Clinical Drug Investigation最新文献

Mazindol, an imidazo[2,1-a]-isoindole anorectic from the 1970s, has recently re-emerged as a candidate therapy for disorders of arousal and reward dysregulation, due to its unique multimodal receptor profile. Despite its 1999 withdrawal from US/EU markets, off-label narcolepsy efficacy spurred immediate-release/sustained-release (IR/SR) development. Clinical trials demonstrate mazindol IR/SR efficacy, reducing excessive daytime somnolence and cataplexy in narcolepsy and attention-deficit/hyperactivity disorder (ADHD) severity symptomatology, with mild adverse events (e.g., dry mouth). Preclinical studies demonstrate potent monoamine transporter inhibition (dopamine, norepinephrine, serotonin) with minimal dopamine release, reducing abuse liability compared with amphetamines. Novel interactions orexin-2, 5-HT_1A, and mu-opioid receptors suggest reward modulation, low abuse potential, and utility in polydrug dependence (e.g., fentanyl-cocaine co-use). This review, covering the period 1970-2025, emphasizes the potential for repositioning mazindol, including its potential utility in managing opioid-stimulant co-dependence and attention-related disorders, and underscores its relevance for future therapeutic repurposing. Although this is a narrative review, we conducted targeted searches of PubMed, Scopus, and ClinicalTrials.gov from this period of time, using terms including "mazindol," "narcolepsy," "ADHD," and "substance use disorder."

Background: Osteoporosis, a common condition of low bone mineral density (BMD), significantly increases fracture risk. Denosumab and alendronate are both established anti-resorptive therapies, yet their comparative effectiveness remains inconsistent across studies.

Objective: The aim of this meta-analysis was to systematically evaluate the efficacy of denosumab versus alendronate for improving BMD at multiple skeletal sites in osteoporosis patients, aiming to provide evidence for clinical decision making.

Methods: Multiple databases were searched for relevant randomised controlled trials published in English (as of November 2024). The primary outcomes were mean change of BMD at different skeletal sites. Data were pooled using fixed- or random-effects models to determine the mean differences (MDs) and 95% confidence intervals (CIs) for various BMD in patients treated with denosumab in comparison to patients treated with alendronate.

Results: This meta-analysis included thirteen randomized controlled trials (RCTs) with a total of 3364 patients and follow-up periods ranging from 6 to 24 months, and the overall quality of the studies was relatively high. The results demonstrated that denosumab was more effective than alendronate in increasing BMD at the lumbar spine (LS), femoral neck (FN), distal radius (DR), and total hip (TH) in osteoporosis patients and high-risk populations. Subgroup analysis revealed that postmenopausal women experienced greater improvements in BMD at the LS (p < 0.001) at 6 months, and at the FN (p < 0.001) at 24 months, compared with non-postmenopausal  subjects.

Conclusions: Denosumab was more effective than alendronate in increasing BMD. However, all the included randomised controlled trials (RCTs) carried a risk of bias, and the patient sample sizes were relatively small. Therefore, further studies with larger sample sizes and better methodological rigor are needed to confirm these findings.

Prospero registration number: CRD420250655676.

Objective: This analysis aimed to evaluate the efficacy of brexpiprazole 2 or 3 mg/day for the treatment of agitation associated with dementia due to Alzheimer's disease, on the basis of pooled clinical trial data.

Methods: Data were pooled from two similarly designed, phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled trials of fixed-dose brexpiprazole in participants in care facilities or community-based settings who had agitation associated with dementia due to Alzheimer's disease. Efficacy outcomes included Cohen-Mansfield Agitation Inventory (CMAI) total score (which measures the frequency of 29 different agitation symptoms), Clinical Global Impression-Severity of illness (CGI-S) score, CMAI factor scores (aggressive behaviors, physically nonaggressive behaviors, and verbally agitated behaviors), and response rates. A sensitivity analysis included a third trial with flexible dosing.

Results: In total, 621 participants were randomized (brexpiprazole, 368; placebo, 253), and completion rates were 320/368 (87.0%) and 225/253 (88.9%), respectively. Mean (SD) baseline CMAI total scores were: brexpiprazole 76.9 (17.2) points and placebo 75.5 (18.0) points. Over 12 weeks, CMAI total scores improved by least squares mean (SE) - 22.8 (0.8) points for brexpiprazole and - 18.3 (1.0) points for placebo, with a least squares mean difference between treatment arms of - 4.50 points (95% CI - 6.90 to - 2.10; p < 0.001; Cohen's d 0.30). CGI-S, CMAI factor, and response analyses also showed greater improvement with brexpiprazole versus placebo. The sensitivity analysis was supportive.

Conclusions: Brexpiprazole 2 or 3 mg/day reduced agitation symptoms compared with placebo over 12 weeks in this large, pooled sample of participants with dementia due to Alzheimer's disease.

Study registration: ClinicalTrials.gov identifiers: NCT01862640, NCT03548584, and NCT01922258.

Background and objectives: In clinical trials, osimertinib combined with chemotherapy has demonstrated improved efficacy in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer. However, the projected long-term outcomes and the associated cost effectiveness compared to osimertinib monotherapy and first-generation EGFR-tyrosine kinase inhibitors remain uncertain.

Methods: A lifetime partitioned survival model was developed from the US healthcare sector perspective using clinical trial data from pivotal trials FLAURA and FLAURA2. Model inputs included drug costs, administration costs, and health utilities sourced from the published literature. Dynamic drug pricing and a 3% discount rate were incorporated. Outcomes included life-years, quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratios. One-way and probabilistic sensitivity analyses were performed.

Results: Combination therapy yielded 2.96 QALYs at a cost of $692,796. The resultant incremental cost-effectiveness ratio was $265,601/QALY versus osimertinib monotherapy and $467,747/QALY versus first-generation EGFR-tyrosine kinase inhibitors. Findings were consistent across sensitivity analyses.

Conclusions: While clinically effective, based on commonly accepted cost-effectiveness thresholds in the USA, our study suggests that osimertinib plus chemotherapy was not cost effective compared to osimertinib alone or first-generation EGFR-tyrosine kinase inhibitors.

Bumetanide nasal spray (ENBUMYST^™) is a loop diuretic developed by Corstasis Therapeutics for the treatment of oedema. It is designed as a short-term therapeutic option, with absorption via the nasal mucosa potentially offering more consistent or predictable bioavailability than oral administration, particularly in patients with gastrointestinal impairment. Bumetanide nasal spray received its first approval on 12 September 2025 in the USA for the treatment of oedema associated with congestive heart failure (CHF), and hepatic and renal disease, including nephrotic syndrome in adults. This article summarizes the milestones in the development of bumetanide nasal spray leading to this first approval for the treatment of oedema.

Background: SCT510 is a proposed biosimilar of bevacizumab (Avastin^®), a monoclonal antibody that targets vascular endothelial growth factor.

Objective: This analysis aimed to characterize the population pharmacokinetics of SCT510, a bevacizumab biosimilar, and its reference product (Avastin^®) in healthy subjects and patients with advanced non-squamous non-small cell lung cancer. Secondary objectives were to evaluate the pharmacokinetic similarity between the two drugs and to investigate the effects of factors, including alanine transaminase, creatinine clearance, and age, on their pharmacokinetic profiles.

Methods: The population pharmacokinetic model was developed by pooling intensive pharmacokinetic data from a phase I trial in healthy male subjects with sparse pharmacokinetic data from a phase III trial in patients with non-squamous non-small cell lung cancer, utilizing a non-linear mixed-effects modeling (NONMEM) approach.

Results: A total of 2647 serum concentration data from 399 subjects were included in the population pharmacokinetic analysis. A two-compartment model with linear elimination adequately described the pharmacokinetic data for both SCT510 and Avastin^®. The final model identified albumin, body weight, creatinine clearance, sex, study drug (SCT510 vs Avastin^®), and subject type (healthy vs patient) as statistically significant covariates. Furthermore, the analysis confirmed the pharmacokinetic similarity of SCT510 and Avastin^®, as no substantial differences in exposure were observed after single or multiple doses in either healthy subjects or patients. Finally, covariates such as alanine transaminase, creatinine clearance, and age were found to have no clinically relevant impact on the pharmacokinetics of either drug.

Conclusions: SCT510 and Avastin^® demonstrated comparable population pharmacokinetic profiles, supporting the biosimilarity of SCT510 to its reference product. The analysis also indicated that no clinically relevant differences in exposure were observed for either agent across a wide range of hepatic or renal function, or age. These findings collectively support that no dose adjustment is necessary for these factors.

Clinical trial registration: NCT05113511, NCT03792074.

Background and objectives: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing epidermal growth factor receptor (EGFR), minimizing related toxicities. This non-randomized, open-label, Phase I study evaluated the absorption, distribution, metabolism and excretion (ADME) of zongertinib (Part A) and its absolute bioavailability (F) (Part B) in healthy male volunteers.

Methods: In Part A, eight subjects received a single oral 60 mg dose of zongertinib (C-14)-solution containing radiolabeled [¹⁴C]zongertinib [3.7 MBq] and unlabeled drug. In Part B, seven subjects received an oral unlabeled zongertinib 60-mg film-coated tablet after fasting, followed by a 15-min intravenous (IV) infusion of 100 μg zongertinib solution (C-14), consisting of 10 μg [¹⁴C]zongertinib [~ 0.03 MBq] and 90 μg unlabeled drug. Plasma pharmacokinetics, excretion pathways, metabolism, and bioavailability were assessed. Safety was evaluated in both study parts.

Results: After oral dosing in Part A, peak plasma concentration occurred at a median of 1-h post-dose (range 0.5‒2.0 h). Mean recovery of the radioactive dose was 93.8%, primarily in feces (92.5%) and minimally in urine (1.30%). Unchanged zongertinib accounted for most circulating radioactivity (74.6%) in plasma and was the most abundant component in feces (31.4% of the dose) and urine (0.18% of dose). In vitro metabolism involved oxidation (48-62%), glucuronidation (13-25%), and glutathione conjugation (13-25%). In part B, the mean F of the oral tablet was 76.2%. Following IV administration, zongertinib showed low plasma clearance (106 mL/min) and a moderate volume of distribution of 138 L. Zongertinib had a manageable safety profile in both study parts.

Conclusions: Zongertinib was rapidly absorbed with high absolute bioavailability. The unchanged zongertinib was the predominant form in plasma and excreta, with fecal excretion as the main elimination pathway. Metabolism occurred primarily through oxidation, with minor contributions from glucuronidation and glutathione conjugation.

Clinical trial registration: Registered under identifier NCT05879991 (25 May 2023).

Background and objectives: The PROVENT study demonstrated the efficacy and safety of a single 300-mg dose of AZD7442 (tixagevimab/cilgavimab) for pre-exposure prophylaxis of COVID-19 in at-risk individuals. Here we report an analysis of repeat dosing of intramuscular AZD7442 300 and 600 mg from the PROVENT sub-study.

Methods: The sub-study enrolled eligible participants from the parent study, creating four sub-study groups. Group 1 received AZD7442 300 mg in PROVENT followed by one 300-mg dose in the sub-study (10-14 months apart). Group 2 received placebo in PROVENT followed by two AZD7442 300-mg doses 6 months apart in the sub-study. Group 3a received AZD7442 300 mg in PROVENT followed by one 300-mg dose and two 600-mg doses 6 months apart in the sub-study. Group 3b received placebo in PROVENT followed by one 300-mg dose and two 600-mg doses 6 months apart in the sub-study. The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-drug antibody (ADA) responses.

Results: Adverse events (AEs) and serious AEs (SAEs) were reported in 75.7-81.5% and 13.2-16.8% of participants, respectively. AZD7442-related AEs, SAEs, and AEs of special interest occurred in 1.4-5.3%, 0-0.2%, and 0-5.3% of participants, respectively, and 3.9-6.7% experienced ≥ 1 cardiac and/or thromboembolic SAE. AZD7442 serum concentrations were dose-dependent with minimal accumulation following redosing, and 4.1-10.7% had treatment-emergent ADAs to AZD7442.

Conclusions: AZD7442 safety, pharmacokinetic, and ADA response profiles were similar regardless of repeat dosing schedule, and consistent with single-dose study data. These results may support future use of long-acting antibodies.

Clinicaltrials:

Gov registration: NCT04625725.