Kojima T, Saito M, Matsuda T
… +12 more, Simmons N, Nagata M, Miyagawa M, Wojtkowski T, Guro S, Koibuchi A, Cruz KS, Neutel JM, Free AL, Sekino H, Haas GP, Takusagawa S
Eur J Clin Pharmacol
· 2026 Apr · PMID 42032338
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PURPOSE: To elucidate mechanisms of renal excretion of pudexacianinium (ASP5354) and evaluate renal impairment effects on pharmacokinetics, safety, and tolerability of pudexacianinium. METHODS: Transcellular transport an...PURPOSE: To elucidate mechanisms of renal excretion of pudexacianinium (ASP5354) and evaluate renal impairment effects on pharmacokinetics, safety, and tolerability of pudexacianinium. METHODS: Transcellular transport and transporter-mediated uptake of pudexacianinium were investigated in cells expressing human renal drug transporters P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, and MATE2-K. A Phase 1, open-label, parallel-group study (N = 28) was conducted in 6 participants each with mild, moderate, and severe renal impairment; 10 with normal renal function. Participants received a single intravenous dose of pudexacianinium 3 mg. Plasma and urine were collected post-dosing for pharmacokinetics. RESULTS: In vitro, pudexacianinium was not a substrate of the drug transporters tested. In humans, mean maximum concentration of pudexacianinium in plasma was comparable across study groups regardless of renal impairment. Systemic exposure was highest with severe renal impairment and decreased in parallel with renal impairment severity. Geometric least-squares mean ratios for area under the plasma concentration–time curve from time 0 to time infinity were 1.53, 2.30, and 3.69, respectively, for mild, moderate, and severe renal impairment, versus matched participants with normal renal function. During the 48-h collection, 64% of pudexacianinium was recovered unchanged in urine in the severe renal impairment group versus ≥ 90% recovered in other groups. Mean renal clearance was comparable with estimated glomerular filtration rate of unbound drug. Pudexacianinium was well tolerated, with an acceptable safety profile. CONCLUSION: Pudexacianinium elimination occurs primarily through glomerular filtration. Renal impairment significantly affected pudexacianinium pharmacokinetics. Single intravenous doses of pudexacianinium were generally tolerable in all participants, regardless of renal impairment. Trial registration. ClinicalTrials.gov identifier: NCT05495581, registered August 9, 2022.
Mueller T, Stobo L, Jarvis L
… +10 more, Millar M, Moore E, Hopkins L, Stark V, Hynd A, Osei-Oppong K, Kurdi A, McTaggart S, Wood R, Bennie M
Eur J Clin Pharmacol
· 2026 Apr · PMID 42029739
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PURPOSE: Pharmacological treatment during pregnancy is often necessary but presents challenges due to limited availability of safety data. In response to a UK-wide review of medicine safety, the Scottish Government commi...PURPOSE: Pharmacological treatment during pregnancy is often necessary but presents challenges due to limited availability of safety data. In response to a UK-wide review of medicine safety, the Scottish Government commissioned the development of a national surveillance infrastructure to monitor medicines use during pregnancy and associated clinical outcomes. METHODS: Two real-world data assets were developed by integrating routinely collected primary and secondary care data: the Scottish Combined Medicines Dataset (SCoMeD) consolidates medicines data, while the Scottish Linked Pregnancy and Baby Dataset (SLiPBD) captures comprehensive data related to pregnancies. Two exemplar case studies were conducted to test the utility of these datasets. First, an audit of anti-seizure medicines (ASM) prescribing 04.2018–03.2025; and second, a retrospective cohort study of pregnancies conceived between 04.2010 and 06.2023, matching ASM exposed to ASM unexposed pregnancies to assess pregnancy, baby, and early childhood outcomes. Study periods were chosen based on data availability. RESULTS: The linkage of SCoMeD and SLiPBD enabled national-level surveillance of ASM prescribing trends and in-utero exposures. ASM prescribing surveillance showed an expected decrease in the use of valproate and topiramate among women of childbearing age, reflecting regulatory risk minimisation measures. Observational analyses confirmed valproate-associated teratogenic and developmental risks, whilst supporting the relative safety of lamotrigine and levetiracetam during pregnancy. CONCLUSIONS: This programme demonstrates the value of leveraging nation-wide, whole system data for the surveillance of medicines safety in pregnancy. The linkage of real-world data provides regulatory-relevant evidence to inform guidelines and risk minimisation strategies. Scotland’s integrated medicines infrastructure positions the country as a key contributor in the European pharmacovigilance landscape.
Henze J, Dormann H, Schneider CV
… +6 more, Meeßen C, Knüppel-Ruppert A, Kriegisch-Stumpf A, Schwab M, Stingl JC, Just KS
Eur J Clin Pharmacol
· 2026 Apr · PMID 42020558
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PURPOSE: Metabolic dysfunction–associated steatotic liver disease (MASLD) as the main cause of chronic liver disease worldwide is associated with increased mortality. Especially in patients with fibrosis, an increased ri...PURPOSE: Metabolic dysfunction–associated steatotic liver disease (MASLD) as the main cause of chronic liver disease worldwide is associated with increased mortality. Especially in patients with fibrosis, an increased risk of adverse drug reactions (ADRs) might be present. Therefore, the impact of high-risk for liver fibrosis on the outcome of ADRs was analyzed. METHODS: Patients of a multicenter cohort study in maximum care emergency departments (ED) with admissions due to ADRs with available FIB-4 score parameters were analyzed. The cohort was divided into patients with low (FIB-4 < 2.67) and high (FIB-4 ≥ 2.67) liver fibrosis risk. Triage at ED admission, ADR seriousness criteria, discharge status, and length of hospital stay were used as outcomes. Logistic and linear regression analyses were applied. RESULTS: Among the 1087 patients, 407 had a high risk of fibrosis (37.4%). High risk of fibrosis was associated with serious ADRs (OR 2.42 (95% CI 1.57–3.73)), a poor discharge status including deaths (3.51 (2.20–5.60)), and a longer stay in the hospital (2.02 (1.00–3.05)), while urgent triage at ED admission was not significantly associated with high fibrosis risk (0.95 (0.71–1.28)). CONCLUSION: In patients at risk of MASLD, careful risk assessment is essential when prescribing drugs, as serious ADRs may occur unnoticed in the presence of liver fibrosis. Even simple non-invasive tests like the FIB-4 score may provide valuable prognostic hints in the acute event of an ADR.
BACKGROUND: Dexamethasone is commonly added to local anesthetic–based perioperative regimens to improve postoperative analgesia and reduce postoperative nausea and vomiting (PONV), but the consistency of benefit across p...BACKGROUND: Dexamethasone is commonly added to local anesthetic–based perioperative regimens to improve postoperative analgesia and reduce postoperative nausea and vomiting (PONV), but the consistency of benefit across procedures remains uncertain. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials comparing dexamethasone-containing regimens versus the same local anesthetic without dexamethasone. PubMed, Web of Science, Scopus, and the Cochrane Library were searched. Outcomes included pain scores at prespecified postoperative timepoints (1–24 h), rescue analgesia use and timing, and PONV. Random-effects models were applied. RESULTS: Nine trials were included from 902 records. Most were laparoscopic cholecystectomy, with one bariatric-surgery trial and one hysterectomy trial; comparisons were generally balanced (20–52 patients/arm). Pain scores significantly favored dexamethasone addition at 1 h (MD − 0.75), 2 h (MD − 0.84), 4 h (MD − 1.91), 12 h (MD − 1.12), and 24 h (MD − 1.28), but heterogeneity was substantial to high across timepoints (I² ≈72%–96%) and prediction intervals generally crossed the null. Rescue analgesia use within 0–24 h was significantly reduced with the addition of dexamethasone (RR 0.85), and time to first rescue analgesia was longer (MD 169 min). PONV was consistently lower with dexamethasone (RR 0.28) with no heterogeneity observed. CONCLUSIONS: Dexamethasone reduces PONV reliably and may improve postoperative pain, rescue analgesia requirements and PONV, although analgesic effects are inconsistent across trials.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specificall...PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
Suthahar T, Veerabhadrappa J, Munshi R
… +4 more, Anbu Raj E, Gota V, Ivaturi V, Mallayasamy S
Eur J Clin Pharmacol
· 2026 Apr · PMID 41984244
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Purpose 5-Fluorouracil (5-FU) is a traditional chemotherapeutic agent used in the treatment of multiple cancers. This systematic review aimed to summarize the population pharmacokinetic (PopPK) models for both intravenou...Purpose 5-Fluorouracil (5-FU) is a traditional chemotherapeutic agent used in the treatment of multiple cancers. This systematic review aimed to summarize the population pharmacokinetic (PopPK) models for both intravenous and pro-drug formulations in cancer patients and to understand the different covariates that affect the pharmacokinetics of 5-FU. Methods the search included studies published from inception to December 2025 in the English language. The non-linear mixed effects model with parametric approach for 5-FU in cancer patients was set as the inclusion criteria. A total of 186 articles were screened for their titles and abstracts from Scopus, PubMed and EMBASE. Out of which 156 were excluded. Out of the 36 articles reviewed, 21 were found suitable for the review. Most of the studies reported a one-compartmental model. Several covariates, including body surface area (BSA), body weight, cancer type, age, gender, UH2/U ratio, serum albumin, creatinine clearance, alkaline phosphatase, total bilirubin, and skeletal muscle index (SMI), influence the pharmacokinetic parameters, including clearance and volume of distribution. Results skeletal muscle index (SMI), body weight, sex, and BSA were the primary covariates influencing the pharmacokinetics of 5-FU. Among the covariates consistently reported as significant, sex was an important determinant of clearance, with males exhibiting higher clearance than females. Increases in body weight and skeletal muscle index were associated with increased clearance, while volume of distribution decreased with lower body surface area. Alkaline phosphatase was reported to have a negative effect on clearance. The substantial interindividual variability observed across studies likely contributes to heterogeneity in reported covariate effects and underscores the need for individualized dosing approaches for 5-FU. Conclusion body weight and sex reported to show clinical significance. This necessitates the need for consideration of these covariates in dosing adjustment. This review summarizes covariates influencing the pharmacokinetics of 5-FU, and reports those identified as significant based on forest plot analysis. This study helps the researchers to perform predictive performance of the reported PopPK models, supporting future model-informed precision dosing strategies for 5-FU-based therapies.
OBJECTIVES: The aim of this study is to indirectly compare and rank the different drugs that have been studied in randomized clinical trials (RCTs) in patients with tardive dyskinesia (TD) in terms of their efficacy in a...OBJECTIVES: The aim of this study is to indirectly compare and rank the different drugs that have been studied in randomized clinical trials (RCTs) in patients with tardive dyskinesia (TD) in terms of their efficacy in ameliorating the symptoms of TD and safety. DESIGN: A network meta-analysis and a systematic review was registered prospectively on PROSPERO under the ID: CRD42023407823 and was conducted in accordance with the PRISMA-NMA guidelines. DATA SOURCES: PubMed, Scopus, The Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and Clinicaltrials.gov were searched to identify relevant records. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Any parallel randomized blinded controlled clinical trials that studied the use of any medications in treating TD and assessed the symptoms using a functional scale that has been previously validated. DATA EXTRACTION: The standardized mean difference of improvement along with the reported adverse events for each drug were extracted from each trial and a network meta-analysis was conducted using a random-effects model. RESULTS: One thousand eight hundred seventeen patients in 33 RCTs were included in the analysis. Twenty-three different drugs were compared to placebo in terms of reduction in TD symptoms. Among these, Insulin (SMD = -2.16, 95%CI = [ -3.62; -0.69]), vitamin E (-1.18, [-1.69; -0.68]), and valbenazine 80 mg (SMD = -0.77, 95%CI = [ -1.48; -0.07]) significantly reduced TD symptoms in comparison to placebo, while deutetrabenazine 36 mg (-0.53, [-1.52; 0.47]) and reserpine (-0.97, [-2.29; 0.36]) were not found to be significant in reducing the symptoms. Some serious adverse events were reported for valbenazine and deutetrabenazine, which included mainly psychiatric symptoms such as depression, worsening of schizophrenia and suicidal ideation, while mild adverse events were reported for other drugs, their incidence in the treatment arms were comparable to those in the placebo arm. CONCLUSIONS: Low-certainty evidence suggests that insulin, vitamin E, and valbenazine 80 mg may reduce TD symptoms. However, the significant side effects of valbenazine should prompt further investigation of alternative treatment modalities.
PURPOSE: Biosimilars offer a cost-effective alternative to originator biologics, but their global adoption remains uneven due to differences in regulatory standards, pharmacovigilance capacity, and healthcare infrastruct...PURPOSE: Biosimilars offer a cost-effective alternative to originator biologics, but their global adoption remains uneven due to differences in regulatory standards, pharmacovigilance capacity, and healthcare infrastructure. This review compares biosimilar regulatory and safety frameworks in developed (United States, European Union, Japan) and developing (India, Brazil, South Africa) markets to identify key gaps and opportunities for alignment. METHODS: A focused narrative review was conducted using peer-reviewed literature from PubMed, Scopus, and Web of Science complemented by official regulatory guidelines, pharmacovigilance reports, and policy documents published by national and international health authorities. RESULTS: Regulatory agencies in developed economies like FDA, EMA, and PMDA maintain rigorous evaluation processes and robust pharmacovigilance systems. In contrast, developing economies exhibit variability: India, while a major biosimilar producer, faces quality and harmonization challenges; Brazil and South Africa struggle with affordability and infrastructure, limiting uptake. CONCLUSION: The successful integration of biosimilars depends on regulatory maturity, strong pharmacovigilance, and stakeholder awareness. Efforts should focus on harmonizing international standards, strengthening safety monitoring, and improving clinician and patient education. Key takeaways include the need for shared international safety data platforms, the elimination of redundant local bridging studies, and the implementation of pharmacy-level substitution to maximize cost-savings. Harmonization is critical to ensuring equitable access to biologics across diverse economic landscapes.
INTRODUCTION: Vulnerability to heat-related illnesses may be increased by certain drugs due to various mechanisms. Whereas in articles only rough classifications of heat-vulnerability increasing drugs (HVID) are mentione...INTRODUCTION: Vulnerability to heat-related illnesses may be increased by certain drugs due to various mechanisms. Whereas in articles only rough classifications of heat-vulnerability increasing drugs (HVID) are mentioned, a detailed compilation of suspected HVID is still missing. Aim of the study was to identify HVID. METHODS: Using data from the literature, potential HVID were searched. The evidence for increasing heat-vulnerability, based on PubMed research, was rated as „high“, „possible“ or „unlikely“ by 3 investigators, independently and blinded to the others’ results. RESULTS: The initial search retrieved 572 potential HVID. After analyzing 27 trials in healthy subjects, 25 cohort-studies, 19 case-reports, 14 reviews, 7 prospective trials in patients and 4 pharmacovigilance-studies, the evidence to increase heat-vulnerability was assessed as “high” for 110, “possible” for 390 and “unlikely” for 72 drugs. Drugs for the nervous-system, cardiovascular-system and alimentary-tract were most frequent. Hypohidrosis (n = 127), disturbed thermoregulation (n = 35) or skin-circulation (n = 15) and dehydration (n = 10) were frequent mechanisms. Outcome events in cohort-studies were heat-illness/dehydration (n = 10), causes of death (n = 5), heat-related hospital admissions (n = 4), heat-stroke (n = 4), drug-overdose in heat-periods (n = 1) and hypohidrosis (n = 1). Comedication, when reported, disclosed additional HVID in all patients. Conflicting results about heat-vulnerability properties were found for 10 HVID. CONCLUSION: Knowledge about HVID and their clinical relevance is limited. The quality of data is poor and derives mainly from young and healthy subjects. The outcome events are heterogeneous. Interdisciplinary research involving pharmacologists, physicians of different disciplines, pharmacists and health-care workers is needed to create and evaluate plans about modification of drug-therapy during heatwaves.
Eur J Clin Pharmacol
· 2026 Apr · PMID 41964759
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BACKGROUND: Increased rates of clozapine prescribing are essential to improving timely patient access within treatment-resistant schizophrenia (TRS) management. The extent of geographical variation in its use suggests it...BACKGROUND: Increased rates of clozapine prescribing are essential to improving timely patient access within treatment-resistant schizophrenia (TRS) management. The extent of geographical variation in its use suggests it is possible to develop interventions to increase clinician engagement. To inform intervention development, a contemporary review of barriers and facilitators to increased clozapine prescribing is required. We aimed to conduct a systematic review of research addressing barriers and facilitators to clozapine prescribing among clinicians within TRS management. METHODS: The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, CINAHL, and PsycINFO were searched from inception to July 2025. Results were synthesized qualitatively. RESULTS: Fifteen studies were included. Barriers related to clinicians, patients and carers, and healthcare institutions. Primary clinician-related barriers included insufficient knowledge of, and confidence in, managing clozapine treatment and the associated administrative burden. Primary patient-related barriers included concerns regarding patients' willingness to consistently adhere to clozapine treatment and associated monitoring requirements. A lack of dedicated systems of care to facilitate clozapine initiation and shared community care were the leading institutional barriers. Major facilitators included improved education for clinicians, access to point-of-care testing, and increased availability of dedicated clozapine clinics. CONCLUSION: Most barriers to systematically increasing clozapine prescribing rates are beyond the influence of individual prescribers. Instead, structural interventions focusing on (i) reducing the administrative burden associated with establishing clozapine treatment, (ii) increasing access to standardised training and supervision opportunities, and (iii) providing longitudinal support to clinicians when managing clozapine treatment, are required.
Mian P, Lok CAR, Dontje AEWK
… +6 more, Prins JR, Oude Munnink TH, Nieuwenhuizen L, Gordijn SJ, Touw DJ, Malik P
Eur J Clin Pharmacol
· 2026 Apr · PMID 41964700
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PurposeTo simulate different dosing regimens of imatinib in third trimester pregnant women with CML that could meet plasma exposure targets for efficacy (Cmin≥1000 ng/mL) without compromising on fetal safety risk.Methods...PurposeTo simulate different dosing regimens of imatinib in third trimester pregnant women with CML that could meet plasma exposure targets for efficacy (Cmin≥1000 ng/mL) without compromising on fetal safety risk.MethodsAn initial physiologically-based pharmacokinetic (PBPK) model from Loer et al. was verified with routine non-pregnant PK data from a single center and then scaled to pregnancy by implementing pregnancy physiological and enzymatic changes relevant to imatinib PK. The pregnancy model was evaluated by comparing predictions with PK data observed in pregnant women receiving imatinib 400 mg once daily (QD). Simulations explored different dosing regimens that would meet Cmin≥1000 ng/mL without meaningfully higher AUC0-24h.ResultsPredictions for imatinib PK in the third trimester were well aligned with the observed data. Simulations indicate that 14.4% of third trimester pregnant women would achieve plasma Cmin≥1000 ng/mL at 400 mg QD, compared to 51.7% of non-pregnant female comparators receiving the same dose.ConclusionsWhile dividing 400 mg QD into 200 mg twice daily (BID) could modestly improve PK target attainment for third trimester pregnant women (28.5%), a dose of 300 mg BID could be needed to match Cmin target attainment (54.2%) and AUC0-24hwith expectations for a non-pregnant population receiving 400 mg QD. However, given the potential for increased fetal exposure, this approach requires careful risk-benefit assessment, and further research is warranted to establish the safest and most effective strategy.
INTRODUCTION: Hepatitis C virus (HCV) infection remains a major cause of liver-related morbidity and mortality, affecting about 50 million people worldwide. Given its global priority, high treatment costs, and equity con...INTRODUCTION: Hepatitis C virus (HCV) infection remains a major cause of liver-related morbidity and mortality, affecting about 50 million people worldwide. Given its global priority, high treatment costs, and equity concerns, evaluating the cost-effectiveness of HCV therapies is crucial for informing policy and resource allocation. This systematic review synthesizes the cost-effectiveness of sofosbuvir/ledipasvir (SOF/LDV) compared with alternative regimens in patients with HCV. METHODS: A systematic search was conducted across major databases and additional sources following PRISMA 2020 guidelines. Eligible studies were full economic evaluations comparing SOF/LDV with other treatments. Methodological quality was assessed using the Quality of Health Economic Studies (QHES) checklist. Incremental cost-effectiveness ratios (ICERs) were adjusted to 2024 U.S. dollars, and findings were synthesized qualitatively. RESULTS: Of 864 retrieved records, 15 met inclusion criteria, with a mean QHES score of 88.6, reflecting high methodological quality. Seven studies identified SOF/LDV as cost-effective or dominant across various healthcare systems, perspectives, and time horizons, particularly for genotype 1 and early stages liver disease. However, results varied by genotype, fibrosis stage, comparator, and national healthcare settings. Sensitivity analyses showed that ICERs were mainly influenced by patient age, utility values, treatment costs, dosage, treatment duration, discount rate, sustained virologic response (SVR) rate, fibrosis progression probabilities, and mortality rates. CONCLUSION: SOF-based regimens play a pivotal role in HCV management. However, contextual factors—such as healthcare infrastructure, willingness-to-pay thresholds, and model assumptions— significantly influence cost-effectiveness. Future research should address geographic inequities, incorporate societal perspectives, reduce methodological heterogeneity, and integrate real-world data to enhance generalizability.