Clinical Drug Investigation最新文献

Background: Iclepertin is a selective inhibitor of glycine transporter 1 recently investigated as a novel treatment for cognitive impairment associated with schizophrenia. Iclepertin is a potential mild inducer of liver cytochrome P450 3A4, which metabolises ethinylestradiol and levonorgestrel, which are used in combined oral contraceptives (OCs).

Objectives: This trial investigated the potential drug interaction effect of steady-state iclepertin on the steady-state pharmacokinetics of combined OCs.

Methods: This phase I, non-randomised, open-label, two-period, fixed-sequence trial was conducted in healthy pre-menopausal female volunteers aged 18-35 years. In period 1, participants received a combined OC (ethinylestradiol 30 µg/levonorgestrel 150 µg once daily; reference treatment). In period 2, participants received a combined OC and iclepertin 10 mg once daily (test treatment). Primary pharmacokinetic endpoints of ethinylestradiol or levonorgestrel in plasma at steady state over a uniform dosing interval τ were area under the concentration-time curve (AUC_τ,ss) and maximum and minimum measured concentration (C_max,ss and C_min,ss); drug interaction potential was estimated by geometric mean ratios (test treatment/reference treatment) with two-sided 90% confidence intervals (CIs) using analysis of variance. Safety assessments included monitoring adverse events (AEs).

Results: In total, 19 participants entered the trial; 17 were treated (periods 1 and 2). Steady-state pharmacokinetics of ethinylestradiol and levonorgestrel were similar with and without iclepertin; geometric mean ratios for AUC_τ,ss, C_max,ss, and C_min,ss were slightly above 100%, and 90% CIs were within standard bioequivalence boundaries (80-125%). The number of on-treatment AEs was similar in period 1 (n = 13) and period 2 (n = 15); AEs were of mild-to-moderate severity.

Conclusion: Iclepertin 10 mg had no meaningful effect on the pharmacokinetics of ethinylestradiol and levonorgestrel, suggesting that these drugs can be administered concomitantly.

Trial registration: ClinicalTrials.gov (NCT05613777; registered on 18 October 2023).

Background and objectives: Benzodiazepines are commonly prescribed medications approved for and used in the treatment of anxiolytic and sleep disorders, as well as for seizures, and alcohol withdrawal. However, benzodiazepines are also controlled substances because of their potential for abuse and personal harm, which are especially prevalent among older people. It is therefore important to understand how benzodiazepines are being prescribed, and the prevalence of off-label benzodiazepine prescribing, of which very little is known because of challenges in documenting treatment indication. The aim of this study was to detail the prevalence of benzodiazepine off-label prescribing.

Methods: Data from the MOXXI (Medical Office of the XXIst century) electronic health record system in Quebec Canada were used, where specifying the treatment indication for each prescription is required, to estimate the prevalence of off-label prescribing and indications for off-label use of benzodiazepines. Each drug indication was retrospectively classified as either on-label or off-label according to the Health Canada drug database. Off-label prescriptions were further classified as having class congruence supporting their prescription if another benzodiazepine had been approved for the indication by Health Canada.

Results: There were 20,125 (17.0%) adult patients prescribed benzodiazepines out of the 118,223 patients enrolled in the MOXXI system. The patients were predominantly female (65.6%) and tended to be older with an average age of 60.14 years at the time of the first benzodiazepine prescription. A total of 101,583 unique prescriptions were written for 14 different benzodiazepines. An approximately equal number of benzodiazepines were prescribed on- and off-label (49.3% on-label, 49.2% off-label). Most off-label prescription indications were classified as having class congruence (95.2%).

Conclusions: Benzodiazepines were frequently prescribed in the province of Quebec and were prescribed off-label approximately half of the time. When prescribed off-label, we found that most of these prescriptions were for indications that were approved for other benzodiazepines. The most common indication for off-label benzodiazepine prescriptions with class congruence was insomnia.

Background and objectives: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare diverse group of malignancies, which range from well-differentiated indolent tumors to high-grade aggressive forms. Based on the World Health Organization classification, GEP-NETs are divided into well-differentiated neuroendocrine tumors and poorly differentiated carcinomas. While localized GEP-NETs are primarily treated surgically, non-resectable GEP-NETs have evolved toward targeted therapies, including radioligand therapy. This study describes inpatient resource utilization and inter-regional healthcare mobility for patients with GEP-NETs in Italy, focusing on radioligand therapy.

Methods: We retrieved Italian Hospital Discharge Records (SDO) from 2018 to 2021. Given the absence of specific International Classification of Diseases, Ninth Revision, Clinical Modification codes for GEP-NETs, all potentially related diagnoses were included. Radioligand therapy-related hospitalizations were identified using Diagnosis-Related Group code 409 for radiotherapy, focusing on discharge disciplines of nuclear medicine, radiotherapy, or radiation oncology. We analyzed hospitalization rates by region and regimen and assessed inter-regional mobility using the Attraction and Escape Mobility Indexes.

Results: Over the study period, 4837 radioligand therapy-related GEP-NET hospitalizations were recorded, with 2942 involving the targeted disciplines. Hospitalizations increased by 48.4%, mainly owing to growth in short-stay (0-1 day) discharges (from 37 in 2018 to 228 in 2021), while longer stays (≥ 2 days) rose from 552 to 644. Day hospital accounted for only 0.2% of cases. Regional disparities were prominent, with Emilia-Romagna, Lombardia, and Sicilia managing 88.9% of cases; ten regions recorded no hospitalizations, reflecting a high mobility index (45.8%) and significant inter-regional patient mobility.

Conclusions: The study underscores the need for regulatory adjustments, resource allocation improvements, and healthcare system adaptations to effectively support innovative therapies for GEP-NETs. Addressing these needs is essential to optimize patient outcomes and address regional disparities in Italy's healthcare system.

Background and objectives: Dyslipidaemia is a key modifiable risk factor for atherosclerotic cardiovascular disease. However, achieving recommended low-density lipoprotein cholesterol (LDL-C) target levels is challenging owing to dose-dependent adverse effects and limited tolerability of high-dose statins. This study evaluated the real-world efficacy and safety of combining very-low-dose rosuvastatin (2.5 mg) with ezetimibe (10 mg) in adult patients with dyslipidaemia across different cardiovascular risk strata.

Methods: This multicentre prospective study in South Korea enrolled 2,388 patients. Participants were stratified into low-, moderate-, or high-risk groups on the basis of the 2019 European Society of Cardiology and European Atherosclerosis Society guidelines. Lipid profiles and safety outcomes were assessed at baseline and after 12 weeks. The primary and secondary outcomes were LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) target level achievements, respectively, and adverse events were monitored.

Results: After 12 weeks, LDL-C target levels were achieved by 82.6% of low-risk (< 116 mg/dL), 73.9% of moderate-risk (< 100 mg/dL), and 50.4% of high-risk (< 70 mg/dL) patients. Non-HDL-C target level achievement followed a similar trend. Combination therapy with ezetimibe and low-dose statin resulted in significant LDL-C reductions, compared with statins alone. Adverse events were infrequent (0.6%), and only 0.2% of patients discontinued treatment owing to medication-related concerns.

Conclusions: Very-low-dose rosuvastatin-ezetimibe combination therapy significantly lowered LDL-C levels and improved lipid profiles across various risk groups, demonstrating a favourable safety profile. These findings support its use as an effective, well-tolerated option for managing dyslipidaemia. Longer-term studies are warranted to evaluate sustained lipid control and cardiovascular outcomes.

Background and objectives: Chronic hepatitis B virus infection remains a Major global public health challenge, affecting over 254 million individuals and causing substantial mortality owing to the limited curative potential of current therapies. This horizon scanning review aims to comprehensively analyze emerging trends and future directions in novel anti-hepatitis B virus therapeutic development, evaluating their progress and potential to achieve functional or complete cures.

Methods: We conducted a systematic horizon scanning review from January 2020 to June 2025, searching databases (PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure [CNKI], and WanFang), clinical trial registries (ClinicalTrials.gov, EU Clinical Trials Register, World Health Organization International Clinical Trials Registry, Chinese Clinical Trial Registry, and chinadrugtrials.org), hepatology conference abstracts (American Association for the Study of Liver Diseases, European Association for the Study of the Liver), and pharmaceutical company websites. Inclusion criteria focused on studies detailing novel anti-hepatitis B virus treatments, with data extracted on category, target, clinical phase, and discontinuation reasons.

Results: Our analysis identified 161 unique anti-hepatitis B virus treatments: 75 in clinical trials, 34 in preclinical development, and 52 discontinued post-clinical trials because of safety or insufficient efficacy. The pipeline reveals a diversification of targets, with capsid assembly modulators, therapeutic vaccines, and monoclonal antibodies being most prevalent. Three therapies representing novel mechanisms have reached phase III-bepirovirsen (an antisense oligonucleotide), canocapavir (a capsid assembly modulator), and εPA-44 (a therapeutic vaccine), illustrating diversification of late-stage pipelines; however, 6-month off-treatment endpoints should be interpreted cautiously across modalities until durability is established.

Conclusions: The robust and diverse pipeline of novel anti-hepatitis B virus treatments offers promise for improving functional cure rates, but definitive conclusions await longer off-treatment follow-up and durability data. Continued research, rational combination strategies, and global collaboration are crucial to overcome challenges and ensure equitable access to these transformative therapies worldwide.

Background and objectives: Direct head-to-head evidence of propranolol and amitriptyline for migraine prophylaxis is limited. This clinical trial compared the efficacy, safety, and cost-effectiveness of low-dose propranolol versus amitriptyline for episodic migraine prophylaxis over a 3-month period.

Methods: This randomized, controlled, open-label, prospective, parallel, single-center trial was conducted at a tertiary care hospital in India. A total of 60 prophylaxis-naïve patients with episodic migraine were randomized 1:1 to receive either low-dose propranolol (80 mg/day) or amitriptyline (10 mg/day). The primary outcome was the improvement in the monthly headache frequency at 3 months from baseline, while the secondary outcomes included improvements from baseline in the proportions of patients achieving a ≥ 50% reduction in monthly headache days, headache severity, headache-induced disability, monthly rescue medication intake, quality of life, and cost-effectiveness (measured by the average cost-effectiveness ratio [ACER] and incremental cost-effectiveness ratio [ICER]).

Results: At 3 months, propranolol showed a significantly greater reduction in monthly headache frequency compared with amitriptyline (- 3.67 ± 1.47 versus -  2.87 ± 1.36 days, P = 0.03). More patients in the propranolol group (60%) achieved a ≥ 50% reduction in monthly headache days compared with the amitriptyline group (43.33%) (P = 0.02). Propranolol also showed a greater reduction in monthly rescue medication intake (P = 0.01), but differences in headache severity, headache-induced disability, and quality of life were not significant. Both groups experienced mild adverse drug reactions. Cost-effectiveness analysis revealed propranolol had a higher ACER (US $5.44) and ICER (US $0.40/1% reduction) than amitriptyline.

Conclusions: In our trial, low-dose propranolol demonstrated superior efficacy to amitriptyline in episodic migraine prophylaxis. Both drugs were well tolerated. Our study suggests that amitriptyline was more cost-effective than propranolol.

Trial registration number: Clinical Trial Registry-India (Date: 27 October 2020; registration no.: CTRI/2020/01/022972).

Background: Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist with favorable safety and side effect profiles. There is a growing body of evidence for memantine as an adjunctive therapy for the positive, negative, and cognitive symptoms of schizophrenia.

Objective: This meta-analysis examined the efficacy of memantine as an add-on to treatment with antipsychotic(s) for the primary negative symptoms (PNS) of schizophrenia.

Methods: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched for relevant publications in PubMed, Cochrane Library, PsycINFO, Embase, and China Journal Net databases from inception using the following search terms: memantine, schizophrenia, randomized controlled trials (RCTs), RCT, and clinical trial. Searches were limited to English- and Chinese-language articles to date. Standardized mean differences (SMDs) with 95% confidence intervals were calculated using RevMan 5.4 to assess the effect size. Risk of bias was assessed using RoB 2.0.

Results: In total, 13 RCTs were identified (N = 681). Memantine was superior to placebo in treating negative symptoms, with an SMD of 0.79 (p = 0.0001, N = 631, 12 RCTs). Analysis of three studies whose corresponding authors provided original datasets showed an SMD of 2.16 (p = 0.25, N = 97) after adjusting for change in psychosis, depression, and extrapyramidal symptoms, suggesting that memantine is efficacious in treating PNS. Additionally, cognitive testing significantly improved, with an SMD of 0.66 (p = 0.0001, N = 395, eight RCTs). Positive symptoms were not significantly improved (SMD = 0.24, p = 0.1, N = 631, 12 RCTs).

Conclusions: To our knowledge, this is the first study showing a large effect size for treating PNS with memantine. Although statistical significance was not reached because of the small sample size (N = 97), the results were as expected because drugs such as memantine that act at NMDA receptors are unlikely to be effective as stand-alone treatments. Future RCTs should evaluate NMDAergic drugs in combination with complementary medications to optimize therapeutic effects for all three domains of schizophrenia psychopathology.

Background: SHR7280 is an oral small-molecule gonadotropin-releasing hormone (GnRH) antagonist that can be developed as therapeutic agent for the treatment of hormone-dependent pathologies, including prostate, breast, and ovarian cancers. SHR7280 dry suspension formulation is being developed to provide an alternative mode of administration for order patients, those using nutritional tubes, and those unable to swallow solid dosage forms.

Objective: This study evaluated the relative bioavailability, pharmacokinetics (PK), and safety of SHR7280 dry suspension and tablets administered in a single dose in healthy Chinese volunteers.

Methods: A randomized, open, two-preparation, two-sequence, two-cycle, double-crossover design was used in this study. The plasma drug concentration was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The main PK parameters of the two formulations of SHR7280 were calculated by noncompartmental analysis using Phoenix WinNonlin (version 8.3.4) software. A total of 16 healthy participants were randomized to receive SHR7280 (200 mg) as tablets (n = 8) or dry suspension (n = 8) formulation.

Results: The geometric least squares mean ratio (90% confidence interval [CI]) for maximum concentration of drug in blood plasma (C_max) and area under the plasma concentration-time curve from time 0 to t (AUC_0-t) and from time 0 to infinity (AUC_0-∞) between the dry suspension of SHR7280 and its tablets were calculated as follows: C_max-101.90% (90% CI 79.50-130.62), AUC_0-t-111.58% (90% CI 91.71-135.76), and AUC_0-∞-111.44% (90% CI 91.70-135.43). A total of nine (56.3%) subjects experienced treatment-emergent adverse events (TEAEs).

Conclusions: The bioavailability of SHR7280 tablets was found to be comparable to that of dry suspension. The safety profile of two formulations was favorable. No serious adverse events or adverse drug reactions were reported.

Trial registration: ClinicalTrials.gov (NCT05868057; 22 May 2023).

SDZ-AFL (SOK583A1; Afqlir^®) is a biosimilar of the reference intravitreal aflibercept, a vascular endothelial growth factor inhibitor. SDZ-AFL has been approved in the EU for the treatment of the same indications in adults as reference aflibercept: neovascular age-related macular degeneration (nAMD), visual impairment due to macular oedema secondary to retinal vein occlusion, visual impairment due to diabetic macular oedema and visual impairment due to myopic choroidal neovascularisation. SDZ-AFL has similar physicochemical and pharmacodynamic properties to those of reference aflibercept, and pharmacokinetic similarity has been demonstrated in patients with nAMD. SDZ-AFL demonstrated clinical efficacy equivalent to that of reference aflibercept in patients with nAMD and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of SDZ-AFL were similar to those of reference aflibercept. The role of reference aflibercept in the management of neovascular retinal diseases is well established, and SDZ-AFL provides an effective biosimilar alternative for patients requiring ophthalmic aflibercept therapy.

Background and objectives: Reports of suspected adverse drug reactions are of a great importance for the safety monitoring of new vaccines to identify potential safety risks promptly and to ensure necessary measures for risk mitigation. We reviewed the reports of fatal adverse drug reactions after coronavirus disease 2019 (COVID-19) vaccination with Comirnaty^®, Spikevax^®, and Vaxzevria^® during the national vaccination campaign in Sweden.

Methods: Swedish reports of suspected adverse drug reactions with fatal outcomes after COVID-19 vaccines were retrieved from the EudraVigilance database. Vaccination data were obtained from the National vaccination register. Reporting rates were calculated by dividing the number of adverse drug reaction reports with fatal outcomes by the number of people exposed to at least one dose of the COVID-19 vaccines or by the number of vaccine doses given. A causality assessment of adverse drug reaction reports was performed by clinically qualified reviewers.

Results: More than 26 million doses of COVID-19 vaccines were administered and 456 reports of suspected adverse drug reactions with fatal outcomes were reported during 27 December, 2020-31 May, 2023. The reporting rate was 5.7 fatal outcomes per 100,000 persons vaccinated with at least one dose of any COVID-19 vaccine or 1.7 per 100,000 vaccine doses given. Most of the fatalities were related to patients' pre-existing conditions, predominantly among people aged 70 years or older. Only ten of the reported fatalities (0.1 per 100,000 persons vaccinated) were assessed as consistent with a causal association to COVID-19 vaccination.

Conclusions: Adverse drug reactions with fatal outcomes after COVID-19 vaccines in Sweden were very rare. No new safety concerns were observed in this study.