European Journal of Clinical Pharmacology

Shan, Dan; Han, Jinbiao; Ji, Yurou; Wu, Yuexiao; Yi, Ke

doi: 10.1007/s00228-025-03804-ypmid: 39836237

BackgroundThe prevalence of conditions necessitating anticoagulation therapy among pregnant women has been steadily increasing. Although low-molecular-weight heparin (LMWH) is commonly used, several studies have investigated the use of fondaparinux in pregnant women. However, the safety profile of fondaparinux in this population remains to be fully elucidated.MethodsA comprehensive literature search across ten databases was conducted in September 2024. This meta-analysis was conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for systematic reviews of observational studies. Dichotomous data from eligible studies were combined using the Mantel‒Haenszel model. Standard mean differences with 95% confidence intervals were assessed. Heterogeneity was evaluated using I2 statistics and the Cochran Q test, and the quality of evidence was appraised using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.ResultsNine studies met the inclusion criteria. Based on the GRADE approach, the quality of evidence ranged from very low to low. Fondaparinux did not increase the incidence of bleeding-related adverse events (vaginal bleeding: OR = 0.99, 95% CI 0.43–2.30, P = 0.98; postpartum haemorrhage: OR = 0.35, 95% CI 0.07–1.73, P = 0.20). Fondaparinux was associated with reduced risks of hepatic transaminase elevation (OR = 0.20, 95% CI 0.08–0.49, P < 0.01), gastrointestinal reactions, allergies, and injection site skin reactions (OR = 0.19, 95% CI 0.09–0.41, P < 0.01).ConclusionThe findings of this systematic review and meta-analysis suggest that the use of fondaparinux among pregnant women has certain advantages. However, these conclusions warrant further validation through high-quality, large-scale studies conducted in multiple countries. (PROSPERO–CRD42024591579).

Wang, Shuang; Cai, Mengting; Xiong, Yajun; Guo, Tianyi; Niu, Xiaoya; Chen, Yu; Feng, Yuying; Song, Chunhua; Xu, Aiguo

doi: 10.1007/s00228-025-03803-zpmid: 39841181

BackgroundThe impact of incorporating immune checkpoint inhibitors (ICIs) into standard chemotherapy on the severity and risk of myelosuppression in advanced non-small cell lung cancer (NSCLC) patients remains uncertain.MethodsWe conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) that evaluated ICIs in people with NSCLC. A comprehensive search of four databases, PubMed, Web of Science, Embase, and the Cochrane Library, was carried out from inception to 30 October 2023. Pooled analyses assessed the risk ratios (RR) for treatment-related hematological adverse events greater than or equal to grade 3. The protocol is registered with PROSPERO and has the CRD42024500056 registration number.FindingsTwenty-three phase 3 RCTs were contained, involving 15,844 people with NSCLC receiving ICIs with or without chemotherapy. Compared with chemotherapy alone, ICI monotherapy or dual immunotherapy reduced treatment-associated leukopenia (relative risk (RR) 0.03, 95% CI 0.01–0.08), neutropenia (RR 0.02, 95% CI 0.01–0.03), thrombocytopenia (RR 0.05, 95% CI 0.02–0.14), and anemia (RR 0.09, 95% CI 0.05–0.15), with a pooled incidence of 0.07%, 0.08%, 0.14%, and 9.07%. Compared with chemotherapy alone, ICIs in combination with chemotherapy increased the risk of developing treatment-related thrombocytopenia (RR 1.35, 95% CI 1.04–1.77), with a pooled incidence rate of 6.83%; it did not increase leukopenia (RR 0.97, 95% CI 0.70–1.35), neutropenia (RR 1.05, 95% CI 0.90–1.23), and anemia (RR 1.10, 95% CI 0.85–1.43), with pooled incidence rates of 4.47%, 14.67%, and 13.36%, respectively.InterpretationFor patients with advanced or metastatic NSCLC, severe hematological adverse events are uncommon when ICIs are used alone, as opposed to chemotherapy. However, when used in conjunction with chemotherapy, these side effects may be intensified, particularly in the form of an elevated incidence of thrombocytopenia of grade 3 or higher.

Hassan, Omar; Elbhairy, Aya Abdulkarim; Siam, Aya Magdy; Abdelwahab, Tasneem; Hamad, Albraa Ashraf; Mahmoud, Omar Ehab; Nabeh, Omnia Azmy

doi: 10.1007/s00228-025-03808-8pmid: 39948217

PurposePregnant women are at heightened risk for severe COVID-19 outcomes. However, treatment options during pregnancy remain limited due to concerns over their safety and efficacy.MethodsThis systematic review and meta-analysis assessed the safety and efficacy of nirmatrelvir-ritonavir in pregnant women diagnosed with mild-to-moderate COVID-19. The analysis focused on cases where the treatment was initiated within five days of symptom onset. A single-arm meta-analysis was performed to comprehensively evaluate outcomes across maternal, delivery, and neonatal domains.ResultsIn line with PRISMA guidelines, six studies involving a total of 427 pregnant patients were included in the analysis. Hospitalization was reported in 2% of patients (95% CI: 1%–5%), with low heterogeneity across studies (I2 = 21.9%). Drug discontinuation and new-onset gestational diabetes (NOGDM) had a pooled estimate of 0.7% (95% CI: 3% to 15%) and 4.0% (95% CI: 1% to 16%), respectively, with substantial heterogeneity (I2 = 64.7% and 66.5%), respectively. New-onset gestational hypertension (NOGHTN) had a pooled estimate of 4% (95% CI: 1% to 26%), with considerable heterogeneity (I2 = 78.81%). For neonatal outcomes, the pooled estimate for birth weight was 3186 g (95% CI: 3123–3248 g; I2 = 0%), and no maternal or neonatal deaths were reported across the included studies.ConclusionNirmatrelvir-ritonavir appears safe and effective for mild-to-moderate COVID-19 in pregnant women, with low rates of hospitalization and adverse maternal outcomes. Larger, randomized studies are crucial to confirm these findings and ensure safety in diverse populations.

Wang, Siru; Sun, Hu; Wang, Zhaoxuan; Sun, Chunxiao; Zhang, Xiaolu; Liu, Chang

doi: 10.1007/s00228-025-03807-9pmid: 39948216

PurposeWe aim to use a network meta-analysis to evaluate the efficacy and safety of antiseizure medications and provide a theoretical basis for rational drug use for children and adolescents in adjunctive treatment.MethodsThe databases of PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for random clinical trials about perampanel, valproic acid, carbamazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide, brivaracetam, cenobamate, eslicarbazepine acetate, and pregabalin from their inception until December 10, 2023. The included studies’ risk of bias was evaluated by the Cochrane Collaboration’s tool (RoB2). The network meta-analysis was performed using Stata 15 on the included studies.ResultsSeventeen studies were identified and of these 19 randomized controlled trials evaluating 9 different antiepileptic drugs were included. In total, 2959 patients were covered in the analysis of the outcomes. For efficacy, lacosamide (OR = 1.91, 95%CI 1.14–3.20), lamotrigine (OR = 3.82, 95%CI 1.86–7.83), levetiracetam (OR = 3.01, 95%CI 1.89–4.80), oxcarbazepine (OR = 2.75, 95%CI 1.52–4.96), perampanel (OR = 2.05, 95%CI 1.15–3.65), and zonisamide (OR = 2.27, 95%CI 1.21–4.24) were more effective than placebo in the 50% responder rate. Lamotrigine ranked first on the cumulative probability curve, followed by levetiracetam. Eslicarbazepine acetate (OR = 6.44, 95%CI 1.43–29.00) and levetiracetam (OR = 5.75, 95%CI 2.45–13.50) were better than placebo in seizure freedom. For safety, topiramate (OR = 4.11, 95%CI 1.43–11.76) and oxcarbazepine (OR = 2.72, 1.28–5.76) were more likely to cause adverse effects in children or adolescents compared to placebo.ConclusionIn terms of efficacy and safety, lamotrigine and levetiracetam may be selected preferentially for the adjunctive treatment of focal epilepsy in children and adolescents. However, owing to the limited random clinical trials, our results need to be verified by further studies.

Jarab, Anan; Al-Qerem, Walid; Khdour, Adam; Awadallah, Heba; Mimi, Yousef; Khdour, Maher

doi: 10.1007/s00228-025-03809-7pmid: 39951117

PurposeSchizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the global population. Traditional antipsychotic treatments, while effective for positive symptoms, often have significant side effects and fail to address cognitive and negative symptoms. Novel pharmacological treatments targeting muscarinic receptors, TAAR1 agonists, serotonergic pathways, and glutamate modulation have emerged as promising alternatives.AimThis systematic literature review aims to critically evaluate the efficacy, safety, and mechanisms of action of novel pharmacological agents in the treatment of schizophrenia.MethodsA comprehensive search was conducted across PubMed, Embase, Cochrane Library, Scopus, and Web of Science for randomized controlled trials (RCTs) and clinical trials published between April 2014 and March 2024. Studies evaluating novel treatments targeting muscarinic receptors, TAAR1 agonists, serotonergic agents, and glutamate modulation were included. Primary outcomes focused on symptom reduction and quality of life, while secondary outcomes included cognitive function and adverse events. The Joanna Briggs Institute (JBI) tool was used for quality assessment.ResultsEleven studies involving 4614 participants (mean age 37–43 years, predominantly male) were included. Drugs evaluated included xanomeline-trospium (KarXT), pimavanserin, ulotaront, emraclidine, and bitopertin. Significant improvements in PANSS and CGI-S scores were observed, with xanomeline-trospium showing a mean reduction of 17.4 points (p < 0.001). Adverse events were mostly mild and transient, with nausea, constipation, and somnolence being common.ConclusionNovel treatments for schizophrenia show promise in managing both positive and negative symptoms, with generally favorable safety profiles. Future studies should focus on large-scale, long-term trials to refine their efficacy, safety, and clinical applicability.

Alban, Heather; Ireifej, Natasha; D’Alessandro, John; Jordan, Garrett; Lee, Ryan; Patricia, Nicholas; Stoltzfus, Jill; Niyibizi, Auguste

doi: 10.1007/s00228-025-03801-1pmid: 39849175

PurposeOpioid medications remain a common treatment for acute pain in hospitalized patients. This study aims to identify factors contributing to opioid overdose in the inpatient population, addressing the gap in data on which patients are at higher risk for opioid-related adverse events in the hospital setting.MethodsA retrospective chart review of inpatients receiving at least one opioid medication was performed at a large academic medical center from January 1, 2022, through December 31, 2022. Patients who received naloxone were designated as the overdose group, while those who received opioids without naloxone served as the control group. Suspected risk factors were included in a multivariable direct logistic regression model to identify patients at higher risk for opioid-related adverse events.ResultsThe review included 11,050 admitted patients who received an inpatient opioid, of whom 130 received naloxone. Analysis revealed that patients with creatinine clearance (CrCl) < 60 mL/min, co-administered benzodiazepine, body mass index (BMI) > 30 kg/m2, underlying pulmonary disease, obstructive sleep apnea, chronic opioid use, and/or substance use disorder were at higher risk for requiring naloxone. These factors significantly influenced the likelihood and magnitude of in-hospital opioid overdose.ConclusionThese validated risk factors should be considered when administering opioid analgesics in the inpatient setting. Consideration should be given to reducing the dose and/or frequency of opioids in addition to the use of alternative analgesic modalities for patients with these risk factors to mitigate the risk of opioid-related adverse events. Incorporating these considerations into clinical practice can enhance patient safety and outcomes.

Bruun, Lina Dorthea; Andersen, Geir Øystein; Kringen, Marianne Kristiansen; Myhre, Peder Langeland; Halvorsen, Sigrun; Hansen, Charlotte Holst; Molden, Espen; Øie, Erik

doi: 10.1007/s00228-025-03806-wpmid: 39900827

PurposeThe clinical benefit of up-titration of metoprolol to a guideline-recommended target dose after myocardial infarction (MI) is unknown. Our aim was to investigate whether variation in metoprolol exposure determined by cytochrome p450 enzyme 2D6 (CYP2D6) influences the occurrence of major adverse cardiovascular events (MACE) and cardiovascular death (CV death) among patients treated with metoprolol after MI.MethodThis Mendelian randomization study was performed using individual-level data from 1554 patients treated with metoprolol after an acute MI. CYPD26 genotype was applied as a binary genetic instrument assigning patients into two metoprolol exposure groups: CYP2D6 normal metabolizers (NM) (low exposure) and CYP2D6 intermediate and poor metabolizers (IM + PM) (high exposure). The null hypothesis of no association between the CYP2D6 metabolizer subgroup and MACE or CV death was tested using the Cox proportional hazards model. All-cause mortality and individual components of MACE were included as secondary outcomes.ResultsIn total, 879 (56.6%) patients were classified as NM and 675 (43.4%) as IM + PM. During the 3-year follow-up, 56 patients (6.4%) in the NM group had an outcome of MACE, and 24 (2.7%) patients died from CV disease. Corresponding frequency in the IM + PM group was 47 (7.0%) and 22 (3.3%), respectively. There was no association between genotype and MACE [unadjusted HR 1.12 (CI 0.76, 1.65)] or CV death [unadjusted HR 1.20 (CI 0.67, 2.14)], or between the CYP2D6 group and any of the secondary outcomes.ConclusionIn patients treated with metoprolol after MI, variation in metoprolol exposure determined by CYP2D6 did not impact the occurrence of cardiovascular events.

Beypınar, İsmail; Urvay, Semiha; Ürün, Müslih; Erçek, Berrak; Demir, Hacer; Yıldız, Canan; Araz, Murat; Oruç, Ahmet; Özilice, Utku; Balçık, Onur Yazdan

doi: 10.1007/s00228-025-03810-0pmid:

Cho, Jaehyeong; Jo, Hyesu; Park, Jaeyu; Lee, Kyeongmin; Lee, Hayeon; Kim, Soeun; Son, Yejun; Oh, Jeongseon; Jeong, Jinyoung; Lee, Sooji; Oh, Jiyeon; Cho, Hanseul; Yang, Jee Myung; Woo, Ho Geol; Yon, Dong Keon; Smith, Lee

Jang, Ji-Hun; Jeong, Seung-Hyun

doi: 10.1007/s00228-025-03813-xpmid: 40000474

BackgroundBioequivalence assessment determines the equivalence between drug formulations and is primarily used to demonstrate that a generic product is equivalent to its reference. The sex of the drug consumer is a major consideration in bioequivalence assessment, but specific ratios or absolute criteria for sex composition are usually not specified.PurposeThis study explored whether the sex of participants in a bioequivalence assessment could significantly affect the pharmacokinetic variability between formulations and decision outcomes. In bioequivalence studies, the sex composition should reflect the drug’s target population, but it is often acceptable to limit it to healthy adult males. Therefore, it is essential to consider the variation in bioequivalence results according to sex.MethodsLevocetirizine and rabeprazole enteric-coated tablets were chosen as investigational agents, and clinical trial data for these were used in the bioequivalence analysis. This analysis was conducted both with and without considering sex, and the final determination of equivalence was based on whether the 90% confidence interval for the ratio of standard pharmacokinetic parameters between the reference and test formulations fell within the 80 to 125% range. Additionally, principal component analysis (PCA) was performed to determine whether there were significant differences in the targeted pharmacokinetic parameter values between drug formulations across each sex group.ResultsBioequivalence of levocetirizine’s reference and test formulations was confirmed, independent of sex. For rabeprazole, bioequivalence was established in males—even without considering sex—but not in females, based on extended criteria for drugs with significant pharmacokinetic variability. The PCA results also showed that there were significant differences (P < 0.05) in the distribution of pharmacokinetic parameters of rabeprazole by gender and formulation. This indicates that equivalence assessments may vary based on pharmacokinetic differences related to sex among subjects in bioequivalence studies. Thus, it was shown that sex may influence pharmacokinetic variability between reference and test formulations of the same drug.ConclusionThis study provided valuable insights into the role of sex in bioequivalence studies. For drugs exhibiting significant pharmacokinetic differences between sexes, it is crucial to recognize that bioequivalence results may vary based on the sex ratio in the participant group. Therefore, further analysis and interpretation, taking sex-related factors into account, will be necessary during bioequivalence evaluations.