Clinical Drug Investigation最新文献

BACKGROUND AND OBJECTIVE: This meta-analysis aims to evaluate ligelizumab's efficacy and safety for chronic spontaneous urticaria (CSU) treatment by analyzing recent clinical trials and comparing it with placebo and omalizumab.

Methods: PubMed, Embase, and Cochrane were searched up to October 2024. Eligible studies were randomized controlled trials (RCTs) comparing ligelizumab with placebo or omalizumab, reporting relevant outcomes. Nonrandomized studies, or those without control groups, were excluded. Risk of bias was assessed using the Cochrane RoB-2 tool, and the Grading of Recommendation, Assessment, Development, and Evaluations approach rated evidence certainty. Statistical analysis used R software (v.4.4.2), assessing heterogeneity by Cochran Q and I² statistics.

Results: Four RCTs with 2488 patients were included. Ligelizumab (< 72 mg) significantly improved itch severity score over 7 days (ISS7) [risk ratio (RR) 5.07; 95% confidence interval (CI) 3.12-8.24; prediction interval (PI) 2.31-11.15; P < 0.01; I² = 0%], urticaria activity score over 7 days (UAS7) (RR 4.61; 95% CI 1.84-11.59; PI 0.34-62.49; P < 0.01; I² = 55%), and overall urticaria activity (RR 4.26; 95% CI 2.63-6.92; PI 0.18-98.29; P < 0.01; I² = 0%) versus placebo. The > 72 mg dose showed greater improvements in ISS7 (RR 5.12; 95% CI 2.72-9.64; PI 1.14-22.96; P < 0.01; I² = 45%), UAS7 (RR 5.35; 95% CI 3.04-9.40; PI 1.78-16.08; P < 0.01; I² = 31%), and overall activity (RR 4.34; 95% CI 2.67-7.04; PI 0.19-99.80; P < 0.01; I² = 0%). Compared with ligelizumab (> 72 mg), omalizumab had fewer injection site reactions (RR 3.04; 95% CI 1.95-4.73; PI 0.17-53.81; P < 0.01; I² = 0%) and erythema (RR 5.05; 95% CI 1.33-19.13; PI 0.08-312.57; P = 0.02; I² = 17%). Moderate certainty evidence indicated that ≤ 72 mg probably improved ISS7, overall urticaria activity, and UAS7. For > 72 mg, improvements in overall urticaria activity were seen, but ISS7 and UAS7 were classified as low quality of evidence.

Discussion: Ligelizumab significantly improves CSU symptoms compared with placebo, reducing disease severity, itching, and hives, with similar safety to omalizumab. Ligelizumab's higher affinity for immunoglobulin E (IgE) may provide better symptom control. Limitations include a small number of studies, short follow-up periods, and patient variability.

Protocol registration: International Prospective Register of Systematic Reviews (PROSPERO), CRD42024593072.

Obesity is associated with increased psoriasis severity and reduced effectiveness of psoriasis treatments. This is a summary of a research article that reports a study evaluating the efficacy and safety of brodalumab (a subcutaneous injectable therapy) in participants with and without obesity who have moderate-to-severe psoriasis. Data were analyzed from two large, phase 3 clinical trials (AMAGINE-2 and AMAGINE-3) of participants with psoriasis who were treated with brodalumab or another subcutaneous injectable therapy, ustekinumab. After brodalumab treatment for 52 weeks, participants with obesity experienced similar rates of skin clearance to those without obesity (90% improvement: 88% versus 85%; 100% improvement: 65% versus 73%, respectively). Brodalumab safety profiles were generally similar between participants with and without obesity. This study demonstrated that brodalumab is effective and safe for treating moderate-to-severe psoriasis, regardless of obesity status.

Background and objective: D-1553 (garsorasib) is a novel and selective oral KRAS^G12C inhibitor. This study aims to evaluate the effect of food on the single-dose pharmacokinetics (PK) of D-1553 tablet in healthy Chinese subjects. Also the safety and tolerability of single-dose D-1553 in subjects are also evaluated.

Methods: A randomized, open-label, single-dose, two-intervention (fed vs fasting), two-period, two-sequence crossover study was performed on 14 healthy Chinese subjects. Plasma concentrations of D-1553 were determined by the liquid chromatography-tandem mass spectrometry method. Safety evaluations were carried out during the study period. The main PK parameters of the two formulations of D-1553 were calculated by non-compartmental analysis using Phoenix WinNonlin (Version 8.3) software.

Results: The geometric mean ratios (90% confidence interval [CI]) of AUC_0-t and AUC_0-∞ in the high-fat meal condition versus the fasting condition were 86.19% (78.30%, 94.87%) and 83.30% (75.77%, 91.58%), respectively. The geometric mean ratio (90% CI) of C_max values in high-fat meal condition to that observed in fasting condition were 109.74% (100.22%,120.15%). The p value of T_max was 0.1484 (fed vs fasting). Two subjects (14.3%) reported 4 treatment-emergent adverse events (TEAEs) in the fasting condition, and no subjects reported TEAEs in the fed condition. All adverse reactions were mild and had recovered by the end of the study.

Conclusion: The study indicated that a high-calorie and high-fat meal has no clinically relevant impact on the PK and bioavailability of D-1553 in healthy Chinese subjects. D-1553 was generally safe and well-tolerated under both fasting and fed conditions. The findings suggest that D-1553 could be administered orally with or without food.

Clinical trials: ClinicalTrials.gov Identifer CTR20212761; registered on 4 Nov 2021.

Introduction: Research on the benefits of medical cannabis (MC) is emerging and supports its use as a treatment for post-traumatic stress disorder (PTSD). This study aimed to evaluate the cost effectiveness of MC as an adjunctive therapy for moderate PTSD under varying reimbursement scenarios.

Methods: A cost-utility analysis was conducted from the US payor perspective, using pricing data from the largest multi-state MC producer and established literature on standard PTSD treatments. We analyzed eight MC product types: dried flower, oral solutions, tablets, and edibles, each available in low/moderate (LM) and high-cost formulations. Incremental cost-utility ratios (ICURs) were calculated for these products across reimbursement levels of 100%, 75%, 50%, and 25%. Probabilistic sensitivity analyses with 10,000 Monte Carlo simulations were conducted to assess cost-effectiveness acceptability across willingness-to-pay (WTP) thresholds of $0-$100,000 per quality-adjusted life year (QALY) gained.

Results: Non-flower MC products (edibles, oral solutions, and tablets) consistently demonstrated cost-effectiveness under a WTP threshold of $50,000, even at 100% reimbursement. Dried flower products, while less cost effective due to higher costs, achieved cost effectiveness under 75% or lower reimbursement levels for LM cost formulations. Sensitivity analyses confirmed robust ICURs for non-flower products, with narrower variability compared to dried flower products.

Conclusions: Medical cannabis products, particularly non-flower formulations, represent a cost-effective adjunctive therapy for moderate PTSD under various reimbursement scenarios. This analysis underscores the importance of evidence-based reimbursement policies to improve patient access to cost-effective treatments while ensuring financial sustainability for payors.

Recent evidence highlights the increasing utilization of guanfacine in the intensive care unit. While dexmedetomidine is a widely used sedative and anti-anxiety agent in the intensive care unit, prolonged use can lead to withdrawal effects when attempting to reduce the dosage. This has generated interest in using guanfacine to manage agitation in patients being weaned off dexmedetomidine. Clonidine has been used for dexmedetomidine weaning, but its use has been associated with adverse cardiovascular events. Some observational studies and case reports have explored the use of guanfacine and have shown its benefits and tolerability for patients taking dexmedetomidine experiencing adverse effects. Guanfacine is increasingly being used in the intensive care unit instead of clonidine and is commonly prescribed for the management of withdrawal effects. While there are limited data from observational studies, it holds promise for future clinical research and broader adoption of guanfacine in the intensive care unit.

Background and objectives: Enarodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor. We evaluated the pharmacokinetics, pharmacodynamics, and safety profile of domestic enarodustat (SAL-0951) and analyzed the influence of ethnic factors.

Methods: In this phase I study, healthy Chinese participants received single and multiple oral doses (1, 5, and 15 mg) of SAL-0951 while in a fasted state. We monitored the pharmacokinetics, pharmacodynamics, and safety characteristics and analyzed the impact of ethnicity on pharmacokinetic characteristics.

Results: In total, 33 healthy Chinese participants were enrolled; the mean age was 31.2 ± a standard deviation of 5.5 years. After single doses of 1, 5, and 15 mg were administered under fasted conditions, SAL-0951 was rapidly absorbed. Mean maximum plasma concentration and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration increased dose proportionately from 0.14 to 2.54 μg/mL and from 0.63 to 9.50 h × μg/mL, respectively. The elimination half-life was 6.13, 6.32, and 6.74 h, respectively, in these three groups, and the mean value of apparent clearance ranged from 1.64 to 1.89 L/h. SAL-0951 was excreted mostly as the parent compound. It reached a stable concentration after 5 days of multiple-dose administration. We observed no drug accumulation or time-dependent pharmacokinetic characteristics and no significant difference in pharmacokinetic characteristics between Chinese and Japanese participants.

Conclusion: SAL-0951 was safe and well tolerated in healthy Chinese participants and had a linear pharmacokinetic profile. We found no ethnic differences in the pharmacokinetic characteristics of the drug between Chinese and Japanese populations.

Clinical trial registration: Registered at Chinadrugtrials.org.cn, registration number CTR2020245.

Background and objectives: Vitamin D receptor activators (VDRAs) are widely used in patients with osteoporosis; however, the frequency of acute kidney injury (AKI) due to VDRAs is unclear. This study aimed to investigate whether the incidence of AKI after VDRA initiation differed among patients with different renal functions.

Methods: The medical records of Japanese patients who were newly prescribed with VDRAs for osteoporosis at the Fujita Health University Hospital or Kyoto University Hospital between April 2012 and March 2022 were retrospectively reviewed in this study. The RIFLE (Risk, Injury, Failure, Loss of function, End-stage kidney disease) criteria were used to assess the incidence of AKI within 7 days after initiation of VDRA therapy. Additionally, the AKI algorithm was used to assess the incidence of AKI from 8 to 365 days after initiation of VDRA therapy.

Results: The incidence of AKI, as defined by the RIFLE criteria, was significantly higher in patients with normal renal function or end-stage renal failure than in those with mild renal decline (p < 0.05); the incidence of AKI, defined using the AKI algorithm, showed a similar trend. We found that the lack of serum calcium level monitoring before the initiation of VDRAs might be a risk factor for AKI defined by the RIFLE criteria (odds ratio = 2.004, p = 0.096).

Conclusions: The incidence of AKI after the initiation of VDRA therapy was high, even if renal function was normal. Thus, our results suggest that monitoring serum calcium levels before the initiation of VDRA therapy is necessary, regardless of renal function.

Background: Isavuconazole is a recent broad-spectrum triazole indicated for the treatment of invasive aspergillosis and mucormycosis when amphotericin B is inappropriate. However, limited information exists on its clinical use.

Objective: We set up a retrospective multicentre study to describe the clinical practice of isavuconazole including indications, exposure, and hepatic safety.

Methods: From January 2021 to June 2023, all patients who received isavuconazole and had at least one therapeutic drug monitoring (TDM) measurement, were included. To identify independent predictors of isavuconazole trough concentrations (C_min), linear regression analyses were performed. Causal relationship between the occurrence of liver injury and isavuconazole was also analysed.

Results: Most of the included patients (n = 102) were admitted into haematology units (41.1% [n = 42]) or intensive care units (ICU) (30.4% [n = 31]). Aspergillosis (47.0% [n = 48]), mucormycosis (25.6% [n = 26]), and off-label empirical treatments (18.6% [n = 19]), were the three most common indications. About half of the patients (46.1% [n = 47]) had an optimal exposure, while 42.2% (n = 43) were underexposed, and 11.7% (n = 12) were overexposed. Albumin level on the day of TDM was a significant factor associated with an increase in isavuconazole C_min (p = 0.010). Among the 11 patients who had liver test abnormalities, isavuconazole was discontinued in six (n = 6) patients and liver injury was attributable to isavuconazole in two (n = 2) patients.

Conclusions: This multicentre analysis highlighted the common use of isavuconazole as an off-label indication, as well as the frequent underexposure of patients to isavuconazole. Albumin on the day of TDM appeared to be an important factor driving isavuconazole exposure, especially in ICU patients.

Background and objective: The introduction of immune checkpoint inhibitors (ICIs) in oncology presents a critical healthcare policy challenge for resource allocation due to their substantial financial burden. This study assessed the reporting quality of health economic evaluation (HEE) studies of ICIs.

Methods: This study conducted a systematic literature search of four databases (PubMed, EMBASE, Cochrane CENTRAL, and the International HTA Database) for studies published between January 1, 2014 and December 31, 2022. All ICIs approved up to December 31, 2022, in the USA, EU, China, and Japan were included. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards published in 2013 (CHEERS 2013), which is the most widely recognised and implemented reporting guideline for HEE studies. Subgroup analyses were also performed based on the risk of sponsorship bias or citation of CHEERS 2013.

Results: A total of 5368 records were identified, 252 of which were included after full-text review. The study design, setting, and ICIs most frequently observed were cost-effectiveness and cost-utility analyses (63.5%), the USA (46.0%), and pembrolizumab (38.1%), respectively. Of the 24 items of CHEERS 2013, fully reported items were limited, particularly in the Methods section. Setting and location were not reported in 94.4% of the records. Subgroup analyses also revealed insufficient reporting of items in the Methods section, particularly "Setting and location".

Conclusion: Health economic evaluation studies on ICIs between 2014 and 2022 had limited reporting across the 24 items of CHEERS 2013, regardless of sponsorship bias risk or citations. The items on setting and location in the Methods section were particularly underreported, emphasising the need for transparent reporting in HEE studies of ICIs.