Clinical Drug Investigation最新文献

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.

This paper aims to introduce a new treatment strategy for salt-sensitive hypertension and heart failure (HF). Hypertension is very common and a major risk factor for cardiovascular disease, coronary heart disease, HF, and death. Yet neither hypertension nor HF are well controlled with the existing medications. Therefore, new means for their control should be pursued. Recently, β-arrestins have been investigated and shown to have beneficial effects in both hypertension and HF. β-Arrestins are a family of intracellular signaling proteins that play a role in the regulation of the G-protein-coupled receptors. The angiotensin II (Ang II) type 1 receptor (AT1R) is also a G-protein-coupled receptor mediating the adverse cardiovascular effects of Ang II. An agonist that activates the β-arrestin pathway downstream of the AT1R, such as TRV027, could act as a therapeutic agent by blocking the adverse effects of Ang II. Yet at present, the therapeutic effects of TRV027 are weak and short lasting. Therefore, there is an urgent need for the development of more effective and long-lasting TRV027 analogs. A review of the recent literature from 2019 to 2024 has disclosed that β-arrestins do possess beneficial effects in lowering hypertension and treating HF.

Background and objectives: Parkinson's disease (PD) affects a large population worldwide with millions of people losing motor function control. Although there is no recognized cure for PD, current medications aim to manage the symptoms and slow down the progression of the disease. Amantadine is one such treatment option that can be used in both early and late stages of PD. The current study aimed to assess the relative bioequivalence of two test prototypes (Ta and Tb) of amantadine extended-release (ER) oral formulation manufactured by Sun Pharmaceuticals Industries Limited with the reference immediate-release (IR) formulation (R) of amantadine hydrochloride manufactured by Morton Grove Pharmaceuticals Inc.

Methods: This was an open-label, balanced, randomized, three-treatment, six-sequence, three-period, single-dose once daily (OD) versus twice daily (BID), crossover relative bioavailability study in healthy adult male subjects under fasting condition with a total of 36 + 2 additional standby subjects meeting the eligibility criteria. The pharmacokinetic parameters including maximum concentration (C_max), time to achieve C_max (t_max), area under the plasma concentration-time curve from time zero to time t (AUC_0-t), area under the concentration-time curve from 0 to 24 h (AUC_0-24), area under the plasma concentration-time curve from time 0 to infinity (AUC_0-∞), and half-life (t_1/2) were assessed. Statistical analysis was performed using analysis of variance (ANOVA) and ratio of least square means (LSM) (log transformed) was used to calculate the relative bioequivalence of the test drugs with the reference drug. Safety monitoring was done by considering adverse and serious adverse events during the duration of the study.

Results: Both Ta and Tb formulations demonstrated similar systemic exposure to the reference product, meeting the criteria for bioequivalence within acceptable limits (80.00-125.00%). The ratios of LSM for log-transformed pharmacokinetic parameters (90% confidence interval [CI]) for Ta versus R were 100.02% (96.75-103.40%) for C_max, and 107.27% (102.75-112.00%) for AUC_0-t; and for Tb versus R were 93.92% (90.38-97.60%) for C_max, and 101.12% (96.73-105.71%) for AUC_0-t. There were no adverse or serious adverse events observed during the study.

Conclusion: These findings confirm the bioequivalence of the two test prototypes of amantadine ER formulation manufactured by Sun Pharmaceutical Industries Limited with the IR BID formulation of amantadine manufactured by Morton Grove Pharmaceuticals Inc. The pharmacokinetic equivalence supports the use of OD amantadine ER as an alternative to the BID IR formulation, with the potential to improve patient adherence due to reduced dosing frequency.

CT-P39 [Omlyclo^® (omalizumab-igec)] is a biosimilar of the reference monoclonal anti-immunoglobulin E (IgE) antibody omalizumab. It is approved for use in all indications for which reference omalizumab is approved, including allergic asthma, chronic rhinosinusitis with nasal polyps, chronic spontaneous urticaria (CSU) and (in the USA) IgE-mediated food allergy. CT-P39 has similar physicochemical and pharmacodynamic properties to those of reference omalizumab, and the pharmacokinetic equivalence and comparability of the agents has been demonstrated in healthy volunteers and patients with CSU, respectively. CT-P39 demonstrated clinical efficacy equivalent to that of reference omalizumab in patients with CSU and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of CT-P39 were similar to those of reference omalizumab, and switching from reference omalizumab to CT-P39 appeared to have no impact on efficacy or safety. The role of reference omalizumab in the management of allergic asthma, chronic rhinosinusitis with nasal polyps, CSU and IgE-mediated food allergy is well established and CT-P39 provides an effective alternative for patients requiring omalizumab therapy.

TONMYA^™ is a sublingual eutectic formulation of cyclobenzaprine being developed by Tonix Pharmaceuticals for the treatment of various conditions, including fibromyalgia, post-traumatic stress disorder (PTSD), acute stress disorder, major depressive disorder, post-acute COVID-19 syndrome, alcohol use disorder, and agitation in Alzheimer's disease. The sublingual formulation was designed for rapid transmucosal absorption to produce diurnal variation in peak-to-trough drug concentrations, making it suitable for long-term bedtime use. On 15 August 2025, sublingual cyclobenzaprine was approved for the treatment of fibromyalgia in adults in the USA. This article summarizes the milestones in the development of sublingual cyclobenzaprine leading to this first approval for fibromyalgia.