinical concern. Esketamine's sympathomimetic properties may protect against these risks while reducing sedative requirements. Hence, we aim to evaluate the efficacy and safety of esketamine in improving intraprocedural sedation during colonoscopy. METHODS: We systematically searched PubMed, Scopus, CENTRAL, and Web of Science until June 2025 for randomized controlled trials. The primary outcome was the incidence of intraprocedural hypotension; secondary outcomes included bradycardia, hypoxemia, and recovery parameters. Dichotomous outcomes were pooled using risk ratios (RR) and continuous outcomes using standardized mean differences (SMD), with heterogeneity assessed via I² statistics. PROSPERO ID: CRD420251105691. RESULTS: Five randomized controlled trials comprising 858 patients were included in our analysis. Esketamine significantly reduced the risk of intraprocedural hypotension (RR: 0.34, 95% CI 0.22-0.53; I²=58%) and the incidence of hypoxemia (RR: 0.38, 95% CI 0.19-0.73; I²=0%). A reduction in injection pain was also observed (RR: 0.42, 95% CI 0.19-0.97; I²=80.5%), though this finding showed sensitivity in leave-one-out analysis. No significant differences were found between groups in bradycardia risk (RR: 0.51, 95% CI 0.23-1.14), total propofol requirement (SMD: -0.23, 95% CI -0.50 to 0.04), induction time, or procedure duration. The reduction in hypotension remained robust in sensitivity analyses. CONCLUSION: Esketamine significantly enhanced hemodynamic stability and reduced sedative demand during colonoscopy without delaying recovery, supporting its use in high-risk patients.
Use of pregabalin and limaprost in the conservative treatment of lumbar spinal stenosis: a systematic review of the current evidence.
Di Cosmo L, Centini FR, El Choueiri J … +8 more , Hammond J, Learmonth C, Natale L, Pellicanò F, Uralov D, Colella FE, Zaed I, Baricich A
Eur J Clin Pharmacol · 2026 Jan · PMID 41546687 · Publisher ↗
BACKGROUND AND OBJECTIVES: Lumbar spinal stenosis (LSS) is a common degenerative condition and a leading cause of pain and disability in older patients. While conservative treatment options like limaprost, a prostaglandi...
BACKGROUND AND OBJECTIVES: Lumbar spinal stenosis (LSS) is a common degenerative condition and a leading cause of pain and disability in older patients. While conservative treatment options like limaprost, a prostaglandin E1 analog, and pregabalin, a neuropathic pain modulator, are increasingly used, their relative efficacy and safety remain unclear. This systematic review aims to evaluate the comparative efficacy of pregabalin and limaprost in managing pain, function, quality of life, and adverse events in LSS. METHODS: A systematic search was conducted following PRISMA guidelines. Searches were performed across PubMed, Embase, Scopus, and Cochrane for studies published between January 2000 and March 2025. Inclusion criteria focused on RCTs and cohort studies evaluating either drug in LSS patients. RESULTS: Nine studies (6 RCTs, 3 cohort studies) with a total of 860 participants were included. Two head-to-head trials found no significant differences between pregabalin and limaprost in improving pain, disability, or quality of life. Both agents were associated with significant within-group improvements. Pregabalin showed efficacy across outcomes when combined with NSAIDs but was consistently associated with a higher frequency of adverse events, primarily including dizziness and gastrointestinal disturbances, compared to limaprost. Limaprost demonstrated mixed results, with several studies reporting benefits primarily when combined with other agents instead of its monotherapy. Evidence on sleep quality outcomes was limited but suggests potential benefits for both drugs in this patient population. CONCLUSION: No agent demonstrated clear superiority in the treatment of LSS, though both pregabalin and limaprost showed significant within-group benefits. Pregabalin’s greater side effect profile and cost may support preferential use of limaprost in LSS patients. Nevertheless, due to limited comparative trials and substantial heterogeneity in interventions and outcome measures, further high-quality studies are needed to elucidate this non-inferiority and inform clinical guidelines.
Safety of immune checkpoint inhibitors: A systematic review of disproportionality analysis studies.
Rathod M, Kadari M, Kadavath AD … +4 more , Thomas C, Raveendran A, Jagtap M, Undela K
Eur J Clin Pharmacol · 2026 Jan · PMID 41546683 · Publisher ↗
BACKGROUND: Immunotherapy has fundamentally changed the treatment landscape for both solid and hematologic malignancies over the past decade. However, an evolving body of literature has reported immune-related adverse ev...
BACKGROUND: Immunotherapy has fundamentally changed the treatment landscape for both solid and hematologic malignancies over the past decade. However, an evolving body of literature has reported immune-related adverse events (irAEs) involving several organs in patients treated with immune checkpoint inhibitors (ICIs). Our study aimed to systematically review published disproportionality analyses on ICIs, to summarize the current state of methodology and potential strengths of the analysis, while highlighting safety signals generated for these pharmacological groups. METHODS: A PubMed, Scopus, and Google Scholar search was conducted on November 7, 2024, and identified published disproportionality analyses of ICIs. Studies were included if they: 1) employed disproportionality analysis in pharmacovigilance databases; 2) investigations focused exclusively on ICIs; 3) analyses examining ICI-related adverse drug reactions (ADRs) (hypothesis-generating analyses and hypothesis-testing analyses); 4) mixed-methods studies incorporating disproportionality analysis with systematic reviews and meta-analysis. Data on results were categorized by ADR type and further analyzed based on exposure and comparator. We collected data on author name, database used, number of reports, age, gender, case/non-case status, exposure/comparison groups, disproportionality measures, signal definitions, confounder control, and sensitivity/subgroup analyses. We then retrospectively applied the READUS-PV (The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance) checklist to all included studies to assess their reproducibility, transparency, and quality. Additionally, we evaluated study quality based on the demographic parameters reported. RESULTS: We have identified 2939 published disproportionality analysis studies. Our study included 89 eligible analyses published between 2019 and 2024. Of these, 35 specifically focused on a single irAE. More than 50% studies predominantly employed the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) as signal detection standards. The analysis of time to onset of ADR revealed a significant variation in the ICI-related ADRs, with some, such as myocarditis and arrhythmic events, manifesting rapidly within weeks, while others, including uveitis, hypophysitis, and certain endocrine disorders, exhibit a delayed onset. Hypophysitis/hypopituitarism is uniquely associated with combined anti-programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, while endocrine and irAEs are common across all ICI treatments. Nivolumab and Pembrolizumab are more frequently associated with Guillain-Barré syndrome, myasthenia gravis, colitis, hepatitis, arthritis, immune-related skin disorders, and endocrinopathies (diabetes mellitus, adrenal insufficiency, and hypophysitis). The included disproportionality studies identified several irAEs that were not detected in pre-marketing clinical trials, including rare life-threatening events like myocarditis, fractures, delayed endocrine irAEs, and hypophysitis. A total of 34 (38.2%) of published disproportionality studies failed to report essential elements needed to understand and reproduce the analyses and results. Additionally, 39 (43.8%) of studies relied on a single disproportionality method for detecting signals. Only 15 studies (16.8%) met our predefined criteria for comprehensive reporting by including all seven critical data elements, while 40 studies (44.9%) demonstrated major reporting deficiencies with three or more missing elements. Concerning gaps persist, as evidenced by 34 recent studies (38.2%) still scoring ≤ 2 points. Furthermore, a quality assessment using the READUS-PV checklist revealed that critical reporting items were frequently missing from these studies, such as information in the title, case-by-case assessments, and comprehensive sensitivity analyses and data availability statements. CONCLUSION: The main organs affected due to ICIs are the skin, digestive, hepatic, lungs, rheumatologic, and endocrine. Disproportionality analysis in pharmacovigilance lacks standardised methods and interpretation, hindering reliable signal detection and requiring the development of clear guidelines, rigorous methodology, and collaborative efforts to improve patient safety. Additionally, the adoption of open-science practices, including protocol registration, should be implemented to enhance transparency and rigour.
Signals of pericardial and myocardial events associated with antiangiogenic drugs: a disproportionality analysis on FAERS.
Santoni FM, Ciccone V, Flaccavento A … +5 more , Morbidelli L, Ziche M, Tuccori M, Spini A, Donnini S
Eur J Clin Pharmacol · 2026 Jan · PMID 41538055 · Publisher ↗
PURPOSE: Antiangiogenic drugs (AADs) are an heterogenous group of molecules widely used in the treatment of cancers. Based on their mechanism of action, AADs are associated with an increased reporting of cardiovascular a...
PURPOSE: Antiangiogenic drugs (AADs) are an heterogenous group of molecules widely used in the treatment of cancers. Based on their mechanism of action, AADs are associated with an increased reporting of cardiovascular adverse events (AEs). However, pericarditis, pericardial effusion and myocarditis were not documented for most of AADs. The aim of this study was to determine whether AADs may be associated with pericarditis, pericardial effusion and myocarditis in a real-world setting. METHODS: We performed an extensive descriptive and disproportionality analysis of pericarditis, pericardial effusion and myocarditis AEs related to AADs on the FDA Adverse Event Reporting System (FAERS) database, using the reporting odds ratio (ROR) as a measure of emerging safety signal. RESULTS: Statistically significant signals of pericardial effusion and myocarditis were found for AADs compared to all other drugs in the database. The RORs for the pooled AADs were 2.37 [(95% CI (2.17–2.59)] for pericardial effusion and 2.26 [95% CI (1.99–2.58)] for myocarditis. In the sub-analysis performed for single AADs, an emerging disproportionality safety signal has been identified for ponatinib for pericarditis, vandetanib, sunitinib, ponatinib, pazopanib, nintedanib, cabozantinib, axitinib, and bevacizumab for pericardial effusion, and regorafenib, lenvatinib, cabozantinib, axitinib and bevacizumab for myocarditis. However, when compared with other anticancer agents to contextualize the risk within oncologic therapies, no overall disproportionality signals were detected, except for pericardial effusion with ponatinib and vandetanib, and myocarditis with lenvatinib. CONCLUSION: Our results show that most AADs were associated with signals of disproportionate reporting of pericardial and myocardial AEs when compared to all drugs in the database, which may be related to their different pharmacological angiogenic targets. Of note, signals persisted for pericardial effusion with vandetanib and ponatinib, and for myocarditis with lenvatinib. These findings highlight potential safety signals of public health relevance, while underlining the importance of therapeutic-context analyses to better characterize cardiovascular risk associated with AADs. Further pharmacovigilance studies are needed to expand knowledge and better characterize the cardiovascular safety profile of the different AADs.
A short review of dose-finding adaptive trial designs for clinical pharmacologists and non-statisticians in oncology.
Franchetti Y
Eur J Clin Pharmacol · 2026 Jan · PMID 41504942 · Publisher ↗
BACKGROUND: Trial designs are one of the important topics for drug developers. Technical understanding of adaptive dose-finding trial designs is beneficial to clinical pharmacologists as they can gain a new perspective f...
BACKGROUND: Trial designs are one of the important topics for drug developers. Technical understanding of adaptive dose-finding trial designs is beneficial to clinical pharmacologists as they can gain a new perspective for effectively using their expertise skills and making their contributions visible in a drug development process. However, there is no introductory review paper on dose-finding adaptive designs available for clinical pharmacologists since trial design publications in statistical journals often do not primarily focus on the practical considerations of clinical pharmacologists. OBJECTIVE: This short article reviews standard dose-finding adaptive designs that are typically employed in oncology clinical trials for clinical pharmacologists and non-statisticians. RESULTS: Standard dose-finding adaptive designs are described without mathematical equations, and basic concepts of model-based designs vs. model-assisted designs are provided in contrast to rule-based designs. Clinical pharmacology (CP) considerations for selecting an adaptive design, regarding objectives and endpoints, safety constraints, linear assumptions, and pre-specification of unknown dose/exposure-response relationships are described. A list of potential design inputs and impact is provided from a clinical pharmacology perspective. CONCLUSION: Familiarizing themselves with adaptive trial designs will help clinical pharmacologists and non-statisticians to well prepare for drug development collaboration in a cross-functional team setting. Proactively getting involved in choosing a trial design will contribute to successful dose-finding in oncology drug development.
Efficacy of Racecadotril in acute diarrhea in children: systematic review of double blind randomized clinical trials.
Bittar I, Guyenard L, Blanchard C … +1 more , Boussageon R
Eur J Clin Pharmacol · 2026 Jan · PMID 41504802 · Publisher ↗
INTRODUCTION: Acute diarrhea in children is a common condition. Standard treatment is oral rehydration, but antidiarrheal drugs are still widely used. However, their efficacy is debated: several trials and meta-analyses...
INTRODUCTION: Acute diarrhea in children is a common condition. Standard treatment is oral rehydration, but antidiarrheal drugs are still widely used. However, their efficacy is debated: several trials and meta-analyses have yielded contradictory results with a low level of evidence. Consequently, an updated and rigorous analysis is warranted. OBJECTIVE: The aim of this study was to evaluate the efficacy of Racecadotril in acute diarrhea in children, through a systematic literature review and meta-analysis of randomized trials. We also introduce a new method for interpreting the available evidence : the REB method. METHOD: A bibliographic search was conducted for articles published until October 2, 2023. The risk of bias was assessed using the RoB2 tool. The three endpoints were duration of diarrhea, stool production and length of hospitalization. The REB method was used to assess the overall level of evidence for efficacy. The REB method evaluates only low-risk-of-bias RCTs with confirmatory results to assess the solidity of evidence. RESULTS: Five trials were selected and included 904 patients. Only one trial was assessed as having a low risk of bias, precluding meta-analysis. This study was included in the REB analysis and showed neither statistically significant nor clinically significant effects. According to the REB method, the conclusion is an “absence of evidence” for efficacy of Racecadotril on all three endpoints. CONCLUSION: This review found insufficient high-quality evidence to support the efficacy of Racecadotril in children with acute diarrhea.
Further elucidation on the effect of food on the pharmacokinetics of trientine.
Weiss KH, Kruse C, Abd-Elaziz K … +6 more , van der Horst E, Fu C, Aliane V, Scherpbier JJ, Gerrits M, Dogterom P
Eur J Clin Pharmacol · 2026 Jan · PMID 41498947 · Publisher ↗
PURPOSE: Trientine dihydrochloride (TETA-2HCl) – a copper-selective chelator that forms a stable soluble complex with copper (Cu) and promotes excretion of this complex via the urine – is used as a treatment in Wilson Di...
PURPOSE: Trientine dihydrochloride (TETA-2HCl) – a copper-selective chelator that forms a stable soluble complex with copper (Cu) and promotes excretion of this complex via the urine – is used as a treatment in Wilson Disease (WD) patients who are intolerant to D-penicillamine. Although in clinical practice patients are instructed to take TETA-2HCl on an empty stomach at least one hour before meals or two hours after meals, the effect of food on the pharmacokinetics of TETA-2HCl has not previously been systematically investigated in humans. METHODS: In this open-label, single dose, randomized, two period cross-over study in healthy adults, a single oral dose of 600 mg of TETA-2HCl (2 × 300 mg capsules) was once administered under fed and once under fasted conditions with a wash-out period of at least one week. Blood samples were collected for up to 48 h after each dosing for analysis of plasma trientine (TETA) and its metabolites N1-acetyltriethylenetetramine (MAT) and N1-N10-diacetyltriethylenetetramine (DAT). RESULTS: Food had a significant effect on the pharmacokinetics of TETA and its metabolites MAT and DAT. Maximum plasma concentrations, and the exposures of TETA are significantly reduced by food (Cmax: 45%, AUC0 − t and AUC0 − inf: 44%.). Similar effects were seen for the metabolites MAT and DAT. The tolerability of treatment with TETA-2HCl was not affected by the intake of food. CONCLUSION: The study shows a significant impact of food on the pharmacokinetics of TETA, supporting the current instruction on administration of TETA-2HCl on an empty stomach in clinical practice. ClinicalTrials.gov Identifier: EudraCT number: 2018-001982-17. Date registered: 16 May 2018.
Cost-minimizing alternative dosage regimens of imipenem/cilastatin/relebactam for patients with renal impairment: a pharmacokinetic/pharmacodynamic simulation study.
Shi X, Lao D, Xu Q … +5 more , Li X, Liu B, He Q, Zhu X, Lv Q
Eur J Clin Pharmacol · 2026 Jan · PMID 41483214 · Publisher ↗
PURPOSE: Renal function significantly influences the pharmacokinetics of imipenem/cilastatin/relebactam (IMI/REL). The standardized single-dose packaging commonly leads to considerable drug wastage when the medication is...
PURPOSE: Renal function significantly influences the pharmacokinetics of imipenem/cilastatin/relebactam (IMI/REL). The standardized single-dose packaging commonly leads to considerable drug wastage when the medication is administered to patients with renal impairment. This investigation aimed to develop and assess alternative dosage regimens that optimize drug utilization and minimize waste. METHODS: Through Monte Carlo simulations, we evaluated alternative regimens involving extended dosage intervals and prolonged infusion times across patients with various levels of renal impairment. We assessed probabilities of target attainment (PTA) against established pharmacokinetic/pharmacodynamic (PK/PD) targets and minimum inhibitory concentration (MIC) breakpoints, and evaluated the risk of drug overexposure. Additionally, we compared the alternative dosage regimens with standard regimens in terms of dose wastage and cost savings. RESULTS: The findings suggest that administering full doses of IMI/REL every 8-12 h with prolonged infusion achieves satisfactory PTAs without significant overexposure risks. These alternative regimens are anticipated to reduce direct medical costs by $335.84 to $671.68 daily compared to standard dosages. CONCLUSION: Alternative dosing regimens for IMI/REL in patients with renal impairment can optimize drug utilization, minimize waste, and provide significant cost savings. However, further clinical studies are necessary to validate the effectiveness and safety of these regimens.
Construction and temporal external validation of interpretable machine-learning models for predicting tigecycline-associated hypofibrinogenemia.
Fu A, Guo D, Zhu M … +3 more , Cai L, Gao A, Cui L
Eur J Clin Pharmacol · 2026 Jan · PMID 41483207 · Publisher ↗
BACKGROUND AND PURPOSE: There is a paucity of available clinical tools with which to accurately predict the risk of tigecycline-associated hypofibrinogenemia, an adverse reaction with a high incidence and serious consequ...
BACKGROUND AND PURPOSE: There is a paucity of available clinical tools with which to accurately predict the risk of tigecycline-associated hypofibrinogenemia, an adverse reaction with a high incidence and serious consequences. This study aimed to developed an optimal machine-learning model for predicting tigecycline-associated hypofibrinogenemia and to facilitate its clinical application. METHODS: A total of 896 inpatients who received tigecycline treatment in a large tertiary teaching hospital between 2016 and 2022 were included in the model development cohort. Subsequent temporal external validation of the models was performed on 313 patients admitted in 2023. Three robust machine-learning algorithms, including LASSO, Boruta, and VSURF were integrated to identify predictors. These features were then utilized to construct nine machine-learning models. The optimal one was identified through model evaluation and validation and was interpreted based on the SHAP method. RESULTS: The three algorithms identified five predictors, including age, treatment duration, pre-dose fibrinogen level, D-dimer level, and activated partial thromboplastin time. The XGboost model was identified as the most suitable due to its stability and excellent discrimination, calibration, and clinical utility. The area under the receiver operating characteristic curve for the model were 0.823 (0.794-0.853), 0.810 (0.746-0.873), and 0.773 (0.721-0.825) in the training, internal validation, and temporal external validation cohorts, respectively. CONCLUSIONS: Machine-learning models are promising in solving the classification prediction problem of tigecycline-associated hypofibrinogenemia. Model interpretation based on SHAP enables clinicians to visualize individualized risk and tailor prophylactic strategies, potentially improving patient safety and treatment outcomes.
Adverse drug-event detection using the tree-based scan statistics (TreeScan) and comparison with common mining methods: new user, propensity score-matched cohorts.
Li H, Zhao H, Lin H … +3 more , Shen P, Zhang L, Zhan S
Eur J Clin Pharmacol · 2026 Jan · PMID 41483171 · Publisher ↗
PURPOSE: Tree-based scan statistics (TreeScan) combined with a new user propensity score (PS)-matched cohort design (PS-TreeScan) enhances post-marketing drug safety surveillance by adjusting for confounding biases. Howe...
PURPOSE: Tree-based scan statistics (TreeScan) combined with a new user propensity score (PS)-matched cohort design (PS-TreeScan) enhances post-marketing drug safety surveillance by adjusting for confounding biases. However, this method has not been compared with other signal mining techniques or used in post-marketing drug safety studies in China. We evaluate the effectiveness of the PS-TreeScan method in identifying statin-associated adverse events (AEs) by comparing it with three established signal detection methods using a Chinese real-world database. METHODS: We used data from the Yinzhou District Medical Database, encompassing patients with hypertension (2010–2016). Statin exposure and AEs were determined via outpatient/inpatient prescriptions and using ICD-10 codes in similar settings, respectively. A new user design with a 1:1 PS matching was implemented. Standard positive and negative signals were obtained from published systematic reviews, meta-analyses, and summary of product characteristics (SPC). PS-TreeScan was compared with three mining methods—incident rate ratio (crude cohort), Bayesian Confidence Propagation Neural Network (BCPNN), and Gamma Poisson Shrinker (GPS)—to identify statin-related AEs. Evaluation indices were calculated using the diagnostic test evaluation method, and area under the receiver operating characteristic curve (AUC) values were compared to assess differences. RESULTS: PS-TreeScan identified 15 positive signals (P < 0.05), including 8 true positives. PS-TreeScan’s sensitivity was equivalent to those of BCPNN and GPS (62%) but higher than that of the crude cohort method. TreeScan AUC values were significantly higher at 77.7% (95% confidence interval: 63.7%–91.6%). CONCLUSION: Compared to the original data, matched data effectively reduced false positives and improved the AUC for all methods. The PS-TreeScan method outperformed the traditional methods, thus it is able to supplement other mining methods for active adverse drug reaction monitoring.
Pharmacogenomic, pharmacokinetic, and safety analysis of CYP3A4/CYP3A5 polymorphisms of midostaurin in patients with acute myeloid leukemia.
Sechaud R, Peters T, Gu H … +4 more , Rahmanzadeh G, Sharma GK, Guichard N, Menssen HD
Eur J Clin Pharmacol · 2025 Dec · PMID 41432755 · Publisher ↗
PURPOSE: Midostaurin is predominantly metabolized by cytochrome P450 (CYP) 3A4 to form two active metabolites, CGP62221 and CGP52421. The current analysis from UNIFY, a randomized, double-blind, phase 3 study, investigat...
PURPOSE: Midostaurin is predominantly metabolized by cytochrome P450 (CYP) 3A4 to form two active metabolites, CGP62221 and CGP52421. The current analysis from UNIFY, a randomized, double-blind, phase 3 study, investigated the impact of genetic polymorphism of CYP3A4/CYP3A5 on the exposure of midostaurin and its active metabolites, and on treatment-related toxicity in patients with FLT3-mutation-negative acute myeloid leukemia (AML). METHODS: Based on the literature, CYP3A4/CYP3A5 polymorphic variants were selected and further interpreted as individual, combined, and clustered phenotypes. The pharmacokinetic (PK) parameters for midostaurin and the active metabolites were estimated based on concentration data collected after the first dose (full PK profile) and during the induction, consolidation, and post-consolidation phases at trough (pre-dose) and post-dose 3 h. Adverse event (AE) summaries included all treatment-emergent AEs starting on or after study day 1 and starting no later than 30 days after study treatment discontinuation. RESULTS: PK profiles and parameters of midostaurin and its metabolites after the first dose and multiple dosing, at steady state, at the different visits through different phases of the study were generally comparable across CYP3A4/CYP3A5 polymorphic variants and clustered phenotypes. The safety profile of midostaurin in this study was consistent with the known safety profile of midostaurin in FLT3-mutation-positive patients with AML. No meaningful differences were observed in the safety profile of midostaurin versus placebo in patients with CYP3A4/CYP3A5 polymorphic variants and clustered phenotype groups. CONCLUSION: Our extensive pharmacogenomic/PK/safety analysis in patients with AML does not indicate the need for dose adjustments of midostaurin based on CYP3A4/CYP3A5 polymorphic variants. CLINICALTRIALS.GOV NUMBER: NCT03512197.
Vancomycin in neonatal patients: systematic review and call for standardized dosing and monitoring practices.
Helbel C, Ferreira CB, Previato CFA … +9 more , da Rocha EMT, Silva GHO, Mascarenhas DC, de Melo GAN, Batistela VR, Louro E, Gonçalves ST, Janeiro V, Cuman RKN
Eur J Clin Pharmacol · 2025 Dec · PMID 41428193 · Publisher ↗
PURPOSE: This systematic review aimed at consolidating evidence regarding vancomycin dosing regimens, therapeutic drug monitoring (TDM) practices, clinical efficacy, and toxicity profiles in neonates admitted to neonatal...
PURPOSE: This systematic review aimed at consolidating evidence regarding vancomycin dosing regimens, therapeutic drug monitoring (TDM) practices, clinical efficacy, and toxicity profiles in neonates admitted to neonatal intensive care units (NICUs). The primary research question focused on identifying the most effective and safe vancomycin protocols for this vulnerable population. METHODS: Following PRISMA guidelines, a comprehensive search was conducted in six databases: PubMed, Scopus, Embase, Web of Science, Cochrane Library, and Lilacs. Eligible studies included observational cohorts and randomized clinical trials involving neonates receiving intravenous vancomycin with reported dosing and TDM data. Data extraction encompassed study design, dosing regimens, serum concentration targets, efficacy outcomes, and toxicity reports. RESULTS: Thirty-two studies met inclusion criteria, revealing substantial heterogeneity in vancomycin dosing strategies, target trough concentrations, and evaluation methods for efficacy and toxicity. Target serum concentrations varied widely (5-30 mg/L), and dosing regimens ranged from 10 to 61 mg/kg/day. Only three studies assessed clinical efficacy, and eleven evaluated nephrotoxicity risk, with reported nephrotoxicity rates between 1.1% and 14%. Variability in methods limited the comparability across studies. CONCLUSIONS: Vancomycin use in neonates lacks standardized dosing and monitoring practices, making it challenging to define an optimal therapeutic protocol. Greater consistency in clinical approaches and further high-quality studies are urgently needed to establish safe and effective vancomycin management strategies for neonatal patients.
A real-world pharmacovigilance study of adverse events associated with esketamine: disproportionality analysis and detection of potential drug-drug interaction signals.
Pisanu C, Imai S, Tsuchiya M … +5 more , Inoue M, Ikegami K, Zammarchi G, Kizaki H, Hori S
Eur J Clin Pharmacol · 2025 Dec · PMID 41428148 · Full text
PURPOSE: We conducted a comprehensive analysis of esketamine-related adverse events (AE) on the FDA Adverse Event Reporting System (FAERS) database, taking into account for the first time drug-drug interaction signals. M...
PURPOSE: We conducted a comprehensive analysis of esketamine-related adverse events (AE) on the FDA Adverse Event Reporting System (FAERS) database, taking into account for the first time drug-drug interaction signals. METHODS: We conducted a retrospective case/non-case study of esketamine-related AEs reported in the FAERS database up to the last quarter (Q4) of 2024. Potential signals were detected using the reporting odds ratio (ROR) and confidence intervals (CI), while drug-drug interactions were studied using different metrics such as lift, conviction and the combination risk ratio detection algorithm. An analysis of sex differences was also performed using the relative ROR and CI. RESULTS: The analysis of 7,790 reports in which esketamine was a primary or secondary suspect identified potential safety signals for 173 AEs. Novel signals include homicidal ideation (ROR = 5.30, 95% CI: 2.38-11.82) and substance use disorder (ROR = 6.12, 95% CI: 2.54-14.73). Women showed a longer time to onset than men (p = 0.003). In addition, we detected sex differences in 23 AEs, seven of which were more likely to be reported in women, while 16 in men. Among these, four were significant exclusively in women (oxygen saturation decreased, abnormal behaviour, unresponsive to stimuli and aggression) and two in men (vision blurred and bradycardia). Potential signals of additive and multiplicative drug-drug interactions were detected for antidepressants (venlafaxine for"dizziness" and bupropion for "agitation") and antipsychotics (risperidone for "vertigo"). CONCLUSIONS: Our results increase knowledge on potential risks related to esketamine AEs and potential drug-drug interaction signals in a real-world setting.
Thrombocheck: a practical pocket guide to pharmacokinetic drug-drug interactions in oral antithrombotic therapy.
Feka A, Zermatten MG, Hugelshofer S … +5 more , Verdugo-Marchese M, Fournier S, Alberio L, Ltaief Z, Perrottet N
Eur J Clin Pharmacol · 2025 Dec · PMID 41428096 · Publisher ↗
Pharmacokinetic drug-drug interactions (DDIs) can compromise the efficacy or safety of oral antithrombotic therapies (defined as oral anticoagulants or antiplatelet agents) due to under- or overexposure. Currently, there...
Pharmacokinetic drug-drug interactions (DDIs) can compromise the efficacy or safety of oral antithrombotic therapies (defined as oral anticoagulants or antiplatelet agents) due to under- or overexposure. Currently, there is limited published data on DDIs involving direct oral anticoagulants, and there is an alarming lack of clear data on DDIs involving antiplatelet agents. In this paper, we elaborated a comprehensive, up-to-date pocket guide on pharmacokinetic DDIs showing five possible levels of DDI (major, moderate or weak increase and major or moderate/weak decrease in antithrombotic drug exposure). The aim of this tool is to help prescribers, in particular cardiologists, to safely prescribe new antithrombotic therapies based on an individualised assessment of bleeding and thrombotic risk.
Itraconazole-associated adverse events in fungal infections: a study of a large real-world sample based on the FAERS database (2019-2024).
Xia T, Chen X, Song X … +1 more , Mei X
Eur J Clin Pharmacol · 2025 Dec · PMID 41428083 · Full text
BACKGROUND: Itraconazole (ITZ) is a broad-spectrum antifungal agent widely used for the treatment and prevention of fungal infections, particularly systemic and cutaneous infections. Although considered safe, recent clin...
BACKGROUND: Itraconazole (ITZ) is a broad-spectrum antifungal agent widely used for the treatment and prevention of fungal infections, particularly systemic and cutaneous infections. Although considered safe, recent clinical reports and studies have indicated that ITZ can cause a range of adverse events (AEs), particularly affecting vital organs such as the heart and liver. The objective of this study was to evaluate ITZ-associated adverse events by conducting data mining using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) to assess potential safety risks. METHODS: A retrospective pharmacovigilance analysis was performed using FAERS data from Q1 2019 to Q2 2024. Four disproportionality algorithms were applied to identify significant signals related to ITZ-AEs, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM). RESULTS: From a total of 6,191,576 case reports in FAERS, 1,041 reports identified ITZ as the primary suspected (PS) agent linked to AEs. A total of 323 ITZ-associated AEs were identified across 16 organ systems at the preferred terms (PTs) level. Expected AEs, including general disorders, administration site conditions, cardiac disorders, and hepatobiliary disorders, were identified, consistent with the drug label. In addition, 31 unexpected AEs were detected, including left ventricular dysfunction (39 cases, EBGM 31.81/EBGM05 15.83), myositis (38 cases, EBGM 29.75/EBGM05 15.94), both associated with vascular disorders at the system organ class (SOC) level. These findings suggest the presence of potential adverse effects that are not currently addressed in the drug’s labeling. CONCLUSIONS: This study identified 31 novel and unexpected AE signals associated with ITZ, which are consistent with clinical observations. These findings provide new insights into the safety profile of ITZ, highlighting the need for increased vigilance in clinical practice regarding its potential adverse effects. Future studies should validate these signals and explore their clinical implications to enhance drug safety monitoring and labeling updates.
Secukinumab improves pregnancy outcomes in recurrent spontaneous abortion with T helper 17 cells/T regulatory cells imbalance: a retrospective cohort study.
Zhu G, Wang X, Bi S … +5 more , Liu J, Yuan G, Li N, Fu J, Zhao L
Eur J Clin Pharmacol · 2025 Dec · PMID 41428078 · Publisher ↗
OBJECTIVE: This study aimed to evaluate the efficacy and safety of secukinumab, an Interleukin-17A (IL-17A) inhibitor, in patients with recurrent spontaneous abortion (RSA) associated with T helper 17 cells / T regulator...
OBJECTIVE: This study aimed to evaluate the efficacy and safety of secukinumab, an Interleukin-17A (IL-17A) inhibitor, in patients with recurrent spontaneous abortion (RSA) associated with T helper 17 cells / T regulatory cells (Th17/Treg) imbalance. METHODS: This retrospective cohort study evaluated 108 RSA patients with confirmed Th17/Treg imbalance (Th17/Treg ≥ 0.6 or IL-17A > 4.74 pg/mL) at a single center. Patients were divided into secukinumab (n = 54; 3 mg/kg subcutaneously plus standard therapy) and control (n = 54; standard therapy alone) groups. Primary outcomes included live birth rate and immunological parameters (Th17/Treg ratio, IL-17A levels), with secondary assessments of neonatal outcomes and safety. RESULTS: The secukinumab group demonstrated significantly higher live birth rates (83.33% [45/54] vs 64.81% [35/54]; P = 0.047), with an odds ratio (OR) of 2.71 (95% Confidence Interval (CI): 1.10-6.73), and greater reductions in Th17/Treg ratios (P = 0.010) and IL-17A levels (P = 0.001) compared to controls. No congenital anomalies, maternal or neonatal infections, or treatment-related serious adverse events were observed in either group. CONCLUSION: For RSA characterized by Th17/Treg imbalance, secukinumab demonstrates both clinical efficacy and an acceptable safety profile, suggesting its therapeutic utility.
New insights into the effects of dissolution profiles on the pharmacokinetics of trientine dihydrochloride.
Weiss KH, Kruse C, Abd-Elaziz K … +6 more , van der Horst E, Fu C, Aliane V, Scherpbier JJ, Gerrits M, Dogterom P
Eur J Clin Pharmacol · 2025 Dec · PMID 41428007 · Publisher ↗
PURPOSE: Trientine dihydrochloride (TETA-2HCl) is an established treatment for Wilson disease. We assessed different dissolution profiles of TETA-2HCl capsules on the pharmacokinetics (PK) of trientine (TETA) and on dire...
PURPOSE: Trientine dihydrochloride (TETA-2HCl) is an established treatment for Wilson disease. We assessed different dissolution profiles of TETA-2HCl capsules on the pharmacokinetics (PK) of trientine (TETA) and on direct copper (Cu) parameters. METHODS: In this open-label, randomized, two way cross-over study, 24 healthy subjects received two single oral doses of 600 mg TETA-2HCl with a washout of at least one week; one dose with a fast and one dose with a slow dissolution profile. Blood and urine samples were collected up to 48 h for analysis of plasma TETA and its metabolites, N1-acetyltriethylenetetramine (MAT) and N1-N10-diacetyltriethylenetetramine (DAT), serum Cu, ceruloplasmin (Cp) and urinary Cu excretion (UCE). The effect of dissolution profile on the PK was assessed through the ratio of geometric mean ratios (GMRs) and two-sided 90%-confidence intervals (CI) of the fast vs. slow dissolution profile. RESULTS: The C of TETA was comparable for the two products (GMR 95.81%; CI 83.87-109.46%) while AUC was slightly lower for the capsules with fast dissolution profile (GMR 90.65; 90% CI 78.32-104.91%). PK parameters were similar for the metabolites of TETA. Additionally, serum Cu and Cp concentrations remained stable over the 12 h period after dosing and were comparable between the two products, as was UCE. CONCLUSION: The pharmacokinetic profiles of TETA after administration of TETA-2HCl capsules with fast and slow dissolution characteristics were similar. Though the lower 90%-CI for AUC was outside the formal bioequivalence ranges, differences were small (9%) and not considered clinically relevant. A difference in dissolution profile did not affect copper parameters and tolerability.
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