Clinical Drug Investigation最新文献

Background and objectives: Bacopa monnieri is a plant used in Ayurvedic medicine with traditional uses for memory and cognitive function. The objective of this study was to examine the effects of supplementation with a Bacopa monnieri extract (Bacumen^®) on cognitive function, stress, and fatigue in adults with self-reported memory and attention problems.

Study design: Two-arm, 12-week, parallel-group, randomized, double-blind, placebo-controlled trial.

Methods: Overall, 101 volunteers aged 40-70 years with self-reported memory and attention problems were supplemented with 300 mg daily of a Bacopa monnieri extract (Bacumen^®) (n = 50) or a placebo (n = 51). Outcome measures included several computer and researcher-administered cognitive tasks assessing verbal learning, attention and working memory (primary outcome measures) and self-report measures assessing memory, mood, and fatigue (secondary outcome measures). Changes in blood concentrations of brain-derived neurotrophic factor, malondialdehyde, and acetylcholine esterase activity were also examined. Cognitive assessments, blood collections and self-reported questionnaires were completed in person on day 0 and week 12. Moreover, self-report questionnaires were completed online at weeks 4 and 8. Participants, researchers and the statistician were blinded until all data was collected and a blind review was completed.

Results: Of the 101 participants randomized, 87 participants completed the study, 47 in the placebo group and 40 in the Bacopa monnieri group. On the basis of complete data collected from 87 participants, there were no between-group differences in changes in the primary outcome measures comprising verbal learning (p = 0.391), attention (p = 0.713), and working memory (p = 0.610). However, in the Bacopa-supplemented participants, there were greater reductions in overall self-reported stress reactivity (p = 0.03); and fatigue and stress levels after exposure to a cognitive-demanding computer task (secondary outcome measures). There were no group differences in changes in blood concentrations of measured markers. Bacopa monnieri supplementation was generally well-tolerated, with no serious adverse reactions, although there was a greater frequency of self-reported adverse reactions in the Bacopa monnieri group (p = 0.024), primarily comprising digestive complaints and headaches.

Conclusions: The results from this study indicate that compared with the placebo, Bacopa monnieri supplementation for 12 weeks did not result in greater improvements in cognitive performance. However, stress reduction and anti-fatigue effects were identified, which requires investigation in future trials.

Clinical trials registration number: Australian New Zealand Clinical Trials Registry (ANZCTR)-ACTRN12623000475640.

Background: Despite international evidence demonstrating pre-emptive pharmacogenetics (PGx) screening is cost effective or cost saving in preventing serious or fatal toxicities, it is not routinely adopted in Australia. This study evaluated the cost effectiveness of PGx screening versus standard of care (SOC) among patients with cancer undergoing fluoropyrimidine-based treatment (FP) in Australia.

Methods: From the Australian healthcare perspective, we developed a cohort-based state transition model in TreeAge Pro 2024. The model used PACIFIC-PGx trial data for the PGx arm and literature-based inputs for the SOC arm. Patients transitioned between four health states (full-dose, reduced-dose, treatment termination or death) over two treatment cycles each corresponding to a standard 3-week period. Outcomes included the incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALYs) gained, per adverse event averted, and per hospitalisation avoided. Deterministic and probabilistic sensitivity analyses (DSA, PSA) evaluated the effects of varying assumptions and the uncertainty associated with input parameters.

Results: PGx screening yielded incremental QALYs of 0.05 at an additional cost of $274.25 AUD (Australian dollars), resulting in an ICER of $6014.5 AUD per QALY gained compared to SOC. DSA showed the model's outcomes remained robust, with the ICER staying below the specified threshold of $50,000 AUD under a ± 20% variation in input parameters. PSA suggested PGx screening was favourable in 97.6% of iterations.

Conclusion: This Australian single-arm study demonstrated that pre-emptive PGx screening prevents severe, fatal FP-related toxicities and hospitalisations and is likely to be cost effective. Our findings suggest the value of PGx screening and warrant implementation and reimbursement within Australian healthcare settings.

Background: Various oral methylphenidate formulations are available to treat attention-deficit/hyperactivity disorder, but unmet needs still exist, particularly for individuals with swallowing difficulties or those requiring more flexible dosing options. Two phase 1 studies evaluated the comparative bioavailability and safety/tolerability of two prolonged-release (PR) methylphenidate formulations, an oral suspension and a chewable tablet, compared with an established immediate-release (IR) oral tablet formulation.

Methods: Healthy volunteers were randomised to receive a single dose of methylphenidate PR oral suspension (total dose 60 mg; study 1) or chewable tablet (total dose 40 mg; study 2) and methylphenidate IR tablets (total dose 60 mg in study 1 and 40 mg in study 2) in a crossover manner, with a 7-day washout between treatment periods. Blood samples were collected over the 24-h post-administration period. Comparative bioavailability was defined as the 90% confidence interval (CI) of the relative mean plasma D-methylphenidate area under the plasma concentration-time curve from zero to last measurable concentration (AUC_last) of methylphenidate PR formulation to methylphenidate IR being between 80 and 125%. Adverse events (AEs) were documented.

Results: In total, 24 individuals (mean age 39-42 years, approximately 50% male) were randomised in each study, of whom 23 received methylphenidate PR oral suspension in study 1 and 23 received methylphenidate PR chewable tablets in study 2; 24 received methylphenidate IR tablets in each study. The relative mean plasma D-methylphenidate AUC_last ratios for methylphenidate PR formulation to methylphenidate IR tablets had 90% CIs of 82.30-87.18% in study 1 and 90.01-97.52% in study 2. Treatment-emergent AEs were reported in 26% and 22% of participants receiving the oral suspension and chewable tablets, respectively (versus 50% and 33% of those receiving the IR tablets in the respective studies). These AEs were typical of orally administered methylphenidate, mild in severity and, in general, resolved prior to study end.

Conclusions: The methylphenidate PR oral suspension and chewable tablet formulations are bioequivalent in terms of the total extent of exposure (AUC_last) to methylphenidate IR tablets and are tolerable in healthy adults.

Background and objectives: Dotinurad is a selective uricosuric drug for patients with gout with hyperuricemia. To our knowledge, this is the first study to evaluate the pharmacokinetics (PK) of dotinurad, following single and multiple oral doses in healthy Chinese adults.

Methods: This single-center, open-label, parallel group, phase 1 study had 3 cohorts: A (1-mg single dose), B (single and multiple doses of 4 mg once daily for 7 days), and C (10-mg single dose). Dotinurad was administered on an empty stomach. Healthy nonsmoking Chinese adults aged 18-45 years with body mass index 19-24 k/m² and weight ≥ 50 kg were enrolled; Cohort B required serum urate ≥ 5.5 mg/dL at screening.

Results: In total, 26 subjects were included. After single oral doses of 1, 4, and 10 mg, mean ± standard deviation (SD) plasma dotinurad concentration reached maximum observed plasma concentration (C_max) of 104 ± 18.5, 365 ± 35.2, and 964 ± 101 ng/mL at 3.00-3.50 h, respectively. The mean ± SD terminal elimination phase half-life was 10.1 ± 1.26, 9.87 ± 1.47, and 10.9 ± 1.53 h for the 1, 4, and 10 mg doses, respectively; both area under the plasma concentration-time curve and C_max increased in a dose-proportional manner across the 1-10-mg dose range. During once-daily doses for 7 days, steady state was reached by the 2nd day after the initiation of multiple dosing, with an average steady-state plasma concentration of 186 ± 31.8 ng/mL, indicating minimal accumulation. Treatment-emergent adverse events (TEAEs) occurred in four subjects (15.4%); all were mild and resolved without treatment. No dose-dependent TEAEs were observed.

Conclusion: Single- and multiple-dose PK of dotinurad in healthy Chinese adults showed rapid absorption, rapid elimination, linear PK, and no accumulation with once-daily dosing. Dotinurad was well-tolerated during the 7-day treatment course.

Trial registration: ClinicalTrials.gov: NCT05278676.

Background: Acute bacterial skin and skin structure infections (ABSSSI), diabetic foot infections (DFI), and osteomyelitis often require extended antimicrobial therapy courses. Dalbavancin's long half-life allows outpatient or emergency department (ED) management of patients not amenable to oral antimicrobials and/or outpatient infusion.

Objective: To provide a budget-impact analysis and real-world assessment of dalbavancin cost and reimbursement data, and model drug acquisition cost-avoidance compared to daptomycin and oral linezolid in outpatient and ED patients at our institution (New Jersey, USA).

Methods: All patients treated with dalbavancin in the ED or outpatient wound clinic during the one-year study period with available drug-specific reimbursement data were included. Wholesale acquisition costs were compared between dalbavancin, daptomycin, and oral linezolid. We conducted a regression analysis studying profit changes with patient weight, indication, drug-specific reimbursement, and treatment duration. We fitted a linear mixed-effects model and paired t-test to explore relationships between potential profit and various predictors while accounting for random effects of different indications. Paired t-tests were conducted evaluating potential profit and cost avoidance from the hospital and institutional pharmacy perspective associated with dalbavancin across treatment durations and indications.

Results: Eighty-eight individual patient encounters were included in the final analysis. Treatment indications included ABSSSI (48.9%), DFI (33%), diabetic foot osteomyelitis (9%), osteomyelitis (6.8%), and septic arthritis (2.3%). An overall positive reimbursement of approximately US$3500 per patient per encounter was realized. Drug acquisition cost modeling demonstrated variable cost avoidance with dalbavancin compared to daptomycin or oral linezolid based on anticipated treatment duration. Average wholesale acquisition cost difference ranged from a potential loss of US$427.64 to a gain of US$12,557.94 and a loss of US$829.28 to possible gain of US$4370.32 compared to daptomycin and linezolid, respectively, based on treatment duration.

Conclusions: Outpatient dalbavancin utilization presents an opportunity to realize net positive reimbursement and minimize pharmacy drug acquisition costs. Our study suggests that dalbavancin utilization presents significant cost advantages over intravenous daptomycin in both short and long treatment durations and over oral linezolid in long durations.

CT-P47/tocilizumab-anoh (AVTOZMA^®) is a biosimilar of reference tocilizumab, an IL-6R inhibitor. CT-P47 is approved for treating rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, Coronavirus disease 2019 and cytokine release syndrome in the USA and the EU. CT-P47 has similar physicochemical properties to those of reference tocilizumab, with demonstrated pharmacokinetic comparability in patients with moderate to severe rheumatoid arthritis. In this patient population, CT-P47 demonstrated clinical efficacy equivalent to reference tocilizumab and was generally well tolerated. The overall safety and immunogenicity profiles of CT-P47 were similar to those of reference tocilizumab, and switching from reference tocilizumab to CT-P47 did not affect safety or efficacy. The role of reference tocilizumab in the management of inflammatory diseases is well established and CT-P47 provides an effective biosimilar alternative for patients requiring tocilizumab therapy.

Rapid treatment of prolonged convulsive seizures (PCS), preferably within the first few minutes after onset in most patients, is important to prevent progression to life-threatening status epilepticus (SE) and its associated complications. In community settings, benzodiazepine rescue medication for PCS is often administered by non-medical caregivers to achieve timely seizure control. Until recently, rectally administered diazepam was the only treatment approved by the European Medicines Agency (EMA) for PCS in adults. However, an oromucosal midazolam formulation, which has been approved by the EMA for PCS treatment in paediatric patients for over a decade, has now also received such approval for use in adults. The aim of this narrative review is to describe the role of midazolam oromucosal solution in the management of PCS in adults in community settings in Europe. The approval of midazolam oromucosal solution was supported by pharmacokinetic modelling studies, which extrapolated the efficacy of oromucosal midazolam to adults through exposure matching, alongside European clinical studies where oromucosal midazolam was used as an off-label treatment, thereby demonstrating its effectiveness for treating PCS and SE in adults and paediatric patients. With this approval, adult patients across Europe now have access to an alternative to rectal diazepam that is easy to administer, socially acceptable, and pharmacokinetically appropriate. The increased willingness of caregivers to administer rescue medication by the oromucosal compared with the rectal route should encourage its appropriate use, thus potentially improving outcomes for adults with PCS in Europe.

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.