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Objective: Adverse Drug Reactions (ADR) add a significant clinical and economic burden to the healthcare system of a country. We present an overview of the different approaches of ADR reporting systems worldwide and their evolution over time., Methods: A systematic review of the literature was made based on PubMed and the Cochrane database of systematic reviews. The articles searched for included original articles, WHO and FDA reports and institute of medicine reports. Reporting ADRs is the cornerstone of detecting uncommon ADRs once the drugs are on the market. In many countries, ADR reporting is regulated by national regulatory bodies and various methods are employed to report ADRs. Direct reporting by healthcare professionals has been adopted by many developed and developing countries. With emerging new technologies in the field of medicine, there is a great potential to develop better ADR reporting systems in the countries where they have poor reporting., Conclusion: Development and acquisition of newer technologies to promote ADR monitoring and reporting is a necessity for an effective pharmacovigilance system in a country., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Every drug development is a complex and long journey. Clinical pharmacology is an essential discipline in modern drug development. With its applications, computational modelling, and simulation techniques, it can significantly contribute to the efficiency in drug development today. In this perspective, we highlight why pharmacokinetics and pharmacodynamics are important, what developers need to consider in their clinical development programme, how modelling influences the development process, and discuss recent trends such as artificial intelligence and machine learning that have the potential to reshape future drug development., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

An aqueous solution of 35S-ampicillin and polyethylene glycol (PEG 4000, unabsorbable marker) was administered orally to 6 healthy subjects with gastrointestinal tubes. The minimal absorption of radioactive material, as shown by urinary excretion of label, differed markedly between subjects and averaged 44% (25-67). As the mean cumulative uptake in the proximal jejunum was 31% (24-45), it appeared that some of the radioactivity had been taken up in more distal parts of the gastrointestinal tract. Chromatographic fractionation of gastrointestinal aspirates indicated that more than 95% of the label usually remained attached to the parent compound. The corresponding figure for radioactive material recovered from urine was about 80-85%. A similar degree of decomposition was also found for label excreted in the urine of an additional subject who received 35S-ampicillin intravenously. In this experiment the urine contained 87% of the administered radioactivity.

The metabolic fate of orally administered (-)-[14C]-ephedrine has been studied in 3 human subjects and the urinary excretion of metabolites determined quantitatively by solvent extraction, paper chromatography and reverse isotope dilution procedures. Following an oral dose of the drug (0.35 mg/kg, 1.6 muCi), 97% of the dose was excreted in the urine within 48 h, 88% in the first 24 h. Unchanged drug was the major urinary excretory product (53-74%), with N-demethylation occurring to a variable extent (8-20%) although there was little interindividual variation in urine pH. Oxidative deamination was also variable (4-13%); the main identified products of this were benzoic acid (free and conjugated) and 1,2-dihydroxy-1-phenylpropane (free and conjugated). No phenolic metabolites could be detected, and thus it would appear that these compounds cannot be implicated in the acquisition of tolerance to ephedrine which can occur on repeated dosage.

The effect of spironolactone on the metabolism of intravenously administered 3H-digitoxin (80 muCi) was investigated in eight patients. In three of them the labelled glycoside was given on a second occasion after spironolactone treatment had been discontinued for at least 65 days. Of total urinary radioactivity 79% was unaltered drug and 12% consisted of water soluble compounds. No digitoxigenin or digoxigenin and only trace amounts (less than 2 %) of digoxin and the bis- and monoglycosides of digoxigenin were found. After spironolactone total urinary radioactivity was unchanged but the fraction eliminated as unchanged digitoxin fell from 79 to 66 % and the water soluble compounds increased from 12 to 26 % (p less than 0.05). In addition spironolactone caused a 20 ( reduction in the half-life of serum radioactivity (p less than 0.01) and a 16 % reduction in the volume of distribution (p less than 0.05). Induction of hepatic enzymes by spironolactone is proposed to explain the alteration in the metabolism of digitoxin in man. Both the altered metabolic pattern and the reduction in the volume of distribution appear to contribute to the reduction in half-life.

Background: Urticaria following the COVID-19 vaccine was rarely reported and had a short self-limited resolution. However, there has been relatively little literature published on CSU induced by COVID-19 vaccines., Purpose: We describe a case series of patients who experienced CSU after SARS-CoV-2 vaccination., Methods: A retrospective case series of 10 patients referred to the Department of Clinical Pharmacology of the University of Monastir (January 2021-January 2022) and included for evaluation of urticaria after COVID-19 vaccination., Results: The median age was 31 years and patients were mostly female. Atopy was presented in 3 patients and urticaria was accompanied by angioedema in 6 patients. The median time interval between vaccination and the onset of urticaria was 28.5 h. The offended dose was the first one in 8 patients. The resolution of the eruption was observed at least 2 months later, despite the regular use of a full dose of antihistamine in nine patients. Polynuclear leucocytosis was identified in 5 patients. Anti-TPOAb was positive in one patient after receiving the BNT162b2 vaccine. Total serum IgE was elevated in 4 patients. Skin tests for the suspected vaccine as well as the vaccine excipient were negative., Conclusion: We add to the medical literature ten new cases of chronic spontaneous urticarial reactions following COVID-19 vaccines uncontrolled with high-dose first-generation H1 antihistamines., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This study aimed to quantitatively evaluate the efficacy and safety of first-line systemic therapies for treating advanced hepatocellular carcinoma (aHCC)., Methods: The study included clinical trials of first-line systemic therapies for aHCC since the approval of sorafenib in 2007. Hazard function models were used to describe changes in overall survival (OS) and progression-free survival (PFS) over time. Monte Carlo simulation was used to compare OS and PFS for different treatments, including sorafenib, antiangiogenic therapies (AATs) (except sorafenib), immune checkpoint inhibitor (ICI) monotherapy, AAT + targeted therapy, AAT + chemotherapy, AAT + ICIs, and ICIs + ICIs. Furthermore, the objective response rate (ORR) and incidence of grade ≥ 3 adverse events were analyzed., Results: Fifty studies comprising 12,918 participants were included. AAT + ICIs demonstrated a significant benefit in median OS (mOS), median PFS (mPFS), and ORR (20.5 [95% CI 17.5-24] months, 7.5 [95% CI 6.5-8.8] months, and 24% [95% CI 17%-30%], respectively). ICIs + ICIs and ICI monotherapy ranked second and third, respectively with an mOS of 20 (95% CI 18.5-21.5) months and 14.5 (95% CI 13.5-16) months, respectively. The OS, PFS, and ORR of patients treated with AAT, AAT + targeted therapy, and AAT + chemotherapy were similar to those of patients treated with sorafenib. A higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage C had a shorter OS. OS was associated with publication year, and PFS was associated with the proportion of patients with BCLC stage C. The incidence of grade ≥ 3 adverse events in the ICIs and ICIs + ICIs treatment groups was low., Conclusions: The study results provide valuable information from which to base rational clinical drug use and serves as a reliable external control for evaluating new treatments for aHCC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Bioequivalence 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., Purpose: This 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., Methods: Levocetirizine 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., Results: Bioequivalence 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., Conclusion: This 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., Competing Interests: Declarations. Ethical approval: Clinical studies were conducted in accordance with the Rules of Good Clinical Practice and the revised Declaration of Helsinki for Biomedical Research with Human Subjects. All subjects had no prior history of hypersensitivity or related reactions to steroid drugs and were physically normal. To confirm their physical health, all subjects underwent a physical examination, clinical screening, complete blood count, urinalysis, and blood chemistry analyses prior to participating in this clinical study. Consent to participate: All subjects provided written informed consent prior to their participation in bioequivalence and pharmacokinetic studies. Consent for publication: All data were anonymized, and participants were informed that the results of this study may be subject to publication and presentation in meetings. Competing interests: The authors declare no competing interests. Clinical trial registration: The clinical trial protocols were thoroughly reviewed and officially approved by the Ministry of Food and Drug Safety (Cheongju-si, Republic of Korea). The approval number of the trial for levocetirizine was MB22-013. The approval number of the trial for rabeprazole was MB22-002., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: We 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., Methods: The 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., Results: Seventeen 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., Conclusion: In 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., Competing Interests: Declarations. Ethical approval: Ethical approval is not applicable because this study is based on published literature. Human ethics and consent to participate: Not applicable. Consent for publication: No informed consent was required. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Inappropriate use of direct oral anticoagulants (DOACs) is common, affecting up to 30% of atrial fibrillation (AF) population receiving treatment for stroke prevention. This study assessed appropriateness of anticoagulation in anticoagulation-naive AF patients treated with DOACs during a 12-month prospective follow-up., Methods: This prospective cohort study included all anticoagulation-naive AF patients referred for anticoagulation for stroke prevention at a tertiary cardiovascular center. Participants were prospectively followed through phone call interviews by a dedicated nurse at 1, 3, 6, 9, and 12 months after enrollment., Results: Of 403 anticoagulation-naive AF patients, rivaroxaban was prescribed for 325 patients (80.7%) and apixaban for 78 (19.3%). Inappropriate therapy was observed in 23% (76/325) and 46% (36/78) of patients treated with rivaroxaban and apixaban, respectively. Undertreatment was predominant scenario for both drugs, detected in 78.5% (78/112) of patients treated inappropriately, and was more frequently observed with apixaban versus rivaroxaban (44.8% vs 16.3%). During 12 months, inappropriate treatment was corrected in only 13% of all patients. The multivariate regression model identified creatinine clearance ≤ 49 mL/min (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.12 to 4.21), female sex (OR, 1.81; 95% CI, 1.11 to 2.97), and age ≥ 80 years (OR, 1.85; 95% CI, 1.22 to 2.83) as independent covariates associated with inappropriate dosing., Conclusions: Inappropriate therapy with DOACs for stroke prevention in patients with AF is common, and the dosage were corrected in few patients during the 12-month follow-up. Our findings highlight the persistent lack of knowledge regarding appropriate DOAC dosage and need for continuous education., Competing Interests: Declarations. Competing interests: Dr. Lip is a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally.  He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multi morbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation program me under grant agreement No 899871., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The effects of first-generation antihistamines in preventing postoperative emergence agitation or delirium are unclear. Determining the postoperative effects of first-generation antihistamines may provide important insights into the management of patient safety. Therefore, we performed a systematic review of randomized controlled trials (RCTs) evaluating the efficacy and safety of postoperative first-generation antihistamines., Methods: Patients who used first-generation antihistamines in the intensive care unit or operating room were included. Primary outcomes were assessed postoperative emergence agitation or delirium with binary and continuous variables. The secondary outcome was any adverse event., Results: Nine studies were included. The frequency of postoperative emergence agitation, measured using binary variables, tended to be lower in patients receiving chlorpheniramine or diphenhydramine than those receiving saline. However, evaluation using the Richmond Agitation-Sedation Scale as a continuous variable revealed that only chlorpheniramine was effective at lowering postoperative emergence agitation. Only one study assessed delirium but found no benefit of first-generation antihistamines. Adverse events for first-generation antihistamines did not differ from that of other drugs., Conclusion: Our results provide limited evidence that some first-generation antihistamines may prevent postoperative emergence agitation and are safe. To further verify this possibility, new RCTs with clear and universal assessment criteria for postoperative emergence agitation or delirium should be conducted., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This review examines the progress of research on posaconazole therapeutic drug monitoring (TDM) that has focused on differences in the TDM of posaconazole after clinical application in different formulations and in different populations, the factors that affect posaconazole concentrations, the advantages of posaconazole TDM in terms of clinical efficacy and cost savings, and measurement methods., Methods: A literature search (2006 to 2024) was performed in PubMed and Embase with the following search terms: noxafil, posaconazole hydrate, posaconazole, drug monitoring, therapeutic drug monitoring, and TDM. Abstracts of review articles, prospective studies, and retrospective studies were reviewed., Results: TDM should be implemented earlier for posaconazole tablets and injections than for oral posaconazole suspensions. Posaconazole TDM is beneficial for improving clinical efficacy, and the incidence of breakthrough invasive fungal infections (IFIs) can be significantly reduced by gradually adjusting the posaconazole dose in response to TDM in patients with inadequate trough concentrations. Early TDM allows more patients to achieve target therapeutic posaconazole concentrations. TDM can also facilitate dose adjustments, which reduce the cost of this expensive drug. Different assay techniques, including chromatography, microbiological detection, chemofluorimetry, paper spray mass spectrometry, and capillary electrophoresis, can be used for posaconazole TDM., Conclusions: Posaconazole TDM has potential clinical utility and cost-saving benefits and could improve the outcomes of IFI treatment., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aims to assess the predictive performance of published valproic acid (VPA) population pharmacokinetic (PPK) models using an external data set in Chinese adults with epilepsy or after neurosurgery., Methods: A total of 384 concentrations from 290 Chinese adults with epilepsy or after neurosurgery were used for external validation. Data on published VPA PPK models were extracted from the literature. Prediction-based diagnostics (such as F20 and F30), simulation-based diagnostics, and Bayesian forecasting were used to evaluate the predictability of models., Results: The results of prediction-based diagnostics of all models were unsatisfactory. Models B, F, and H showed the best prediction performance in simulation-based diagnostics and Bayesian forecasting, demonstrating superior precision and accuracy. Bayesian forecasting demonstrated significant improvements in the model predictability., Conclusion: The published PPK models showed extensive variation in predictive performance for extrapolation among Chinese adults with epilepsy or after neurosurgery patients. Fixed parameters of Vd and Ka in the PPK modeling of VPA might be the reason for the unsatisfied predictive performance. Bayesian forecasting significantly improved model predictability and may help to individualize VPA dosing., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Cough is a prevalent symptom driving patients to seek medical attention in general practice. Despite its widespread use, the clinical efficacy of oxomemazine, the second most reimbursed molecule in France for symptomatic cough treatment, remains uncertain. This study aims to systematically evaluate the clinical efficacy of oxomemazine in cough., Methods: A systematic literature review with meta-analysis of randomized controlled trials (RCTs) was conducted according to the Rebuild the Evidence Base (REB) protocol. Clinical trials comparing the efficacy of oxomemazine versus placebo or active comparator in cough were searched for. Trials with insufficient data were excluded. Searches were conducted across major databases (Medline, Cochrane Central Register of Controlled Trials, and Embase) and trial registries (World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov). RCTs comparing oxomemazine versus placebo or active comparators in cough were sought. Risk of bias was assessed using the Cochrane Collaboration's RoB2 tool. The protocol was preregistered on PROSPERO under the number CRD42022345496 (15). This study received no funding., Results: No RCTs were at low risk of bias. Therefore, no meta-analysis was conducted, in accordance to the pre-specified protocol., Conclusions: This systematic review highlights the lack of evidence regarding the efficacy of oxomemazine in cough treatment and underscores the need for further well-designed clinical trials to inform its clinical utility in primary care settings., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Drug protocols in intensive care units may require the concomitant administration of many drugs as patients' venous accesses are often limited. A major challenge for clinicians is to limit the risk of simultaneously infusing incompatible drugs. Incompatibilities can lead to the formation of particles and inactivation of drugs, whose consequences on the body have already been indicated. Our objective was to assess current strategies to counter the risk of incompatible infusions and control the resulting clinical consequences., Methods: This review was independently conducted by three investigators in respect of the PRISMA statement. Three online databases were consulted. Full-text articles, notes, or letters written in English or French, published or in press between the 1990s and the end of February 2020, with clinical study design, were eligible. Parameters of interest were mainly number and size of particles, and a number of observed/avoided incompatibilities., Results: All in all, 382 articles were screened, 17 meeting all the acceptance criteria. The strategies outlined and assessed were filtration, the use of multi-lumen devices, the purging of infusion lines, incompatibility tables and databases, and the use of standard operating procedures., Conclusion: Although many strategies have been developed in recent years to address drug incompatibility risks, clinical data is still lacking. All studies with in vitro design were excluded although some current innovative strategies, like niosomes, should be considered and studied by means of clinical data in the future., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose: Drug-drug interactions (DDIs) with antiretroviral drugs (ARVs) represent an important issue in elderly people living with HIV (PLWH). Amlodipine is a commonly prescribed antihypertensive drug metabolized by CYP3A4, thus predisposed to a risk of DDIs. Guidance on the management of DDIs is mostly based on theoretical considerations derived from coadministration with other CYP3A4 inhibitors. This study aimed at characterizing the magnitude of DDIs between amlodipine and ARV drugs in order to establish dosing recommendations., Methods: A population pharmacokinetic analysis was developed using non-linear mixed effect modelling (NONMEM) and included 163 amlodipine concentrations from 55 PLWH. Various structural and error models were compared to characterize optimally the concentration-time profile of amlodipine. Demographic and clinical characteristics as well as comedications were tested as potential influential covariates. Model-based simulations were performed to compare amlodipine exposure (i.e. area under the curve, AUC) between coadministered ARV drugs., Results: Amlodipine concentration-time profile was best described using a one-compartment model with first-order absorption and a lag-time. Amlodipine apparent clearance was influenced by both CYP3A4 inhibitors and efavirenz (CYP3A4 inducer). Model-based simulations revealed that amlodipine AUC increased by 96% when coadministered with CYP3A4 inhibitors, while efavirenz decreased drug exposure by 59%., Conclusion: Coadministered ARV drugs significantly impact amlodipine disposition in PLWH. Clinicians should adjust amlodipine dosage accordingly, by halving the dosage in PLWH receiving ARV with inhibitory properties (mainly ritonavir-boosted darunavir), whereas they should double amlodipine doses when coadministering it with efavirenz, under appropriate monitoring of clinical response and tolerance.

Background: The use of proton pump inhibitors (PPIs) has increased over the past decades. One potential gateway into new PPI use is following a hospital admission. The study aimed to examine the incidence of new PPI usage following admission to internal medicine services and the ratio of new persistent users., Methods: A retrospective descriptive study was conducted among all adults who had been admitted to internal medicine wards at the National University Hospital of Iceland from 2010-2020. Data was obtained from the Icelandic Internal Medicine Database. The proportion of patients who started treatment with PPI within 3 months of discharge (new users) and the proportion of patients who continued to use it after 3 months (persistent users) were examined., Results: Among 85.942 admissions during the study period, 7238 (15.6%) became new users, and of those 4942 (68%) were new persistent users. The incidence of new PPI use was highest for patients discharged from gastroenterology (32.2%), hematology (31.8%), and oncology (29.2%). Patients with new PPI use more commonly had a history of malignancy (19.5%) and liver disease (22.7%) and more commonly were admitted to the ICU during their hospitalization. The highest ratio of persistent usage was among patients discharged from geriatric medicine (84%)., Conclusion: One in every six patients admitted to internal medicine wards filled out a prescription for PPI within 3 months from discharge, and a large proportion of them became persistent users. The high rate of new PPI users from oncology and hematology is noteworthy and requires further research., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Topiramate, a broad-spectrum antiepileptic drug, exhibits substantial inter-individual variability in both its pharmacokinetics and therapeutic response. The aim of this study was to investigate the influence of patient characteristics and genetic variants on topiramate clearance using population pharmacokinetic (PPK) models in a cohort of Chinese pediatric patients with epilepsy., Method: The PPK model was constructed using a nonlinear mixed-effects modeling approach, utilizing a dataset comprising 236 plasma concentrations of topiramate obtained from 181 pediatric patients with epilepsy. A one-compartment model combined with a proportional residual model was employed to characterize the pharmacokinetics of topiramate. Covariate analysis was performed using forward addition and backward elimination to assess the influence of covariates on the model parameters. The model was thoroughly evaluated through goodness-of-fit analysis, bootstrap, visual predictive checks, and normalized prediction distribution errors. Monte Carlo simulations were utilized to devise topiramate dosing strategies., Result: In the final PPK models of topiramate, body weight, co-administration with oxcarbazepine, and a combined genotype of GKIR1-UGT (GRIK1 rs2832407, UGT2B7 rs7439366, and UGT1A1 rs4148324) were identified as significant covariates affecting the clearance (CL). The clearance was estimated using the formulas CL (L/h) = 0.44 × (BW⁄11.7) 0.82  × e OXC for the model without genetic variants and CL (L/h) = 0.49 × (BW⁄11.7) 0.81  × e OXC  × e GRIK1-UGT for the model incorporating genetic variants. The volume of distribution (Vd) was estimated using the formulas Vd (L) = 6.6 × (BW⁄11.7). The precision of all estimated parameters was acceptable. Furthermore, the model demonstrated good predictability, exhibiting stability and effectiveness in describing the pharmacokinetics of topiramate., Conclusion: The clearance of topiramate in pediatric patients with epilepsy may be subject to the influence of factors such as body weight, co-administration with oxcarbazepine, and genetic polymorphism. In this study, PPK models were developed to better understand and account for these factors, thereby improving the precision and individualization of topiramate therapy in children with epilepsy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: This study aimed to analyze the factors influencing warfarin-related major gastrointestinal bleeding (GIB) and to develop a score that would provide a reference for assessing the risk of major GIB associated with warfarin treatment., Methods: This was a retrospective analysis of clinical and follow-up data from warfarin-treated patients. Scores were analyzed using logistic regression. The area under the subject working characteristic curve (AUC), sensitivity, specificity, and Hosmer-Lemeshow test were used to evaluate the scoring performance., Results: A total of 1591 patients who met the requirements for warfarin use were included in this study, and 46 developed major GIB. After univariate analysis as well as multivariate logistic regression analysis, nine factors were found to be associated with increased risk of major GIB, namely age ≥ 65 years, history of peptic ulcer, history of major bleeding, abnormal liver function, abnormal renal function, cancer, anemia, labile international normalized ratio, and combination of antiplatelet agents/non-steroidal anti-inflammatory drugs. The Alfalfa-Warfarin-GIB score was constructed using these nine factors. The AUC and Bootstrap method-corrected AUC of the Alfalfa-Warfarin-GIB score were 0.916 (95% CI: 0.862-0.970, P < 0.001) and 0.919 (95% CI: 0.860-0.967, P < 0.001), respectively, which were higher than those of the HAS-BLED score (AUC = 0.868, 95% CI: 0.812-0.924, P < 0.001)., Conclusion: Based on nine risk factors, the Alfalfa-Warfarin-GIB score was constructed to predict the risk of warfarin-related major GIB. The newly developed Alfalfa-Warfarin-GIB score has a better predictive value than the HAS-BLED score and may be an effective tool to help reduce the occurrence of major GIB in patients on warfarin., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Vancomycin is commonly used in the prevention and treatment of intracranial infections in postoperative neurosurgical patients with narrow therapeutic window and large pharmacokinetic variations. Several population pharmacokinetic (PPK) models of vancomycin have been established for neurosurgical patients. But comprehensive external evaluation has not been performed for almost all models. The objective of this study was to evaluate the predictive ability of published vancomycin PPK models in adult postoperative neurosurgical patients using an independent dataset., Method: PubMed, Embase and China National Knowledge Internet databases were searched to identify published vancomycin PPK models in adult postoperative neurosurgical patients. Prediction-based and simulation-based diagnostics were used to evaluate model predictability. Bayesian forecasting was used to assess the influence of prior concentration on model prediction performance., Result: A total of 763 vancomycin plasma concentrations from 493 postoperative neurosurgical patients were included in the external dataset. Eight population pharmacokinetic models of vancomycin in postoperative neurosurgical patients were included and evaluated. The model by Zhang et al. exhibited the best predictive performance in prediction-based diagnostics and prediction-corrected visual predictive checks, followed by the model by Shen et al. The predictive performance of other models was not satisfactory. The normalized predictive distribution error test shows that none of the models is suitable to describe our data. The predictive performance of vancomycin models was obviously improved by maximum a posteriori Bayesian forecasting., Conclusion: The published PPK models for adult postoperative neurosurgical patients show extensive variation in predictive performance in our patients. Although it is challenging to recommend initial doses of vancomycin from these predictive models, the combination of model-based prediction and therapeutic drug monitoring can be used for dose optimization., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To summarize the pharmacokinetics of linezolid to optimize the dosing regimen in special populations., Methods: A literature search was performed in three largest medical databases, including Embase, Scopus, and PubMed. The main applied keywords were linezolid and pharmacokinetics. Of 3663 retrieved publications in the English language, 35 original research articles, clinical studies, and case reports about linezolid pharmacokinetics in different populations such as pregnant women, pediatrics, elderly subjects, obese people, individuals with organ dysfunction, and critically ill patients were included. RESULTS AND CONCLUSION: Dose adjustment is not currently recommended for linezolid in patients with mild to moderate renal or hepatic impairment, older adults, and pregnant women. Although dose adjustment is not recommended in patients with severe renal or hepatic impairment, it should be considered that these patients are more vulnerable to linezolid adverse effects and drug interactions. In pediatrics, reducing the linezolid dosing interval to 8 h is suggested. Despite the lack of sufficient information in obese individuals, dosing based on body weight or use of higher dose seems to be justifiable to prevent sub-therapeutic concentrations. Although dose adjustment of linezolid is not recommended in critically ill patients, administration of linezolid as continuous intravenous infusion is suggested in this population. Blood level monitoring should be considered in populations that are vulnerable to linezolid underexposure (such as critically ill patients with augmented renal clearance, pediatrics, overweight, and obese patients) or overexposure (such as elderly, patients with hepatic and renal impairment). To assess the efficacy and safety of linezolid, the area under the concentration-time curve over 24 h to minimum inhibitory concentration (AUC0-24 h/MIC) equal to 80-120, percentage of time above the MIC ≥ 85%, and serum trough concentration between 2 and 7 mg/L are suggested., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To compare survival outcomes, response rates, and adverse events (AEs) in proton pump inhibitor (PPI) user and non-user patients with metastatic colorectal cancer (mCRC) treated with regorafenib., Methods: We included 272 patients with mCRC treated with regorafenib in this study. Patients were divided into two categories according to their status of PPI use. The primary endpoint was overall survival (OS). The secondary endpoints were time to treatment failure (TTF), response rates, and safety. To exclude immortal time bias in survival analyses, we compared PPI non-user patients and all patients., Results: There were 141 and 131 patients in the PPI non-user and user groups. Baseline characteristics were similar in each group. Pantoprazole was the most used PPI. At the median 35.2 (95% confidence interval (CI): 32.6-37.9) months follow-up, the median OS was similar in PPI non-user and all patients (6.9 months (95% CI: 5.3-8.5) and 7.7 months (95% CI:6.6-8.8), p = 0.913). TTF was also similar in PPI non-user and all patients (3.3 months (95% CI: 2.7-3.9) and 3.5 months (95% CI: 3.0-4.0), p = 0.661). In multivariable analysis, no statistically significant difference was observed between PPI user and non-user groups in OS and TTF (hazard ratio (HR), 0.99; 95% CI, 0.77-1.28; p = 0.963 for OS; HR, 0.93; 0.77-1.20, p = 0.598 for TTF). The objective response rates (ORR) were similar in the PPI non-user and user groups (19.8% and 16.8%, p = 0.455). The rates of any grade AEs were also similar in each group., Conclusion: This study found no worse outcome in the combined use of PPI and regorafenib among patients with mCRC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To determine the influences of one or two consecutive missed topiramate (TPM) doses on TPM pharmacokinetics and to suggest the proper TPM replacement dosing schemes using Monte Carlo simulations., Methods: Monte Carlo simulations were performed for various replacement dosing schemes using the parameters from the published population pharmacokinetic models. The lowest percentage of deviation of simulated concentrations outside the reference range of 5-20 mg/L from the compliance scenario for each replacement dosing scheme was used as a criterion for choosing the proper replacement dosing scheme., Results: For the one missed dose, the replacement with an immediate regular dose and a partial dose resulted in the lowest and highest percentages of concentration below 5 mg/L, respectively. While the opposite results were observed for the upper bound of the reference range (20 mg/L). For the two consecutive missed doses, the replacement with one and a half-missed doses resulted in a lower percentage of deviation of concentrations below 5 mg/L from the compliance scenario than the replacement with one regular dose., Conclusions: For the one missed dose, taking an immediate regular dose might be suitable for patients who require higher TPM levels, while for patients who require lower TPM levels, an immediate partial dose could be used. For the two consecutive missed doses, an immediate one and a half regular dose might be suitable. However, these results were merely based on simulations; thus, they should be used alongside the clinician's justification based on seizure control., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aimed to investigate the factors affecting the plasma concentration of monohydroxylated derivative (MHD) of oxcarbazepine (OXC) in children with epilepsy., Methods: We recruited 125 children with epilepsy who received OXC monotherapy. Among them, 16 single nucleotide polymorphisms were detected by MassARRAY genotyping technology to evaluate the influence of related factors on the plasma concentration of OXC monotherapy. MHD is the main active metabolite of OXC, and its plasma concentration was measured by high-performance liquid chromatography (HPLC)., Results: Bivariate correlation analysis revealed that concentration-dose ratio (CDR) increased with weight, and the corresponding maintenance dose decreased with weight (r=0.317, P=0.001 for CDR; r=-0.285, P=0.000 for OXC maintenance dose). The duration of seizure was found to be associated with CDR (0.90 ± 0.36 vs 0.74 ± 0.26 μg·kg/mg/mL for ≥6 years vs <1 year, P=0.028; 0.90 ± 0.36 vs 0.64 ± 0.21 μg·kg/mg/mL for ≥6 years vs 1-3 years, P=0.004; 0.90 ± 0.36 vs 0.69 ± 0.18 μg·kg/mg/mL for ≥6 years vs 3-6 years, P=0.031). The CDR of patients with ABCB1 rs1045642 mutation homozygous GG type is higher than heterozygous AG type (0.79 ± 0.30 vs 0.68 ± 0.20 μg·kg/mg/mL for AG vs GG, P=0.032)., Conclusion: This study clarified the association of weight, duration of seizure, and gene polymorphisms of ABCB1 rs1045642 with MHD plasma concentration in children with epilepsy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To date, no study has identified a clear relationship between drug and a specific clinical presentation of DRESS., Objectives: To investigate the particularities of DRESS and analyze the variation of DRESS pattern according to culprit drugs., Methods: We analyzed cases of DRESS notified to the Department of Clinical Pharmacology at the University Hospital of Monastir over a 15-year period. The statistical study was performed using the comparative and multivariate analysis., Results: DRESS was mostly induced by anticonvulsive agents (27%) followed by allopurinol (26.3%) and antibiotics (24%): For anticonvulsive agents, the occurrence of lymphadenopathy was higher, renal involvement was rare and mild, and positive skin tests were more frequent. The allopurinol group was associated with the patient's older age and a lower incidence of lymphadenopathy and kidney injury. For antibiotics, eosinophilia rate was lower, time to recovery was shorter, and RegiSCAR score was low. The multivariate analysis showed a link of allopurinol with severe renal impairment, antibiotics with short latency period and low RegiSCAR score, and anticonvulsants with high propensity of positive skin test., Conclusion: We report the largest African and south Mediterranean cohort of DRESS and evaluated the usefulness of skin tests in identifying the culprit drug. The prominent finding was that latency period and renal involvement may independently differ according to culprit drugs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To investigate the prevalence of non-medical use (NMU) of codeine in Germany, Italy, Spain and the UK and whether availability of OTC codeine has any association with NMU of the drug., Methods: Data collected in the online Survey of Non-Medical Use of Prescription Drugs, in surveys launched in the second half of 2018 from (Germany (n = 14,969), Italy, (n = 9974), Spain (n = 9912) and the UK (n = 9819) were analysed. For each survey, the estimated prevalence and 95% confidence interval (CI) of respondents reporting NMU of prescription and/or OTC codeine within the last 12 months were calculated and compared., Results: The prevalence of last 12-month NMU in Spain was 12.6% (95% CI 11.7-13.6) for prescription codeine, 6.3% (5.6-7.0) for OTC codeine and 16.1% (15.1-17.3) for any codeine (prescription and/or OTC). The prevalence of last 12-month NMU in the UK was 5.4% (4.9-5.8) for prescription codeine, 4.5% (4.1-5.0) for OTC codeine and 8.3% (7.8-8.9) for any codeine (prescription and/or OTC). The prevalence of last 12-month NMU for prescription codeine was 2.1% (1.9-2.4) in Germany and 1.9% (1.7-2.2) in Italy., Conclusion: The prevalence of last 12-month NMU of any codeine product is approximately eight times greater in Spain and four times greater in the UK compared to Germany and Italy where the drug is only available by prescription. While other factors may contribute, these findings suggest that availability of codeine OTC is associated with greater NMU., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis is a rare autoimmune disease. Mycophenolic acid (MPA) is widely used for ANCA-associated nephritis (AAN) but with large pharmacokinetic variability. This study aims to investigate clinical factors impacting MPA disposition in pediatric AAN., Methods: We retrospectively collected 391 MPA concentrations from 25 children diagnosed with AAN. A population pharmacokinetic model was developed to explore the potential effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimen., Results: MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for K a , CL/F, V c /F, V p /F, and Q/F were 0.45 h -1 , 9.86 L/h, 19.69 L, 408.32 L, and 23.01 L/h. Dosage form significantly affected drug absorption. CL/F significantly decreased with increasing cystatin C, while decreasing with myeloperoxidase. Cystatin C was superior to serum creatinine in predicting apparent clearance of MPA. A dose regimen of 650 mg/m 2 twice daily was required to achieve target exposure in children with normal renal function and no inflammation. The combined effects of myeloperoxidase concentration and renal function resulted in a sixfold range of MPA dose., Conclusion: This was the first study of MPA population pharmacokinetic model in children with AAN. Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To develop and validate a population pharmacokinetic (PPK) model of valproic acid (VPA) in adult Chinese patients with bipolar disorder, and provide guidance for individualized therapy in this population., Methods: A total of 1104 serum concentrations from 272 patients were collected in this study. The data analysis was performed using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, biological characteristics, and concomitant medications. Bootstrap validation (1000 runs), normalized prediction distribution error (NPDE), and external validation of 50 patients were employed to evaluate the final model., Results: A one-compartment model with first-order absorption and elimination was developed for VPA extended-release tablets. VPA clearance was significantly influenced by three variables: sex (12% higher in male patients), daily dose (increasing with the 0.13 exponent), and body weight (increasing with the 0.56 exponent). Typical values for the absorption rate constant (K a ), apparent clearance (CL/F), and apparent distribution volume (V/F) for a female patient weighing 70 kg administered VPA 1000 mg/day were 0.18 h -1 , 0.46 L/h, and 12.84 L, respectively. The results of model evaluation indicated a good stable and precise performance of the final model., Conclusions: A qualified PPK model of VPA was developed in Chinese patients with bipolar disorder. This model could be used as a suitable tool for the personalization of VPA dosing for bipolar patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate time trends in the prevalence of antithrombotic and statin use in four European countries., Methods: Using population-based data from the United Kingdom, Denmark, Spain and Italy between 2010 and 2018, we calculated standardized annual prevalence proportions of antithrombotics and statin use, and changes in prevalence proportions (2018 vs. 2010)., Results: Prevalence proportion of statins increased from 24.8% to 24.6% (UK), 21.0% to 22.3% (Region of Southern Denmark [RSD]), 12.9% to 14.3% (Udine, Italy), and 20.3% to 23.2% (Spain). Prevalence proportions of antithrombotics declined in all four countries: 18.7% to 15.9% (UK; - 2.8% points), 18.9% to 18.1% (RSD; - 0.8% points), 17.7% to 16.6% (Udine; - 1.1% points) and 15.0% to 13.6% (Spain; - 1.4% points). These declines were driven by reductions in low-dose aspirin use: 15.3% to 8.9% (UK; - 6.4% points), 16.3% to 9.5% (RSD; - 6.8% points), 13.5% to 11.6% (Udine; - 1.9% points), and 10.2% to 8.8% (Spain; - 1.4% points). In the UK, low-dose aspirin use declined from 9.1% to 4.3% (- 4.8% points) for primary CVD prevention, and from 49.6% to 36.9% (- 12.7% points) for secondary prevention. Oral anticoagulant use gradually increased but did not fully account for the decrease in low-dose aspirin use., Conclusions: Antithrombotic use in the UK, RSD, Udine and Spain declined between 2010 and 2018, driven by a reduction in use of low-dose aspirin that is not completely explained by a gradual increase in OAC use. Use of statins remained constant in the UK, and increased gradually in the RSD, Udine and Spain., (© 2021. The Author(s).)

Purpose: This study aimed to assess the impact of the patient-centered prescription (PCP) model in medication adherence and effective prescribing in patients with multimorbidity., Methods: Uncontrolled before-after study in an intermediate care facility in a mixed urban-rural district. Inpatients aged ≥ 65 years with multimorbidity exposed to polypharmacy before hospital admission were consecutively enrolled. Every patient's treatment plan was analyzed through the PCP model, which includes interventions aimed at improving medication adherence. The primary endpoint was the change in the proportion of adherent patients between pre-admission and after discharge for all regularly scheduled long-term medications, using the proportion of days covered (PDC). Secondary endpoints included the change on mean PDC for all long-term medications, number of long-term medications, proportion of patients with hyperpolypharmacy, medication regimen complexity index (MRCI) score, drug burden index (DBI) score, number of potential inappropriate prescribing (PIP), and proportion of patients with ≥ 2 PIPs., Results: Ninety-three non-institutionalized patients were included (mean age 83.0 ± SD 6.1 years). The proportion of adherent patients increased from 22.1 to 51.9% (P < 0.001). Intervention also improved mean PDC [mean difference (95% CI) 10.6 (7.7, 13.5)] and effective prescribing through a reduction on the number of long-term medications [- 1.3 (- 1.7, - 0.9)], proportion of patients exposed to hyperpolypharmacy (- 16.1%, P < 0.001), MRCI score [- 2.2 (- 3.4, - 1.0)], DBI score [- 0.16 (- 1.8, - 1.3)], number of PIPs [- 1.6 (- 1.8, - 1.3)], and proportion of patients with ≥ 2 PIPs (- 53.7%, P < 0.001)., Conclusion: Studied intervention provides significant effective prescribing and medication adherence enhancements in non-institutionalized older patients with multimorbidity and polypharmacy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: There is no specific evidence on the antithrombotic management of survivors of out-of-hospital cardiac arrest (OHCA) due to acute myocardial infarction (AMI). We sought to compare the short-term outcome of unfractioned heparin (UFH) vs fondaparinux in OHCA survivors due to AMI admitted in our Institution in the last decade., Methods: We performed a retrospective cohort study on survivors of OHCA due to AMI managed with UFH or fondaparinux during the hospitalization. The primary outcome was the occurrence of any bleeding, all-cause mortality, cerebrovascular accidents, re-MI, and unplanned revascularization at 1 month. A propensity-score matching was performed to compare the outcome between UFH and fondaparinux., Results: Out of 2083 AMI patients undergoing successful PCI, OHCA was present in 94 (4.5%): 41 (43.6%) treated with UFH and 53 (56.4%) with fondaparinux. At clinical follow-up, the incidence of the primary outcome was 65.9% in UFH and 35.8% in fondaparinux group (p = 0.007). More than half of the events included in the primary outcome were related to bleeding complications. In the matched cohort of 56 patients, the primary outcome occurred in 46.4% and 25.0% (p = 0.16), while bleeding was present in 32.1% and 7.1% (p = 0.04), in the UFH and fondaparinux group, respectively., Conclusions: The present analysis suggests that fondaparinux is safer than UFH in the management of OHCA due to AMI by reducing early bleeding complications at one month., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To identify factors in community pharmacy that facilitate error recovery from medication incidents (MIs) and explore medication safety prevention strategies from the pharmacist perspective., Methods: Thirty community pharmacies in Sydney, Australia, participated in a 30-month prospective incident reporting program of MIs classified in the Advanced Incident Management System (AIMS) and the analysis triangulated with case studies. The main outcome measures were the relative frequencies and patterns in MI detection, minimisation, restorative actions and prevention recommendations of community pharmacists., Results: Participants reported 1013 incidents with 831 recovered near misses and 165 purported patient harm. MIs were mainly initiated at the prescribing (68.2%) and dispensing (22.6%) stages, and most were resolved at the pharmacy (76.9%). Detection was efficient within the first 24 h in 54.6% of MIs, but 26.1% required one month or longer; 37.2% occurred after the patient consumed the medicine. The combination of specific actions/attributes (85.5%), appropriate interventions (81.6%) and effective communication (77.7%) minimised MIs. An array of remedial actions were conducted by participants including notification, referral, advice, modification of medication regimen, risk management and documentation corrections. Recommended prevention strategies involved espousal of medication safety culture (97.8%), better application of policies/procedures (84.6%) and improvements in healthcare providers' education (79.9%)., Conclusion: Incident reporting provided insights on the human and organisational factors involved in the recovery of MIs in community pharmacy. Optimising existing safeguards and redesigning certain structures and processes may enhance the resilience of the medication use system in primary care., (© 2020. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose: Variability in teicoplanin pharmacokinetics has been explained by multiple factors such as body weight, renal function, and serum albumin level. To improve mechanistic understanding of the causes of variability, a physiologically based pharmacokinetic (PBPK) model can be used as a systematic platform. In this study, a PBPK model of teicoplanin was developed to quantitatively assess the effects of physiological changes due to disease status using virtual populations., Methods: Predictive performance of the models was evaluated by comparing simulated and observed concentration-time profiles of teicoplanin. Subsequently, sensitivity analyses were conducted to identify potential factors contributing to individual differences in teicoplanin PK., Results: The developed PBPK model generated concentration-time profiles that were comparable to clinical observations in healthy adults, including Caucasians and Japanese, and after single-dose and multiple-dose administration. The predicted PK parameters (i.e., C max , AUC, clearance) were within a two-fold range of the observed data in patients with renal impairments as well as healthy adults. Changes in total and unbound teicoplanin concentrations at 72 h, after various dosing regimens (tested 4-14 mg/kg q12h for three doses as a loading dose and then 4-14 mg/kg daily as a maintenance dose), were sensitive to renal function and serum albumin concentrations., Conclusion: The PBPK model of teicoplanin provides mechanistic insight into the factors altering its disposition and allows assessments of the theoretical and quantitative impact of individual changes in physiological parameters on its PK even when an actual assessment with adequate sample sizes of patients is challenging., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Purpose: Study drug discontinuation is commonplace in clinical trials of older populations. Little is known about why older participants discontinue the study drug. This qualitative study aimed to understand factors contributing to permanent study drug discontinuation among participants aged ≥ 70 years within an ongoing primary prevention trial of statins by exploring their experiences and perceptions., Methods: Trial participants who had permanently discontinued the study drug within 2 years of randomisation were purposively sampled by age (< 75 and ≥ 75 years) and sex to participate in semi-structured phone interviews between March 2019 and February 2020. Interviews were audio-recorded, transcribed and analysed thematically., Results: Thirty participants were interviewed (21 females; mean age, 77 years), and three themes were identified from the data. Perceived adverse events (AEs) and their effect on daily living (mobility, functional capacity, quality of life) were identified as the major factors leading to the participants permanently discontinuing their study drug, despite an ambiguity about the cause of the AE. For some, concurrent challenging life circumstances further lowered their tolerance to perceived AEs thus making discontinuation more likely. A few discontinuations were attributed to other factors (e.g. GP advice, unrelated illness)., Conclusion: Among healthy older participants enrolled in a statin trial, perceived AEs and their related impact were key factors contributing to the permanent study drug discontinuation. Addressing anticipated participant-reported AEs and their concerns about drug-related side effects at trial entry, as well as offering timely medical assistance and support when AEs occur, may be useful to reduce drug discontinuation rates.

Purpose: To examine the impact of new controlled drugs legislation introduced in May 2017 on benzodiazepine receptor agonist (BZRA) prescribing in Ireland., Methods: A repeated cross-sectional analysis was conducted using publically available monthly pharmacy claims data from the General Medical Services (GMS) database. The study population comprised all GMS-eligible individuals aged ≥ 16 years from January 2016 to September 2019. Monthly prevalence rates of individuals receiving BZRA prescriptions per 10,000 eligible population were calculated and trends examined over time. Segmented linear regression of prevalence rates was used to examine changes before and after introduction of the legislation stratified by gender and age groups. Regression coefficients (β) and 95% confidence intervals (CIs) for monthly change were calculated., Results: Pre-legislation (January 2016 to April 2017), there was a significant monthly decline in benzodiazepine prevalence rate (β = - 1.18; 95% CI - 1.84, - 0.51; p < 0.001) but no significant change in Z-drug prescribing. Post-legislation (May 2017 to September 2019), increases in prevalence rates were observed for benzodiazepines (β = 1.04; 95% CI 0.17, 1.92; p = 0.021) and Z-drugs (β = 1.04; 95% CI 0.26, 1.83; p = 0.010). Post-legislation trends showed increases in BZRA prevalence rates among the youngest subgroup (16-44 years), with variable changes in the middle-aged subgroup (45-64 years) and no changes in the oldest subgroup (≥ 65 years)., Conclusions: This study indicates that introduction of new legislation had limited impact on BZRA prescribing on the main public health scheme in Ireland. Interventions targeting specific population subgroups may be required to achieve sustained reductions in prescribing.

Purpose: Tizanidine, an alpha-adrenergic substance with antinociceptive and antihypertensive effects, is extensively metabolized via cytochrome P450 (CYP) 1A2. Therefore, coadministration with potent CYP1A2 inhibitors, such as ciprofloxacin, is contraindicated. However, both drugs are broadly utilized in various countries. Their concomitant use bears an inherent high risk for clinically significant symptoms, especially in multimorbid patients experiencing polypharmacy. This study aims to investigate the impact of coadministration of tizanidine and ciprofloxacin using real-world pharmacovigilance data and to raise awareness of this potentially underestimated safety issue., Methods: We conducted a retrospective study including Individual Case Safety Reports (ICSR) registered until March 1, 2017, in the World Health Organization (WHO) global database. Demographic data, drug administration information, the course of the adverse drug reaction (ADR), its severity, and outcomes were analyzed for cases reporting ciprofloxacin comedication., Results: In 91 (2.0%) of the identified 4192 worldwide ICSR on tizanidine, coadministration of ciprofloxacin was reported. Most of the patients were female (n = 59, 64.8%) with a median age of 54 years (range 13-85 years). The countries contributing most reports were the USA (n = 54, 59.3%) and Switzerland (n = 16, 17.6%). ADRs reported most often affected the nervous system and the cardiac function, especially with large tizanidine doses or drugs with CNS and cardiovascular depressant effects. In two cases, a fatal outcome was reported., Conclusion: Despite the existing formal contraindication, the concomitant use of tizanidine and ciprofloxacin can be observed in real-world clinical practice. Reactions mainly affected the central nervous and the cardiovascular system resulting in potentially severe adverse effects. The concomitant use of tizanidine and ciprofloxacin should absolutely be avoided.

Purpose: To assess, with all available trial information, whether the assessment of the PRECIS-2 nine domains could provide a clear distinction between medicine masked pragmatic randomized controlled trials (pRCTs) and open-label pRCTs., Methods: A search was conducted of participant-level pRCTs on medicines published on 25 influential medical journals in July 2018-December 2019. All pre-licensing (phases 1-3) and cluster pRCTs were excluded. All trials' available reports were searched through the published article information, Google Scholar, and trial websites. Instead of providing a score to each PRECIS-2 domain, these were classified as E (explanatory), N (neutral), or P (pragmatic)., Results: Of 128 pRCTs, 18 (14%) were participant-level pRCTs on medicines. The full trial protocol was available for 14 trials; 12 had published the protocol and nine had additional reports published. All trials were prospectively registered, and none was funded by industry. Ten and eight were masked and open-label trials, respectively. Masked pRCTS had 34% of pragmatic and 60% of explanatory domains; open-label pRCTS had 45% pragmatic and 45% explanatory domains. Among the 10 masked trials, only one had a majority of five pragmatic domains; among the eight open-label trials, four had a majority of six or five pragmatic domains. "Follow-up" was considered explanatory in the 18 pRCTs; "primary analysis" was pragmatic in 17 pRCTs., Conclusion: The PRECIS-2 tool seems not to be sensitive enough to clearly discriminate between medicine masked pRCTs and open-label pRCTs. When conducting systematic reviews, it is suggested that the PRECIS-2 tool should not be used to support placing masked trials in the pragmatic side of the explanatory/pragmatic continuum.

Purpose: Tigecycline is one of few antibiotics active against multidrug-resistant bacteria; however, the assessment of dosing strategies to optimize its activity is needed. The purpose was to use Monte Carlo Simulation (MCS) to determine if safe tigecycline dosing options attaining breakpoints for pharmacokinetic/pharmacodynamic (PK-PD) targets in non-critically ill adults could be identified., Methods: Publications that evaluated tigecycline dosing regimens and provided mean PK variables of interest (minimum 2 of: elimination rate constant or half-life and volume of distribution or clearance), with SDs, were included. Weighted mean (±SDs) for each PK parameter were determined. Food and Drug Administration minimum inhibitory concentration (MIC) tigecycline breakpoints for susceptible (MIC ≤ 2 μg/mL), intermediate (MIC 4 μg/mL), and resistant (MIC ≥ 8 μg/mL) Enterobacteriaceae were used. MCS probability distributions for PK-PD target attainment of AUC for total tigecycline plasma concentration from 0 to 24 h following an intravenous dose (AUC total, 0-24h ) to MIC ratios of ≥ 18, 7, and 4.5 were generated, with success defined as ≥ 80% probability of target attainment at a given MIC., Results: Ten studies (n = 442) were eligible. Tigecycline 150 mg IV q12h for ward patients with resistant bacteria up to a MIC of 0.48, 1, and 2 μg/mL for an AUC total, 0-24h /MIC target attainment of 18, 7, and 4.5, respectively, may be appropriate., Conclusion: Bacterial infections with tigecycline MICs ≥ 0.48-2 μg/mL, depending on AUC total, 0-24h /MIC target, may require treatment with alternate antibiotics due to target attainment failure.

Purpose: Oxcarbazepine (OXC) is an antiepileptic drug metabolised to active 10-monohydroxy derivative (MHD) following oral administration. There are no MHD population pharmacokinetic (PPK) models that describe the influence of genetic factors on MHD pharmacokinetics (PK). We developed a PPK model of MHD to investigate gene polymorphism of enzymes associated with MHD PK in Chinese paediatric epilepsy patients and evaluated its utility for dose individualisation., Methods: Data were prospectively collected from 141 paediatric epilepsy patients (aged ≤ 14 years) who received OXC therapy at the First Affiliated Hospital of Fujian Medical University. The trough concentrations at steady state were determined by enzyme-multiplied immunoassay. Patients were genotyped for four single nucleotide polymorphisms (UGT2B7 802T>C, UGT1A9 I399C>T, ABCB1 3435C>T, and ABCB2 1249G>A). Patient gender, age, body weight (BW), hepatorenal function, and co-administrations were recorded. The PPK model was developed using nonlinear mixed-effects modelling software. The clinical performance of the final model was evaluated by including additional paediatric patients (n = 20) in the validation group., Results: Oral clearance of MHD was significantly influenced by BW. The MHD PK was unrelated to the other covariates, such as the four single nucleotide polymorphisms and co-administration with new-generation antiepileptic drugs. The final BW-dependent exponent model showed the best fit with our data and predicted the trough concentrations in the validation group more accurately than the basic model. A new dosing strategy combining the dosage guideline and Bayesian method is proposed to individualise OXC regimens., Conclusion: A PPK model was established to estimate individual MHD clearance in paediatric patients taking OXC to develop individualised OXC dosing regimens for Chinese paediatric epilepsy patients.

Purpose: Although guidelines caution against initiation of transdermal (TD) fentanyl among those who are opioid naïve, there is concern that not all people receive adequate prior opioid exposure. This study examined the percentage of people who are opioid naïve at the time of TD fentanyl initiation in Australia; strengths initiated; and characteristics associated with being opioid naïve., Methods: This is a national retrospective cohort study derived from a 10% sample of Pharmaceutical Benefits Scheme concessional beneficiaries initiating TD fentanyl between 29 September 2009-31 December 2013. Individuals were deemed opioid naïve if they had no opioid dispensings in the previous 90 days. Logistic regression was used to determine characteristics associated with being opioid naïve, including socio-demographics, likely comorbidities and previous analgesic use., Results: A total of 13,166 people initiated TD fentanyl; 60.4% were female and 76.2% were aged ≥ 65 years. Three in ten (30.4%) were opioid naïve and 63.2% initiated the 12 mcg/h patch. Those who were opioid naïve were more likely to be female (adjusted odds ratio (aOR) 1.35; 95% CI 1.25-1.46), older (aOR 1.85; 95% CI 1.54-2.28 for those ≥ 85 years) and previously dispensed medicines for dementia (aOR 1.37; 95% CI 1.04-1.80). People previously dispensed medicines for cancer were less likely to be opioid naïve (aOR 0.57; 95% CI 0.48-0.67)., Conclusions: Three in ten Australians initiating TD fentanyl are opioid naïve. Our findings suggest that specific patient sub-populations already at increased risk of opioid-related adverse events are not receiving prior opioid treatment before initiation, highlighting the need for greater adherence to current treatment guidelines.

Purpose: Pulmonary hemorrhage is a life-threatening condition characterized by blood leakage into lung tissues, leading to severe respiratory distress. Nebulized tranexamic acid (TXA) has emerged as a promising treatment option for pulmonary hemorrhage due to its localized hemostatic effects and minimal systemic side effects. This review aims to summarize the research progress on the effectiveness and safety of nebulized TXA in pulmonary hemorrhage., Methods: A comprehensive search of the Embase, PubMed, and Scopus databases was conducted to identify relevant studies published between the date of inception of each database and November 2023. A comprehensive search was conducted in the PubMed, Embase, Scopus, and Google Scholar databases using the following keywords: "hemoptysis," "haemoptysis," "pulmonary hemorrhage," "tranexamic acid," "antifibrinolytic," "nebulize," and "inhale." Additional articles were identified by reviewing the references of the retrieved studies. Studies were selected based on their focus on the application of nebulized TXA for pulmonary hemorrhage. The authors and dates of publication, study type, patients, diseases, intervention and main outcomes of these papers are tabulated. This consisted of two randomized controlled trials (RCTs), six case series, and nine case reports., Results: The commonly used dosage of nebulized TXA in the studies reviewed was 500 mg/5 ml, administered 3-4 times daily. Evidence suggests that nebulized TXA effectively controls bleeding in pulmonary hemorrhage with a hemostatic efficacy comparable to systemic administration, but with a lower risk of venous thrombosis. Safety data indicates that nebulized TXA is generally well-tolerated, with no significant systemic adverse reactions reported. Local reactions, such as bronchospasm, were rare and resolved with short-term bronchodilator treatment., Conclusion: Nebulized TXA appears to be an innovative and minimally invasive therapy for pulmonary hemorrhage, providing targeted hemostatic effects with a favorable safety profile. However, the predominance of small-scale studies and case reports highlights the need for large-scale, high-quality research to establish standardized guidelines., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: The shape and position of the hemoglobin-oxygen dissociation curve (ODC) is of critical importance in medicine, as it determines the uptake of O 2 in the lungs and the delivery of O 2 to the tissues. Numerous reports have identified affinity-modulating effects of drugs in humans. Such effects may be relevant to conditions such as pulmonary diffusion disorders, peripheral vascular disease, or coronary artery disease. The aim of this scoping review was to assess and summarize the current evidence on these effects., Methods: The review was based on the PRISMA-ScR guidelines. We searched PubMed and the Cochrane Library and only included papers with free full-text access. The search covers all papers published before September 2024 and used the following keywords: "Oxygen affinity" or "oxygen dissociation curve" in combination with > 100 substance classes that should cover most drugs in clinical use., Results: The search returned 2447 hits of which 80 were selected for further full text review. In terms of discipline, cardiology accounted for the largest proportion, and in terms of effect quality, a right-ward shift resulting in improved tissue oxygenation was most common. For example, quantitative data show an increase in P 50 of 6.1-12.4% and 25-53% for propranolol and RSR13, respectively., Conclusion: Despite a substantial body of data, the effects of the vast majority of drugs on the ODC have not been studied or have not been studied in sufficient detail. The undeniable potential for medical interventions to alter the ODC calls for revival of this area of research., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Multiple sclerosis (MS) is an immune-mediated disease that has a considerable health-related quality of life interference. Various disease-modifying therapies (DMTs) in MS management have been approved by the Food and Drug Administration or are currently used off-label. DMTs aim to slow down the progression of MS and decrease the frequency of relapses. This systematic review aimed to evaluate the budget impact of DMTs worldwide., Methods: A systematic search query was made to identify related articles in scientific databases. Eligible papers included their characteristics and model inputs, and results were extracted and reported. To critique the standard reporting of studies, a 32-item quality assessment checklist was used., Results: From 1865 records, 22 original budget-impact analyses (BIAs) were included. All BIAs were accepted in the quality assessment (Mean score: 84.4). The most used DMT was β-interferons and natalizumab among novel DMTs. The results of BIAs were highly sensitive to the route of administration, costs of side effects and administration, and presence of biosimilars. However, glatiramer acetate has not experienced significant discounts was the most reported budget-saving DMT., Conclusion: From the results, it can be concluded the budget impact of DMTs in managing symptoms and improving the quality of life of MS patients according to the setting included in the modeling and according to specific conditions and context is different and significantly affects the results of BIAs. For accurate predictions of the effects of DMTs on the distribution of budgets in the MS population, more specific BIAs with higher quality should be done., Competing Interests: Declarations. Ethics approval: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This paper was aimed at unveiling the effect of low-molecular-weight heparin calcium (LMWH) combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function, and pregnancy outcome in early-onset severe preeclampsia (EOSP)., Methods: Pregnant women with EOSP were divided into the control group and the study group, each with 62 cases. Patients in the control group were treated with labetalol and magnesium sulfate, and those in the study group were treated with LMWH in combination with the control grou Blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), 24-h urine protein, coagulation indices [D-dimer (D-D), plasma fibrinogen (Fg), prothrombin time (PT), activated partial thromboplastin time (APTT), and prothrombin time (TT)], endothelial function [endothelin (ET-1) and nitric oxide (NO)], oxidative stress indices [oxidized low-density lipoproteins (ox-LDL), lipid peroxidation (LPO), superoxide dismutase (SOD), and malondialdehyde (MDA)], pregnancy outcome, and adverse effects occurred in the two groups were compared., Results: After treatment, lower SBP, DBP, and 24-h urine protein levels; lower Fg and D-D levels; higher PT, APPT, and TT levels; higher NO levels; lower ET-1 levels; lower ox-LDL, MDA, and LPO levels; higher SOD levels; and lower incidence of adverse pregnancy and adverse reactions were noted in the study group in contrast to the control group., Conclusion: EOSP patients given with LMWH combined with magnesium sulfate and labetalol can effectively reduce the patient's blood pressure and urinary protein level; improve coagulation function, oxidative stress, and vascular endothelial function indices; reduce the adverse pregnancy outcomes; and improve the safety of treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Central nervous system (CNS) tumors are among the most common malignancies in various age ranges. Low-grade glioma (LGG) can account for nearly 30% of pediatric CNS malignancies. Progression or recurrence after the first-line treatments is common among these patients. Therefore, more treatments are required. Bevacizumab as an anti-VEGF antibody has come into the spotlight recently and is especially used in relapse or recurrence settings. This review aims to study the safety and efficacy of bevacizumab for patients with recurrent LGG., Methods: This study was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Scopus, Web of Science, and Embase were comprehensively searched using the relevant key terms until 24th August 2023 to retrieve the studies that investigated clinical outcomes of bevacizumab in patients with recurrent LGG. All statistical analysis was performed by STATA v.17., Results: A total of 1306 papers were gathered, out of which 13 were incorporated in the meta-analysis. The pooled incidence rate of treatment according to the RANO scale was 70% (95% CI = 43-98%) for objective response rate, 26% (95% CI = 58-96%) for partial response, 21% (95% CI = 15-28%) for minor response, 14% (95% CI = 3-24%) for complete response, 48% (95% CI = 37-59%) for stable disease, and 8% (95% CI = 4-11%) for progressive disease. Furthermore, according to progressive survival after treatment, it was 4% (95% CI = -1 to 9%) for 6-month PFS, 41% (95% CI = 32-50%) for 2-year PFS, and 29% (95% CI = 22-35%) for 3-year PFS., Conclusion: According to the RANO scale and PFS, clinicians should be aware that Bevacizumab could be a favorable alternative therapy for recurrent LGG. Furthermore, bevacizumab exhibits minimal toxicity and high tolerability in recurrent LGG., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)