Clinical Drug Investigation最新文献

Background and objective: Fixed-dose combinations (FDCs) of amlodipine and telmisartan are widely used for hypertension management owing to their efficacy and improved adherence. This study aimed to characterize the pharmacokinetics (PKs) of both drugs after a single oral dose of a single-pill FDC of amlodipine 5 mg/telmisartan 80 mg in healthy Korean males.

Methods: A total of 681 amlodipine and 1500 telmisartan plasma concentrations from 32 healthy Korean males were retrospectively obtained from a bioequivalence study. Noncompartmental analysis and population analysis were conducted using WinNonLin™ (Pharsight Corp., Mountain View, CA, USA) and NONMEM^® (ICON Development Solutions, Hanover, MD, USA), respectively. A two-compartment model with first-order absorption and elimination was selected for both drugs. Covariate screening using a stepwise approach evaluated 38 demographic and clinical factors.

Results: Amlodipine exhibited a longer half-life and a larger apparent volume of distribution than telmisartan. Telmisartan PKs showed high interindividual (45.9% for absorption rate constant, 45.3% for apparent volume of distribution of the central compartment [V₁/F], and 40.9% for apparent clearance [CL/F]), interoccasion (53.7% for V₁/F), and residual (80.3%) variabilities. Preliminary covariate analysis suggested that body surface area and age potentially influenced V₁/F and CL/F for amlodipine, while height, smoking status, and total bilirubin levels were associated with telmisartan V₁/F and CL/F.

Conclusions: To our knowledge, this is the first population PK study to characterize the PKs of amlodipine and telmisartan co-administered as a single-pill FDC and to identify preliminary covariates that may influence their PK profiles.

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 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.