International journal of clinical pharmacology and therapeutics最新文献

Objective: To quantitatively and qualitatively evaluate research trends and hotspots for immune checkpoint inhibitors (ICIs), according to the most frequently cited clinical trials.

Background: Numerous clinical trials have been carried out using ICIs for activating anti-tumor immunity in cancer patients. The most frequently cited clinical trials have been used as a database for achieving the objectives of this analysis.

Materials and methods: The most frequently cited articles on ICIs meeting the inclusion criteria were extracted from the Web of Science database. Citation report information including annual outputs, most relevant journals, and country of origin together with burst references, keywords, information on co-occurrence, citation networks, and cluster topics were analyzed using standard bibliometric procedures.

Results: A total of 112 most frequently cited articles on clinical trials of ICIs were retrieved for the period 2013 to 2021 of which the journal JAMA Oncology had the highest number of citations. Most studies originated in the U.S., and therefore studies from this country had a determinant effect of the results of the investigation. Burst reference topics included studies on ipilimumab for melanoma, anti-PD-L1 antibody in advanced cancer, anti-PD-1 antibody in cancer, nivolumab combined with ipilimumab or as monotherapy in untreated melanoma, and pembrolizumab for PD-L1 positive non-small-cell lung cancer. Nine clusters were grouped in the citation network. The topic/keywords "cancer", "immunotherapy", "PD-1 blockade", "PD-L1", "expression", "ipilimumab", "nivolumab", "pembrolizumab", and "safety" were the search priorities, whereas "multicenter", "resistance", "adverse events", and "renal-cell carcinoma" were seen as emerging topics in this specific field.

Conclusion: The bibliometric analysis of the most frequently cited clinical trials with ICIs provided information on the characteristics of the studies evaluated as well as hotpots and trends in evolving immunopharmacotherapy research on ICIs.

Objective: Aplastic anemia (AA) is a life-threatening disease, and drug-induced AA is rare. Recently, studies on cases that possibly developed AA following osimertinib treatment have been conducted. This study evaluated the association of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including osimertinib, with AA and characterized such registered patients using a large spontaneous adverse event reporting database.

Materials and methods: Data from the Food and Drug Administration's Adverse Event Reporting System spanning from the first quarter of 2015 to the second quarter of 2023 were used. Disproportionality analyses with reporting odds ratio (ROR) and information component (IC) were performed for signal detection. Furthermore, we described a case series of patients who experienced AA during osimertinib treatment.

Results: A signal was detected with osimertinib (ROR: 4.16, 95% confidence interval (CI): 2.54 - 6.80; IC: 1.80, 95% CI: 1.10 - 2.51); however, no signals were detected with other EGFR-TKIs. 16 individuals treated with osimertinib had AA, of whom 14 (87.5%) were registered as suspected drugs. The median age of these individuals was 70.5 years (interquartile range (IQR), 64.8 - 78.3 years), with varying time to onset (IQR, 4 - 210 days) and outcomes, including 3 (18.8%) deaths.

Conclusion: Our analyses generated a safety signal for the association between osimertinib and AA. Further studies are required to understand and confirm the role of osimertinib administration in the development of AA.

Background and objectives: This study aimed to determine whether there is an association between the use of α-blockers to treat benign prostatic hyperplasia (BPH) and the development of heart failure in elderly Asian patients.

Materials and methods: An Elderly Cohort Database of the National Health Insurance Service was used to select 22,540 patients with newly diagnosed BPH between January 1, 2008, and December 31, 2018. They were divided into two equal groups, one prescribed α-blockers and one not. They were followed up through December 31, 2019. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the occurrence of heart failure with α-blockers. In addition, α-blockers were categorized according to α1a receptor selectivity to estimate the hazard ratios for heart failure.

Results: Heart failure occurred in 283 patients in the non-user group and 74 patients in the α-blocker group, with an incidence rate of 553.4 in the non-user group and 516.8 in the α-blocker group per 100,000 person-years. Although α-blocker users had a higher hazard ratio for heart failure compared to the non-user group, this was not statistically significant (HR: α-blocker HR 1.14, 95% CI 0.87 - 1.491). Furthermore, when α-blockers were stratified by selectivity, the results were also not statistically significant (non-selective α-blocker HR 0.86, 95% CI 0.31 - 2.36).

Conclusion: In this nationwide, population-based cohort study, treatment with α-blockers was not associated with the incidence of heart failure in patients with BPH.

Objectives: To evaluate the indications and dosing regimens for oral metronidazole monotherapy (OMM) for the management of oral anaerobic infections (OAIs) other than periodontitis.

Materials and methods: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in literature of PubMed/Medline, Scopus, and Cochrane databases. Data were retrieved from reports published in English in the period January 1, 1980 - August 30, 2023. Joanna Briggs Institute Critical Appraisal Tools were used to assess study risk of bias.

Results: A total of 228 articles were retrieved from the databases of which 16 met the inclusion criteria necessary for achieving the aims of the study. OAIs in which OMM was used or recommended included pericoronitis; necrotizing ulcerative gingivitis/periodontitis/stomatitis, osteomyelitis, acute periapical infection, and cellulitis. OMM was prescribed in dosages ranging from 200 to 500 mg t.i.d. for periods ranging from 2 to 7 days. Osteomyelitis of the jaw was the only infection for which the dosage regimen of metronidazole was not clearly described.

Conclusion: Evidence from the databases searched support the view that OMM has clinical efficacy in the treatment of specific OAIs namely pericoronitis and necrotizing oral infections in immune-competent and immune-compromised patients. The evidence does not support the use of OMM in "deep tissue" infections such as osteomyelitis, and odontogenic infections such as acute apical infection and cellulitis. Clinical trials are warranted to determine the efficacy of OMM in comparison with other antibiotic regimens.

Objective: The purpose of this study is to evaluate the pharmacokinetics (PK) parameters of an ezetimibe 10 mg (test drug) and assess its bioequivalence to the branded reference product in healthy Chinese subjects under fasting and fed conditions.

Materials and methods: A single-center, randomized, open-label, four-period, two-sequence, full replicate crossover study was conducted in 88 healthy Chinese subjects under fasting or fed conditions. Subjects received a single oral dose of 10 mg ezetimibe tablet as test or reference formulation. There was a minimum 14-day washout period between each dose. Blood samples were collected at prescribed time intervals, the plasma concentration of free ezetimibe and total ezetimibe (ezetimibe + ezetimibe glucuronide) was determined by a validated ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Pharmacokinetik and bioavailability parameters were estimated via non-compartmental methods. Adverse events were also recorded.

Results: 40 and 48 eligible healthy subjects were enrolled in the fasted and fed study. Under fasting state, total ezetimibe with 90% confidence intervals (CIs) of C_max, AUC_0-t, and AUC_0-∞ were 87.17% (81.99 - 92.66%), 95.98% (92.38-99.72%), and 96.04% (91.37 - 100.95%), respectively. Under fed state, total ezetimibe with 90% confidence intervals (CIs) of C_max, AUC_0-t, and AUC_0-∞ were 98.71% (90.11 - 108.13%), 98.32% (94.71 - 102.06%), and 97.90% (92.68 - 103.42%), respectively. The 90% CIs of the ratio of geometric means (GMRs) of C_max, AUC_0-t, AUC_0-∞ of the test and reference formulation in both fasting and fed conditions fell within the conventional bioequivalence criteria of 0.80 - 1.25. No severe adverse events were observed.

Conclusion: The test and reference 10-mg ezetimibe tablets were bioequivalent under fasting and fed conditions in Chinese subjects. Both preparations showed good safety and tolerability.

Objective: Only limited data are available on trough plasma voriconazole concentration in elderly patients. This study aimed to assess the association between voriconazole concentration and adverse drug reactions (ADR).

Materials and methods: A retrospective analysis was conducted to investigate the correlation between voriconazole trough concentration and adverse reactions among elderly patients admitted between October 1, 2017, and September 30, 2020.

Results: In total 147 patients were included in this study, with 248 measurements of voriconazole concentrations available. ADR occurred in 75 patients after drug therapy, with liver injury showing the highest incidence (n = 37, 49.33%), followed by hypokalemia (n = 27, 36%), and neurological disorder (n = 20, 26.67%). 121 measurements (48.79%) in 82 patients (55.78%) showed that the monitored trough concentration did not match the occurrence of ADR, mainly including hyponatremia, hypokalemia, liver injury, and kidney injury.

Conclusion: The accuracy of predicting the trough concentration of voriconazole as recommended by current guidelines for elderly patients might be limited. Consequently, it is advisable to establish a tailored treatment range of voriconazole concentration specifically catered to this patient demographic.

Objectives: To demonstrate adequate skin adhesion of a new once-daily rotigotine transdermal patch (ROT-TDS) compared to the originator product (reference) in patients with Parkinson's disease (PD).

Materials and methods: Pharmacokinetic bioequivalence (PK BE) was assessed with the 4 mg/24h patches in healthy adults in a single-/multiple-dose, crossover trial. The trial investigating skin adhesion in PD patients (stable dose ≥ 8 mg/day rotigotine) was performed with the 8 mg/24h patches as a multiple-dose, crossover trial (4 alternating once-daily patch applications). Skin status (seborrhea, sweating) was characterized at screening. Adhesion was assessed 5 minutes after application and 5 minutes before removal of each patch. Systemic safety and skin irritation/sensitization were monitored.

Results: ROT-TDS was bioequivalent to the reference product in the PK BE trial in 48 randomized healthy subjects. In the skin adhesion trial in 43 randomized PD patients, the cumulative mean percentage of adhesion (90% CI) at the end-of-dosing interval was 92.948% (90.156 - 95.740%) for ROT-TDS and 90.471% (87.574 - 93.367%) for the reference. For ROT-TDS, 80.23% of patches were ≥ 90% adhered at the end-of-dosing interval, while this was the case for 67.44% of the reference patches. Safety and skin tolerability of both products were comparable; the most frequent treatment-related adverse event was application-site pruritus for both treatments at comparable extent.

Conclusion: ROT-TDS - with shown BE to the originator reference product - displayed similar safety and local tolerability as the reference product in patients with PD. The results show a trend to improved skin adhesion of the new patch compared to the reference in the target population.

Objective: To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles.

Materials and methods: This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120 hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit.

Results: Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC_0-t, 90.26 - 105.52% for C_max, and 93.49 - 104.05% for AUC_0-∞.

Conclusion: The 90% CI for the geometric mean ratios (test/reference) of C_max, AUC_0-t, and AUC_0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.

Pulmonary fibrosis (PF) is a chronic and progressive pulmonary interstitial disease of unknown etiology and is also a sequela in severe patients with the Coronavirus Disease 2019 (COVID-19). Seven databases were systematically searched to evaluate the preclinical evidence of Tanshinone IIA (Tan IIA) on PF. The quality of the included studies was assessed using a 10-item risk of bias tool, and data were analyzed using RevMan 5.3 software. 22 experiments from 12 studies on a total of 248 animals were included. The results showed that PF phenotype, such as fibrotic score, collagen I (Col-I), collagen III (Col-III), hydroxyproline (Hyp), in the group treated with Tan IIA were significantly lower than those in the model group (p < 0.00001). The potential mechanisms of Tan IIA improvement of PF involve reducing inflammation, antioxidation, and suppressing activation of transforming growth factor beta 1 (TGF-β1). The subgroup analysis of different models, different rat species, and different dosage time showed significant reduction in fibrotic scores and Hyp levels with Tan IIA. The preclinical evidence indicated that Tan IIA might be a potent and promising agent for PF, but this conclusion should be further confirmed with more research.

Background: Obesity is a complex disease for which pharmacotherapy is often used. Anti-obesity drugs (AODs) are characterized by inducing a variable inter-subject body weight reduction (BWR), the attainment of a plateau after their maximal effect is achieved, and weight regain after drug discontinuation, which complicate individualized treatment of obesity.

Objective: This exploratory analysis aimed to compare the first-month body weight reduction in kg (1mo-BWRkg) and tolerance development (moT) of four known interventions with low (placebo), intermediate (phentermine or mazindol monotherapy), and high (5 active ingredients fixed-dose combination) efficacy, as predictors of their 6-month body weight reduction efficacy in percent (6mo-BWR%). In addition, a detailed analysis of the 6-to-12-month BWR follow-up in subjects under orlistat or diet and exercise regimens was performed.

Materials and methods: The analysis included 662 adult subjects with obesity. After the construction of average efficacy and weight rebound curves, subjects were grouped into various 1mo-BWRkg, moT, and 6mo-BWR% intervals, or 6-month body weight rebound parameters for further evaluation.

Results: The 6mo-BWR% efficacy level of interventions was confirmed, although a general high intersubject variation was observed. 1mo-BWRkg + moT was found as an acceptable predictor of 6mo-BWR%. Between 50 and 80% of the 6-to-12-month follow-up completers maintained at least 5% BWR%.

Conclusion: Short-term AODs are useful adjuvants for the 1-year rational treatment of obesity. 1mo-BWRkg + moT is an acceptable parameter to predict the 6mo-BWR% efficacy of these interventions.