Clinical Drug Investigation最新文献

The selection of an inhaler device is a key component of respiratory disease management. However, there is a lack of clarity surrounding inhaler resistance and how it impacts inhaler selection. The most common inhaler types are dry powder inhalers (DPIs) that have internal resistance and pressurised metered dose inhalers (pMDIs) that use propellants to deliver the drug dose to the airways. Inhaler resistance varies across the DPIs available on the market, depending largely on the design geometry of the device but also partially on formulation parameters. Factors influencing inhaler choice include measures such as flow rate or pressure drop as well as inhaler technique and patient preference, both of which can lead to improved adherence and outcomes. For optimal disease outcomes, device selection should be individualised, inhaler technique optimised and patient preference considered. By addressing the common clinically relevant questions, this paper aims to demystify how DPI resistance should guide the selection of the right device for the right patient.

Background and objectives: Drug-related acute kidney injury is quite common in older adults. The associated drugs, including antibiotics, are often co-prescribed. The objective of this study was to ascertain antibiotic-associated acute kidney injury (AKI) in older adults aged 65 years or above in New Zealand using a case-crossover study design.

Methods: The International Statistical Classification of Diseases and Related Health Problems, tenth revision, Australian modification code N17.x was used to identify all individuals aged 65 years and above with a diagnosis of incident AKI on admission between 1 January 2005 and 31 December 2020, from the New Zealand National Minimum Data Set. A case-crossover cohort for antibiotic exposures, with a 3 day case period and two 30 day washout periods, summed up to a 66 day study period, was created. Using conditional logistic regression, the changed odds of AKI due to exposure to an antibiotic was calculated as matched odds ratios and their 95% confidence intervals.

Results: A total of 2399 incident cases of AKI were identified between 2005 and 2020 among older adults. The adjusted odds of consuming sulfamethoxazole/trimethoprim antibiotic during the case period was 3.57 times (95% CI 2.86-4.46) higher than the reference period among the incident AKI cases. Fluoroquinolone utilization was also associated with incident AKI (adjusted OR = 2.56; 95% CI 1.90-3.46).

Conclusion: The potential of sulfamethoxazole/trimethoprim and fluoroquinolones to be associated with AKI raises the significant need for vigilant prescribing of these antibiotics in older adults.

Background: Allergic rhinitis (AR) has shown an increasing prevalence leading to a considerable medical and social burden. Nasal congestion is the cardinal symptom of AR, and the upper respiratory tract is most affected by this long-lasting ailment. Intranasal corticosteroids alleviate nasal congestion, along with other symptoms of AR, but their effect is not evident immediately. Oxymetazoline has a rapid onset of action, but its use should be limited to 3-5 days.

Objective: The study aimed to evaluate the safety and effectiveness of the fixed-dose combination nasal spray containing fluticasone furoate and oxymetazoline hydrochloride (FF + OXY) 27.5/50 mcg once daily in patients with AR in a real-world clinical setting.

Methods: The study was a prospective, open-label, single-arm, multicenter, real-world observational study conducted in patients with AR for a period of 28 days. Patients (n = 388) with a diagnosis of AR were treated with a combination of FF + OXY nasal spray. Total nasal symptom score (TNSS), total ocular symptom score (TOSS) and total symptom score (TSS) were documented at baseline and at the end of study period. The overall effectiveness of treatment with FF + OXY was rated by the investigators as very good/good/satisfactory/poor (4-point Likert scale) for each patient.

Results: Treatment with FF + OXY resulted in significant reduction in the TNSS, TOSS and TSS, from 7.18 ± 3.38 at baseline to 0.20 ± 0.84 (p < 0.001), from 2.34 ± 2.29 at baseline to 0.09 ± 0.53 (p < 0.001), from 9.51 ± 4.94 at baseline to 0.29 ± 1.32 (p < 0.001) at 28 days respectively. With respect to effectiveness, the investigators reported very good effectiveness in 52.12% of patients. No serious adverse events were reported.

Conclusion: The fixed-dose combination of once-daily fluticasone furoate and oxymetazoline hydrochloride nasal spray 27.5/50 mcg was effective in relieving the nasal congestion and reduction of TNSS, TOSS and TSS in patients suffering from AR. The combination was safe and well tolerated with no rebound congestion throughout the treatment period.

Background and objective: Several associations between diabetes mellitus and delirium have been reported; however, they have been inconsistent, and evidence on the effects of antidiabetic medications on delirium is also limited. This study aimed to investigate whether the use of antidiabetic drugs is a risk factor for delirium development.

Methods: Using the Japanese Adverse Event Reporting Database, we analyzed 662,899 reports between 2004 and 2022. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) for delirium associated with diabetes and using each antidiabetic medication were calculated after adjusting for potential confounders.

Results: Overall, 8892 of the reports analyzed were associated with delirium. A comparison of the incidence of delirium between patients with and without diabetes showed no significant difference, with 1.34% in patients without diabetes and 1.37% in those with diabetes. In each antidiabetic medication, signals for delirium were detected for sulfonylurea (crude ROR, 1.35; 95% CI 1.21-1.51) and insulin (crude ROR, 1.28; 95% CI 1.13-1.44). These results were maintained even after adjusting for factors with potential confounders (sulfonylurea: adjusted ROR, 1.75; 95% CI 1.54-2.00, insulin: adjusted ROR, 1.35; 95% CI 1.20-1.54).

Conclusions: Our results suggest no association between diabetes and delirium; however, using sulfonylurea and insulin may be associated with delirium development. Nonetheless, these findings should be validated in future studies.

Background and objective: Ethnic and racial differences are key factors affecting the results of clinical studies. However, the influence of these factors on the efficacy and safety of medicinal products remains unclear. Race-dependent nature is considered to be one of the factors causing differences in clinical findings, and we investigated its influence on the safety evaluation of drugs.

Methods: We searched PubMed and a Japan drug approval list to find relevant studies, and extracted phase I studies conducted with Japanese and non-Japanese participants using the same protocol and at the same study site. Pooled estimates of odds ratios (ORs) for the incidence of major adverse events in Japanese and non-Japanese participants were calculated, using a DerSimonian-Laird method with a random-effects model.

Results: Odds ratios for some adverse events in the active drug arm were significantly lower in Japanese participants: headaches [OR 0.65 (95% confidence interval [CI] 0.52-0.82), p = 0.0003], neurological disorders NEC [OR 0.70 (95% CI 0.53-0.93), p = 0.0135] in a High-Level Group Term, nervous system disorders [OR 0.64 (95% CI 0.49-0.82), p = 0.0004], infections and infestations [OR 0.71 (95% CI 0.53-0.95), p = 0.0202], and musculoskeletal and connective tissue disorders [OR 0.66 (95% CI 0.48-0.91, p = 0.0107] in the System Organ Class.

Conclusions: Our research suggested that racial factors such as race-dependent nature influence a drug safety assessment. With knowledge of these differences, it is expected that Japan will actively conduct multi-regional clinical trials, in which more diverse populations are included.

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder. However, studies of hospitalisation patterns with replacement treatment are scarce.

Objectives: The aim of this study was to investigate the current therapeutic management of VWD and determine the key drivers of coagulation factor uses in patients during hospitalisation.

Methods: Hopscotch-WILL was a multi-centric retrospective study conducted over a 48-month period in any patients with VWD. The data were collected from the BERHLINGO Research Database and the French Hospital database.

Results: A total of 988 patients were included; 153 patients (15%) were hospitalised during 293 stays requiring treatment with von Willebrand factor (VWF) concentrates-pure or in association with Factor VIII (FVIII). Their median basal concentrations of VWF and FVIII were significantly lower than in untreated patients: VWF antigen < 30 IU/dL, VWF activity < 20 IU/dL and FVIII:C < 40 IU/dL. The median (interquartile range) concentrate consumption was similar between highly purified VWF or VWF combined with FVIII (72 [110] vs 57 [89] IU/kg/stay, p = 0.154). The use of VWF was highly heterogeneous by VWD type; type 3 had a particularly high impact on VWF consumption in non-surgical situations. The main admissions were for ear/nose/throat, hepato-gastroenterology, and trauma/orthopaedic conditions, besides gynaecological-obstetric causes in women.

Conclusions: The use of VWF concentrates is mostly influenced by low basal levels of VWF and FVIII, but also by VWD type or the cause for hospitalisation. These results could inform future studies of newly released recombinant VWF.

Background and Objective

VC004 is a novel next-generation tropomyosin receptor kinase (TRK) inhibitor that is approved for the treatment of advanced or metastatic NTRK fusion-positive solid tumors and abrogated the drug resistance of the first-generation TRK inhibitors. The objective of the present study was to evaluate the effect of food on the pharmacokinetics and safety of VC004.

Methods

The study was a randomized, open-label, two-period crossover, single-dose, phase I clinical trial. A total of 16 healthy subjects participated the trial. Subjects fasted for 10 h before drug administration in both fasting and fed states. Subjects received VC004 50 mg orally in the fasting state and after a high caloric food in the fed state. Blood samples at the designated time points were collected to determine the plasma concentration of VC004. Safety evaluation in both the fasted and fed periods were assessed via vital sign monitoring and clinical laboratory tests.

Results

The maximum plasma concentration (C_max) of VC004 in fed group decreased by 32.8%, corresponding with the slower absorption rate (time to C_max (T_max) delayed by almost 3 h) compared with the fasting group. Ratios of geometric means (GMRs) and 90% confidence intervals (90% CIs) of C_max, the area under the curve of plasma concentration-time from zero to the last measurable concentration (AUC_0–t), and AUC from zero to infinity (AUC_0–∞) for VC004 between the two states were 67.18 (58.16–77.60), 103.59 (95.04–112.92) and 103.55 (95.63–112.11), respectively. No serious adverse events (AEs) occurred; only three grade 1 or grade 2 adverse events occurred in the fasted group, who recovered by the end of the study.

Conclusions

The intake of high calorie food decreased the absorption rate and increased the T_max of VC004, while the AUC values were similar in both groups. No serious adverse event was reported. In conclusion, food does not alter the pharmacokinetics and safety profile of VC004 in a clinically meaningful manner.

Trial Registration

ClinicalTrials.gov ID: NCT055528120.

Abstract