Clinical Drug Investigation最新文献

Background and objectives: The H018 tablet is an orally administered selective inhibitor of Janus kinase 1 and has been specifically developed for the treatment of rheumatoid arthritis. To our knowledge, this study is the first to investigate the safety, pharmacokinetics, and pharmacodynamics of H018 tablets after single and repeated administrations.

Methods: This study was a phase I, randomized, double-blind, placebo/positive drug-controlled trial. In the single-dose part, 58 healthy subjects received a single oral dose of 10, 20, 40, 80, 120, or 160 mg. In the multiple-dose part, 60 healthy subjects received an oral dose of 80, 120, 160, or 200 mg of H018 once daily for 7 consecutive days; an oral dose of 200 mg of filgotinib once daily for 7 consecutive days; or an oral dose of 100 mg of H018 every 12 h, with a total of 13 doses administered. Pharmacokinetic parameters were determined from H018 plasma concentrations through a non-compartmental analysis. The dose proportionality of H018 after individual doses and its pharmacodynamic, safety, and tolerability profiles were evaluated.

Results: In the single-dose part, the area under the plasma concentration-time curve and maximum plasma concentration did not exhibit a typical dose-exposure proportional relationship at increasing doses. Urine and feces were not the main excretion routes for H018, M10, and M8. A total of 42 metabolites were identified in plasma, and the parent drug H018 accounted for the highest proportion (69.66%), followed by metabolite M10 (15.57%). The proportions of all other metabolites in plasma were less than 10%. The maximum inhibition rate of phosphorylated signal transducer and activator of transcription 1 was achieved at 1 h after H018 administration, and the inhibition rate increased with the administered dose and plasma drug concentration. The plasma concentrations of H018, its metabolites, or the positive control drug (filgotinib) were undetectable during the multiple-dose phase. Comparable to the maximum phosphorylated signal transducer and activator of transcription 1 inhibition rate of filgotinib, the phosphorylated signal transducer and activator of transcription 1 inhibition rate was essentially reached or very close to the maximum value approximately 1 h after the first and last administrations of H018 tablets, and H018 showed favorable safety and tolerability profiles.

Conclusions: H018 tablets exhibited a rapid onset of action upon oral administration, and the peak inhibition rate was attained approximately 1 h after administration. H018 demonstrated favorable safety and tolerability profiles within the tested dose range, showing potential as a therapeutic option for rheumatoid arthritis treatment.

Background and objectives: Using valproate during pregnancy carries risks of major congenital malformations and neurodevelopment disorders. Women with epilepsy and pregnancy plans should switch to an alternative and safe epilepsy management strategy. The present healthcare database study aimed at identifying treatment patterns that lead to successful epilepsy management and their associated factors, in females of childbearing potential (FCBP) after valproate discontinuation.

Methods: FCBP who had been using valproate for epilepsy and discontinued its use (index date) between 2014 and 2017 were identified in the French and UK databases, Système National des Données de Santé/ Clinical Practice Research Datalink (SNDS/CPRD) and followed-up for 1 year. Clusters that most likely reflected a 'success' in epilepsy management were identified using a partition-around-medoids clustering algorithm. Success was defined on the basis of a combined approach including no valproate reintroduction and no negative medical parameters during follow-up. Baseline factors associated with successful/unsuccessful clusters were assessed in SNDS.

Results: A total of 7345/358 (SNDS/CPRD) FCBP diagnosed with epilepsy were included, of whom 67.3%/49.4% identified in successful clusters. The three most frequent clusters were 'predominantly no antiseizure medication (ASM)' (27.7%/20.9%), "predominantly monotherapy with another ASM' typically lamotrigine or levetiracetam (25.5%/20.7%), and 'predominantly return to valproate monotherapy' (17.5%/24.0%). Factors most strongly associated with no reintroduction of valproate were closer medical supervision (OR = 2.30), valproate dose-tapering prior discontinuation (OR = 2.40), pregnancy at index date (OR = 1.96), levetiracetam or lamotrigine delivery in the 90-days pre-index date (OR = 1.81, OR = 1.54). Factors most strongly associated with reintroduction of valproate included: older age (OR = 0.49 for [40-49] versus [13-29] year old), longer duration of epilepsy (OR = 0.63 for ≥ 5 versus < 1 year of history).

Conclusions: Around half of women discontinued valproate successfully, especially if young, with a stabilised disease, with one quarter switching to monotherapy with another ASM, mainly lamotrigine or levetiracetam. Risk factors for unsuccessful discontinuation were identified, which may be useful as 'warning signs' to identify patients who need close follow-up during valproate discontinuation.

Background: Osteoporosis, a common condition of low bone mineral density (BMD), significantly increases fracture risk. Denosumab and alendronate are both established anti-resorptive therapies, yet their comparative effectiveness remains inconsistent across studies.

Objective: The aim of this meta-analysis was to systematically evaluate the efficacy of denosumab versus alendronate for improving BMD at multiple skeletal sites in osteoporosis patients, aiming to provide evidence for clinical decision making.

Methods: Multiple databases were searched for relevant randomised controlled trials published in English (as of November 2024). The primary outcomes were mean change of BMD at different skeletal sites. Data were pooled using fixed- or random-effects models to determine the mean differences (MDs) and 95% confidence intervals (CIs) for various BMD in patients treated with denosumab in comparison to patients treated with alendronate.

Results: This meta-analysis included thirteen randomized controlled trials (RCTs) with a total of 3364 patients and follow-up periods ranging from 6 to 24 months, and the overall quality of the studies was relatively high. The results demonstrated that denosumab was more effective than alendronate in increasing BMD at the lumbar spine (LS), femoral neck (FN), distal radius (DR), and total hip (TH) in osteoporosis patients and high-risk populations. Subgroup analysis revealed that postmenopausal women experienced greater improvements in BMD at the LS (p < 0.001) at 6 months, and at the FN (p < 0.001) at 24 months, compared with non-postmenopausal  subjects.

Conclusions: Denosumab was more effective than alendronate in increasing BMD. However, all the included randomised controlled trials (RCTs) carried a risk of bias, and the patient sample sizes were relatively small. Therefore, further studies with larger sample sizes and better methodological rigor are needed to confirm these findings.

Prospero registration number: CRD420250655676.

Objective: This analysis aimed to evaluate the efficacy of brexpiprazole 2 or 3 mg/day for the treatment of agitation associated with dementia due to Alzheimer's disease, on the basis of pooled clinical trial data.

Methods: Data were pooled from two similarly designed, phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled trials of fixed-dose brexpiprazole in participants in care facilities or community-based settings who had agitation associated with dementia due to Alzheimer's disease. Efficacy outcomes included Cohen-Mansfield Agitation Inventory (CMAI) total score (which measures the frequency of 29 different agitation symptoms), Clinical Global Impression-Severity of illness (CGI-S) score, CMAI factor scores (aggressive behaviors, physically nonaggressive behaviors, and verbally agitated behaviors), and response rates. A sensitivity analysis included a third trial with flexible dosing.

Results: In total, 621 participants were randomized (brexpiprazole, 368; placebo, 253), and completion rates were 320/368 (87.0%) and 225/253 (88.9%), respectively. Mean (SD) baseline CMAI total scores were: brexpiprazole 76.9 (17.2) points and placebo 75.5 (18.0) points. Over 12 weeks, CMAI total scores improved by least squares mean (SE) - 22.8 (0.8) points for brexpiprazole and - 18.3 (1.0) points for placebo, with a least squares mean difference between treatment arms of - 4.50 points (95% CI - 6.90 to - 2.10; p < 0.001; Cohen's d 0.30). CGI-S, CMAI factor, and response analyses also showed greater improvement with brexpiprazole versus placebo. The sensitivity analysis was supportive.

Conclusions: Brexpiprazole 2 or 3 mg/day reduced agitation symptoms compared with placebo over 12 weeks in this large, pooled sample of participants with dementia due to Alzheimer's disease.

Study registration: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, and NCT01922258.

Background and objectives: Discrete choice experiment (DCE) is increasingly recognized for its utility to elicit patient preferences in benefit-risk (BR) evaluation, particularly when options entail complex tradeoffs. This rimonabant case study focused on the methodology and versatility of DCE to elicit patient preferences for anti-obesity drugs. This study aimed to demonstrate the application of DCE as a tool to capture patient preferences concerning the BR profile of rimonabant, focusing on attribute-based choices, preference elicitation, experimental design, quantitative analysis, and practical application.

Methods: A DCE was conducted involving standard steps: identifying attributes and levels, constructing choice sets, designing the questionnaire, and analyzing responses. Two benefit and three risk attributes important to the BR profile of anti-obesity drugs were selected based on their significance to patients from published literature. Responses were analyzed using probit regression to quantify the preference for each attribute. Preference weights, derived from DCE, were combined with efficacy and safety data from clinical trials to estimate the utility function and probability of treatment selection. Lastly, the generated marginal rates of substitution (MRS) were used to present the extent to which patients were willing to trade off benefits to avoid risks.

Results: The coefficients from the probit model indicated that psychiatric conditions (i.e., mild anxiety to severe depression) significantly impacted treatment preference, followed by cardiovascular conditions, weight loss, and gastrointestinal conditions. On average, rimonabant was preferred over placebo 67% of the time. On the basis of MRS, to avoid a 1% increase of psychiatric condition, patients would be willing to forgo a 3.9% reduction in number of people achieving 10% weight loss, or a 0.44 level of improvement in high-density lipoprotein cholesterol, which elucidates how patients value benefits and risks when deciding on a treatment.

Conclusions: This case study reaffirmed the utility of DCE as a valuable tool for BR evaluations, which aligned with what patients deemed important. The case study demonstrated essential attributes for anti-obesity medications. The methodological rigor and flexibility of DCE provided a robust framework for understanding, quantifying and analyzing preferences. The integration of elicited patient preferences, utility functions, and relevant clinical data offered quantitative insights into the structured BR assessment for regulatory decision-making and beyond.

Insulin aspart-szjj (MERILOG^™) is a biosimilar of the reference rapid-acting insulin analog, insulin aspart, and is approved for the same indication as reference insulin aspart: to improve glycemic control in adult and pediatric patients with diabetes mellitus. The physicochemical characteristics of insulin aspart-szjj were similar to reference insulin aspart, and the pharmacodynamic and pharmacokinetic equivalence of the agents has been shown in patients with type 1 diabetes. Insulin aspart-szjj demonstrated clinical efficacy similar to that of reference insulin aspart in patients with type 1 or type 2 diabetes and was generally well tolerated in this population. The tolerability, safety, and immunogenicity profiles of insulin aspart-szjj were similar to those of reference insulin aspart. The role of insulin aspart in the management of diabetes mellitus is well established, and insulin aspart-szjj provides an effective biosimilar alternative for patients with diabetes mellitus requiring reference insulin aspart.

Background and objectives: Effective pain management in children is a public health priority, while opioid-related risks remain a major concern. The aim of the present study was to describe trends of opioids and nefopam use in children in France.

Methods: We conducted a nationwide drug utilization study using the French National Health Data System (SNDS), covering > 98% of the French population. All children with at least one prescription for a weak opioid, strong opioid, or nefopam between 2009 and 2023 were included. Annual prevalence of use was estimated per 1000 children, stratified by age group (< 2, 2-6, 7-11, 12-17 years). Joinpoint regression was used to analyze temporal trends. Contraindicated use was defined according to age restrictions in marketing authorizations.

Results: Overall, 4,443,648 children were included in the study. Overall prevalence of analgesic use increased from 22.7‰ in 2009 to 27.4‰ in 2023, mainly driven by weak opioids (26.3‰ in 2023). In 2023, tramadol was the most prescribed weak opioid (13.5‰), followed by codeine (10.1‰). Nefopam use, contraindicated for use under 15 years of age, rose sharply to 1.9‰. Strong opioids, notably morphine and oxycodone, steadily increased but remained low (0.4‰ and 0.08‰, respectively). Most children receiving prescriptions were aged 12-17 years, although weak opioid use declined in this group over the study period. In contrast, children aged 2-6 years showed a fivefold increase in overall analgesic use, driven almost entirely by tramadol, which increased eightfold, while codeine use declined. Contraindicated use remained frequent for tramadol, codeine, opium powder, and nefopam, increasing as children approached the minimal approved age.

Conclusion: Tramadol was the most commonly prescribed opioid used in pediatric outpatients in France in 2023, followed by codeine. Tramadol off-label use steadily increased, whereas codeine off-label use decreased. The sharp rise in tramadol, especially in children aged 2-6 years, and nefopam prescribing, together with increasing morphine and oxycodone use, in association with frequent contraindicated use, underscores the need for enhanced surveillance and pediatric-specific safety data.

Background and objectives: Patients with metastatic triple-negative breast cancer (mTNBC) have poor prognosis and survival outcomes. Sacituzumab govitecan (SG) has shown significant survival benefits, but its cost-effectiveness still needs evaluation. The present study aimed to evaluate the cost-effectiveness of SG versus physician's choice of treatment in patients with mTNBC in the context of the Spanish National Health system.

Methods: A partitioned survival model using data from the ASCENT clinical trial was developed to assess lifetime costs and benefits for patients with mTNBC. Quality-adjusted life years (QALYs) were employed as a measure of effectiveness. Data on costs and subsequent treatment were gathered from Spanish sources and validated by health professionals. Analyses were performed from the perspective of the Spanish NHS over lifetime.

Results: The average health cost of treating patients with SG for 120 months was €94,335 compared with €7926 for treatment of physician choice. Effectiveness pertaining to the SG group was 1.05 QALY compared with 0.48 QALY in the control group. The incremental cost-utility ratio (ICUR) was €151,716/QALY. Univariate sensitivity analyses produced ICURs that ranged between 102,764 and 216,077 €/QALY.

Conclusions: Despite clinical benefits of SG in patients with mTNBC, its cost exceeds accepted thresholds. The findings suggest a need for price reassessment within the Spanish National Health System to ensure value-based, equitable access.

BACKGROUND AND OBJECTIVE: The evidence on molnupiravir for the treatment of adults with nonsevere coronavirus disease 2019 (COVID-19) remains underexplored. We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of clinically relevant outcomes from randomized controlled trials (RCTs) of molnupiravir for treatment of nonsevere COVID-19 in adults.

Methods: We searched for publications of RCTs of molnupiravir for nonsevere COVID-19 in appropriate bibliographic databases up to 1 February 2025. We pooled appropriate data utilizing an inverse variance, random-effects model, with results expressed as relative risk (RR) with associated 95% confidence intervals (CIs), and statistical heterogeneity between pooled estimates calculated using the I² statistic. We appropriately conducted risk of bias assessment for the included RCTs and graded the quality of pooled evidence for each outcome using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Results: Out of 680 screened literature citations, nine RCTs involving a total of 30,971 patients met the eligibility criteria for inclusion in this review. The majority (78%) of these RCTs were of a low risk of bias. We determined that there was more viral clearance with molnupiravir treatment compared with placebo or no treatment (RR 1.08 [95% CI 1.01-1.16], I² 40.8%, five RCTs, 1785 patients, moderate quality evidence) and that treatment with molnupiravir did not reduce the risk of hospitalization (RR 0.73 [95% CI 0.47-1.14], I² 58.3%, five RCTs, 28,626 patients; high quality evidence), and all-cause mortality (RR 0.51 [95% CI 0.15-1.69], I² 36.8%, four RCTs, 27,445 patients; high quality evidence). We also determined that molnupiravir did not increase adverse or serious adverse reactions. However, TSA suggested more RCTs should be conducted before any conclusions can be reached for viral clearance, all-cause mortality, and adverse reactions, but that further RCTs on the risk of hospitalization and serious adverse reactions may not be needed.

Discussion: Notwithstanding a paucity of RCTs, our findings suggest that molnupiravir may only be efficacious for clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; the virus responsible for COVID-19) in adults with nonsevere COVID-19 although the evidence is not sufficient for conclusions to be drawn. More high quality RCTs are needed for a stronger evidence base.

Background and objectives: Anemia is a serious heath concern due to its high prevalence in the global population. Its occurrence in surgical patients varies greatly and correlates with worse outcomes. Higher costs and severe complications could also result from insufficient iron status. An effective way to mitigate the burden of iron deficiency could be the adoption of national patient blood management (PBM) programs. This study aimed to quantify the potential health economic benefits of implementing preoperative anemia management (the first pillar of PBM) with ferric carboxymaltose (FCM) in Romanian hospitals.

Methods: An already published decision-tree-based health economic model was adapted and populated with Romanian cost and epidemiological data from 2019. Cardiac (coronary artery bypass grafting) and non-cardiac (hip and knee arthroplasty) elective surgery cases were analyzed. Costs of complications per discharged case were assessed on the basis of data from ten local hospitals.

Results: A total of 14,641 cases met the inclusion criteria. On the basis of our sample of ten hospitals, the complication costs per case ranged from €1067.43 (for stroke) to €2896.14 (for sepsis with pneumonia). The health economic model simulated two scenarios. In the first scenario, all cases with anemia received FCM treatment. The total savings at the national level total were at least €1,500,875. In the second scenario half of the cases with anemia received treatment, resulting in savings of €363,779.

Conclusions: Our results suggest that introducing iron deficiency anemia treatment with FCM in case of elective surgical interventions results in considerable cost reduction for the healthcare system.