Clinical Drug Investigation最新文献

Background and objectives: The high costs associated with biological agents often limit accessibility for many patients, whereas biosimilars allow the wider application of biological treatment. The objectives of this phase I clinical trial were to compare the pharmacokinetics, immunogenicity, and safety profiles of the biosimilar adalimumab-WIBP and the reference product Humira^® and to assess the precision of the bioequivalence evaluation.

Methods: In this randomized, double-blind, parallel-group bioequivalence study, 164 healthy male Chinese participants were selected and randomly divided into two groups on a 1:1 ratio. The subjects were administered a single 40 mg subcutaneous dose of either adalimumab-WIBP or Humira^®. Blood samples extracted at multiple intervals after administration were analyzed to interpret pharmacokinetic parameters, and any adverse events were documented. Alongside ensuring safety measures, the subjects were monitored for immunogenicity.

Results: The pharmacokinetic results demonstrated similar serum concentration-time curves in both groups. There were no significant differences in safety and no differences in immunogenicity profiles between the two groups. The bioequivalence was confirmed: the 90% confidence interval for the geometric mean ratio of the main pharmacokinetic parameters was within the range of 80-125%.

Conclusion: The trial indicated the bioequivalence between adalimumab-WIBP and the reference product Humira^® based on pharmacokinetics, immunogenicity, and safety profile. These findings reinforce the use of the adalimumab-WIBP biosimilar as a possible therapeutic alternative to Humira^®.

Background: Iron deficiency is prevalent among heart failure patients and is associated with worse clinical outcomes, including decreased quality of life and functional capacity. This condition often results in a higher incidence of hospitalization and mortality. Iron supplementation, particularly with intravenous ferric carboxymaltose (FCM), has shown potential benefits as an adjunct therapy in heart failure management. This study aims to evaluate the efficacy of FCM in the treatment of patients with heart failure and iron deficiency anemia, with a focus on its impact on mortality and hospitalization rates.

Methods: A comprehensive search was conducted in PubMed, Web of Science, and Scopus databases from their inception until 1st December 2023. Meta-analysis was performed using RevMan 5.4, employing a random-model effect. The results were reported as risk ratios (RRs), standard mean differences (SMDs), and 95 % confidence intervals (CIs).

Results: The meta-analysis included 13 studies with a total of 6271 patients. Ferric carboxymaltose administration resulted in a significant improvement in the 6-minute walk distance (SMD: 1.45; 95 % CI: 0.55, 2.36; p = 0.002), quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) (SMD: 1.49; 95 % CI: 0.87, 2.11; p < 0.00001), the rate of first hospitalization for heart failure or cardiovascular death (RR: 0.91; 95 % CI: 0.84, 0.98; p = 0.02). However, FCM did not show a significant impact on the risk of cardiovascular death (RR: 0.90; 95 % CI: 0.77, 1.05; p = 0.17), the need for intervention due to worsening heart failure (RR: 0.41; 95 % CI: 0.04, 4.51; p = 0.47), or all-cause mortality rates (RR: 0.89; 95 % CI: 0.69, 1.16; p = 0.28).

Conclusion: While FCM treatment in patients with heart failure and iron deficiency anemia significantly improves functional capacity and quality of life, it has no notable effect on mortality rates or the likelihood of hospitalization. These findings highlight the need for further research to explore comprehensive treatment strategies that address both the symptomatic and survival aspects of heart failure management in this patient population.

Background and objective: Pulmonary hypertension (PH) is a progressive hemodynamic condition associated with significant morbidity and mortality, especially in patients undergoing cardiac surgery. Therefore, the objective of this network meta-analysis (NMA) is to compare the efficacy of various pulmonary vasodilators in perioperative control of PH among patients undergoing mitral valve replacement surgery (MVRS), aiming to address the existing knowledge gap and improve perioperative outcomes.

Methods: Electronic databases including PubMed, Cochrane Central Registry of Controlled Trials, Scopus, Embase, and Web of Science (WOS) from inception to 17 September 2024. Only randomized controlled trials (RCTs) evaluating vasodilators in PH patients undergoing MVRS were included. We used netmeta package in RStudio to analyze the outcome data with their corresponding mean difference (MD) and confidence intervals (CI).

Results: Seventeen RCTs including 862 patients were analyzed. Prostacyclin, nitric oxide (NO), and sodium nitroprusside (SN) significantly reduced mean pulmonary arterial pressure with effect sizes [MD, 95% confidence interval (CI)] of (11.77, - 18.78; - 4.76; - 8.3, - 15.9; - 0.6; - 11.02, - 20.1; - 3.8, respectively). While no treatment showed significant efficacy on pulmonary capillary wedge pressure, systolic pulmonary arterial pressure, or heart rate, nitroglycerin, NO, and prostacyclin, showed significant increases in cardiac index with effect sizes (MD, 95% CI) of (1, 0.3; 1.7; 1.2 0.8; 1.6; 1.2 0.8; 1.6, respectively). Additionally, NO, prostacyclin, SN, and nitroglycerin demonstrated significant reductions in systemic vascular resistance (SVR), with effect sizes of. (- 0.54, - 0.82; - 0.26, - 0.37, - 0.65; - 0.09; - 0.47, - 0.77; - 0.16; - 0.14, - 0.24; - 0.03, respectively).

Conclusions: This NMA highlights prostacyclin, nitroglycerin, NO, and SN as consistently effective in improving hemodynamics for patients with PH undergoing MVRS, and provides valuable insights for surgeons to choose the suitable vasodilator for these surgeries. However, limitations and the need for further RCTs are acknowledged.

Background and objective: IcoSema is being developed as a subcutaneous once-weekly fixed-ratio combination of the once-weekly basal insulin icodec and the once-weekly glucagon-like peptide-1 receptor agonist semaglutide. This study investigated the pharmacokinetics of icodec and semaglutide in IcoSema versus separate administration of each component in individuals with type 2 diabetes mellitus (T2DM).

Methods: In a randomised, double-blind, three-period crossover study, 31 individuals with T2DM (18-64 years, body weight 80-120 kg, glycosylated haemoglobin 6.0-8.5%) received single subcutaneous injections of IcoSema (175 U icodec, 0.5 mg semaglutide), icodec (175 U) or semaglutide (0.5 mg) with 6-9 weeks' washout. Pharmacokinetic blood samples were drawn up to 840 h post-dose.

Results: Icodec pharmacokinetics were unaffected by combining icodec with semaglutide. The 90% confidence interval (CI) of IcoSema/icodec was within 0.80-1.25 for total exposure (area under the curve from zero to last quantifiable observation; AUC_0-t: ratio [90% CI] 1.06 [1.01; 1.12]) and maximum concentration (C_max): 1.12 [1.06; 1.18]. Semaglutide AUC_0-t was also unaffected by combination with icodec (IcoSema/semaglutide 1.11 [1.05; 1.17]). However, semaglutide C_max was higher for IcoSema versus semaglutide alone (IcoSema/semaglutide 1.99 [1.84; 2.15]) and occurred earlier for IcoSema (12 versus 84 h). Results of in vitro albumin binding studies and animal pharmacokinetic studies supported that the change in semaglutide absorption pharmacokinetics in IcoSema is owing to competition for albumin binding locally at the injection site with icodec outcompeting semaglutide. IcoSema, icodec and semaglutide were well-tolerated, although more gastrointestinal related adverse events occurred with IcoSema versus icodec or semaglutide alone.

Conclusion: The combination of icodec and semaglutide in IcoSema leads to a higher and earlier maximum semaglutide concentration, which will guide the dose recommendations for IcoSema.

Clinical trial: ClinicalTrials.gov identifier: NCT03789578.

Background: Current literature and a real-world study suggest that diroximel fumarate (DRF) is safer than dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). However, no real-world study to date has significantly addressed the efficacy of this treatment.

Objectives: This study aims to elucidate the safety, tolerability, and efficacy of DRF in a real-world setting, utilizing data from a Spanish national registry of patients commencing DRF therapy post-market introduction.

Methods: In this multicenter, prospective observational study, data were collected from MS patients who initiated DRF treatment. The study monitored demographic and clinical characteristics, safety outcomes (including adverse events, reasons for discontinuation, and lymphocyte counts), and efficacy outcomes (radiological and clinical activity).

Results: A total of 195 MS patients across 26 neurological departments were included, predominantly female (79.5%), with a mean age of 42.17 years, and a mean duration of treatment with DRF of 6.3 months. Most patients (70.3%) reported no adverse events, while gastrointestinal issues and flushing were the most common adverse events observed. The majority of patients (84.6%) continued with DRF treatment, with tolerability issues being the primary reason for discontinuation. Efficacy analysis showed low relapse rates post-DRF initiation, with most patients exhibiting stable or improved Expanded Disability Status Scale scores and radiological assessments demonstrating minimal activity.

Conclusion: This comprehensive analysis provides valuable insights into the real-world application of DRF, confirming its safety and tolerability while offering preliminary evidence of its efficacy in managing MS.

Background and objective: Mitiperstat (AZD4831) is a novel irreversible oral myeloperoxidase inhibitor in clinical development for heart failure with preserved ejection fraction, metabolic dysfunction-associated steatohepatitis and chronic obstructive pulmonary disease. This study evaluated the pharmacokinetics, safety and tolerability of multiple ascending doses of mitiperstat in healthy male Japanese and Chinese volunteers.

Methods: Three cohorts of eight Japanese participants were randomized to receive once-daily oral doses of mitiperstat 2.5, 5 or 10 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo, per cohort). One cohort of eight Chinese participants was randomized to receive mitiperstat 5 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo).

Results: Mitiperstat was rapidly absorbed, with a time to maximum plasma concentration of 1-2 h. Exposure was dose proportional over the investigated dose range, as assessed by area under the concentration-time curve and maximum and trough plasma concentrations. Steady state was reached within 10 days, and accumulation was observed, consistent with the observed long elimination half-life of mitiperstat (50.2-57.8 h). Except for a few events of maculopapular rash, mitiperstat up to 5 mg was well tolerated in participants of Japanese or Chinese origin.

Conclusions: The pharmacokinetics of mitiperstat were similar among Japanese and Chinese participants. These characteristics were similar to those in a previous multiple ascending-dose study in healthy primarily white and Black/African American volunteers. Therefore, the pharmacokinetics of mitiperstat do not affect dosing regimens in these different populations.

Trial registration: NCT04232345 (03/01/2020).

Background and objective: The efficacy and safety of empagliflozin in the treatment of chronic kidney disease (CKD) were demonstrated in the EMPA-KIDNEY trial, which showed a 28% reduction in combined risks of kidney disease or death from cardiovascular causes (hazard ratio, 0.72; 95% confidence interval, 0.64-0.82; p < 0.001) compared with placebo. Based on these results, the present study aimed to assess the cost-effectiveness of empagliflozin + standard of care (SoC) compared with SoC alone in the treatment of CKD in France.

Methods: A Markov state microsimulation model was adapted to compare the health and economic outcomes in France, considering a healthcare system perspective, in patients treated with empagliflozin in addition to SoC versus patients treated with SoC alone. The model simulated the intention-to-treat population of the trial, transitioning between 18 mutually exclusive and collectively exhaustive health states defined based on the Kidney Disease: Improving Global Outcomes classification. For each arm, the model estimated (over a 25-year time horizon) the number of events and deaths, and the costs associated with these events, to calculate the incremental cost-effectiveness ratio. The resources used were derived using French authorities reports, literature, and French CKD guidelines. Both economic and health outcomes were discounted at a 2.5% annual rate according to French guidelines.

Results: The model predicted that using empagliflozin + SoC to treat patients with CKD would prevent CKD-related complications and deaths associated with a cardiovascular event or all-cause deaths while in kidney replacement therapy, resulting on average in a discounted gain of 1.29 years in overall survival (9.48 years vs. 8.19 with SoC alone). Empagliflozin costs (treatment, events, and disease management) were completely offset by the cost savings from avoided kidney failure events. Overall, empagliflozin + SoC would be more effective and less costly than SoC alone and would therefore be the dominant treatment strategy. The sensitivity analyses conducted support the results' robustness in showing the dominance of empagliflozin + SoC over SoC alone.

Conclusions: The base-case results indicate that empagliflozin + SoC is a dominant strategy compared with the current SoC for the management of CKD in France. Empagliflozin + SoC would have a positive impact on patients with CKD by slowing CKD progression and leading to the prevention of kidney failure events on top of all-stages CKD complications.

Background and objective: Rifaximin is used to treat diarrhea-predominant irritable bowel syndrome (IBS-D). However, determining the most effective regimen remains a challenge. This study aimed to evaluate the effectiveness and safety of a 10-day high-dose course of rifaximin (2200 mg/day) and its effects on both abdominal symptoms and quality of life (QOL) in patients with IBS-D.

Method: Adult patients with moderate to severe IBS-D (Rome IV) and fecal urgency and bloating were prescribed rifaximin 1100 mg twice daily for 10 days. Demographic information, the IBS Symptom Severity Index (IBS-SSI) score (using a 7-point Likert scale), and Bristol Stool Scale (BSS) score were recorded at baseline, day 10, and 4 weeks after treatment cessation. IBS Symptom Severity Score (IBS-SSS) and IBS-QOL scores were recorded at baseline and day 10. Any drug adverse effects were recorded.

Results: In total, 39 patients completed the study. Average scores for all abdominal symptoms and BSS showed significant improvement at day 10 and 4 weeks after treatment cessation (all p < 0.001). A significant improvement was seen in IBS-SSS and overall IBS-QOL score at day 10 (p < 0.001), with the highest improvement (31%) in interference with activity. Moreover, composite improvement rates were 38.64% for all abdominal symptoms, together with BSS < 5, bi-composite (66.67% for abdominal pain + bloating; 61.54% for abdominal pain + urgency), and 56.41% for tri-composite (abdominal pain + bloating + urgency) symptoms. Notably, no serious adverse effects were reported, and the adherence rate was 94.9%.

Conclusions: Abdominal symptoms and overall QOL, especially in social and work dimensions, significantly improved in patients with moderate to severe IBS-D following a regimen of rifaximin 2200 mg/day, which was well tolerated.

Drug-induced interstitial lung disease (DI-ILD) is a significant complication in patients undergoing treatment with certain anti-cancer therapies, with incidence rates rising, particularly with newer drugs such as trastuzumab-deruxtecan, which may impact their safe and effective use. Although the exact pathophysiological mechanisms remain unknown, and different drugs may induce lung damage through different pathways, the most recognized mechanisms are cytotoxic- and immune-mediated effects. Multidisciplinary teams play a crucial role in the diagnosis, management, and prevention of DI-ILD. Given the wide variability in the onset of DI-ILD, which may occur within the first few days of treatment or months after, patient education and clinician training are essential for early detection and improved outcomes. Moreover, the diagnostic confirmation requires the exclusion of alternative causes through clinical, imaging and bronchoscopy evaluation. Treatment strategies largely depend on the grade of severity of the clinical manifestations of DI-ILD, ranging from interruption or discontinuation of the offending drug to corticosteroid therapy and hospitalization for appropriate monitoring. Nonetheless, further research is needed to better understand the impact of emerging anti-cancer drugs on DI-ILD and to establish standardized management protocols.

Background and objectives: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently become a standard treatment for heart failure and renal failure. The number of patients using these drugs is expected to increase further. However, no adverse drug event profiles have been published for the use of SGLT2i in patients without diabetes. To analyze and clarify the differences in adverse event profiles associated with the use of SGLT2i in patients with diabetes or heart failure using the Japanese Adverse Drug Event Report (JADER) database, a Japanese reporting system for adverse events.

Methods: The JADER database, containing reports submitted between April 2004 and January 2024, was used. Our study focused on patients with diabetes or heart failure, analyzing adverse events associated with empagliflozin and dapagliflozin. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated for signal detection.

Results: We identified risks of adverse drug events such as ketoacidosis, urinary tract infection, dehydration, and acidosis in both patient groups. However, the risks of cerebral infarction and ischemic heart disease were identified only in patients with diabetes, while risks of renal dysfunction, hypoglycemia, and sepsis were identified only in those with heart failure.

Conclusion: Adverse events should be managed appropriately for patients using SGLT2i, as the adverse event profiles differ between those with diabetes and those with heart failure. Understanding these differences is crucial for improving patient safety and optimizing treatment outcomes.