Clinical Drug Investigation最新文献

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.

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.

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.

Aim: This study was conducted to examine disproportionality, times to onset, incidence rates, and outcomes of trastuzumab deruxtecan-associated pulmonary adverse events (AEs) using the Japanese Adverse Drug Event Report database.

Methods: We analyzed data for the period from April 2004 to December 2024. Data on pulmonary AEs were extracted, and the relative disproportionality of AEs was estimated using reporting odds ratios (RORs).

Results: Of the 3,221,393 reports analyzed, we identified 1561 reports of AEs associated with trastuzumab deruxtecan, including 505 pulmonary AEs. Only 474 reports were identified as signal-positive: interstitial lung disease, pulmonary toxicity, pneumonitis, and Pneumocystis jirovecii pneumonia. Among these, interstitial lung disease was the most frequently reported (26.6%) and included several fatal cases. Histograms of median times to onset for the four detected pulmonary AE signals showed that AEs occurred at a median of 7-27.5 days after trastuzumab deruxtecan administration. Weibull distributions showed that interstitial lung disease occurred early after administration (early failure type), but pulmonary toxicity occurred constantly throughout the exposure period (random failure type).

Conclusions: We focused on pulmonary AEs associated with trastuzumab deruxtecan as postmarketing AEs. Serious outcomes can arise after trastuzumab deruxtecan administration. Patients should be monitored for signs of onset of these AEs not only at the start of administration but also over an extended period.

Mitomycin intravesical solution (ZUSDURI^TM), a hydrogel formulation of the DNA synthesis inhibitor mitomycin, has been developed by UroGen Pharma, Inc. for the treatment of low-grade intermediate-risk non-muscle invasive bladder cancer (LG-IR-NMIBC) via intravesical instillation. In June 2025, mitomycin intravesical solution was approved for the treatment of recurrent LG-IR-NMIBC in the USA. This article summarizes the milestones in the development of mitomycin intravesical solution leading to this first approval for LG-IR-NMIBC.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD) involving hepatocyte destruction, inflammation, and typically pericellular fibrosis, potentially progressing to cirrhosis. Resmetirom, a T3 analogue and an oral agonist of thyroid hormone receptor-β(THR-β), represents a significant advancement in targeted drug therapy for MASH as the first US Food and Drug Administration (FDA)-approved treatment. Clinical trials have shown that resmetirom effectively improves MASH markers, reduces liver fat content, and exhibits high selectivity for THR-β, which is predominantly expressed in the liver. Despite promising research data, challenges remain in the treatment of MASH with resmetirom, including adverse reactions and limited efficacy in some patients. This article reviews the discovery, mechanisms, and clinical evaluation of resmetirom in detail, and discusses the challenges encountered in MASH precision therapy.

Background: Mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease that predominantly affects mucosae. Treatments for MMP often lack robust evidence and may be poorly tolerated, especially in elderly patients.

Objective: This scoping review aims to provide an overview of MMP outcome measurement of the last two decades by mapping and listing all previously reported outcomes and outcome measurement instruments (OMIs).

Design: A large scoping review was performed in scientific databases and trial registries (MEDLINE, Embase, CINAHL, PsycINFO, Cochrane CENTRAL, Web of Science, the International Clinical Trials Registry Platform and Clinicaltrials.gov) covering January 2002 to December 2023. Clinical trials, prospective cohort studies, and systematic reviews were included, while retrospective studies were excluded.

Results: Thirty-nine studies met the inclusion criteria, including 20 prospective cohort studies, 13 systematic reviews, and 6 clinical trials. A total of 285 outcomes were extracted verbatim and categorized into 29 domains and 9 overarching areas. The most commonly reported outcome areas were related to clinical response, safety, and resource use. The majority were investigator-reported outcomes (85%), with only 8% being patient-reported. Various OMIs (n = 14) were employed, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI) score and tools for assessing ocular impairment and quality of life. Reported outcomes and OMIs are very diverse due to the heterogeneity in the presentation of MMP.

Conclusions: The standardized use of consensus-based outcome definitions and high-quality instruments that consider the patient perspective is expected to increase the efficacy of future MMP research and can be achieved by consensus-based selection of outcomes and critical appraisal of the measurement properties of OMIs.

Background: Patients with early-stage non-small-cell lung cancer (eNSCLC) often experience disease recurrence after surgery and adjuvant chemotherapy, leading to a substantial clinical and economic burden. The introduction of immunotherapy such as atezolizumab in the adjuvant setting may offer both clinical benefits and healthcare cost reductions by preventing disease progression.

Objectives: This analysis aimed to estimate the economic impact of prevented recurrences by measuring the costs avoided in the Italian population potentially eligible for adjuvant atezolizumab.

Methods: A cost-consequence analysis was developed using a published model, adapted to the Italian context, to estimate the number of recurrences per year from 2023 to 2033, comparing scenarios 'with' and 'without' atezolizumab. Epidemiological and clinical input was obtained from published literature, clinical trials, and local market research. Direct healthcare costs were sourced from an Italian real-world study. The Italian national health system (NHS) perspective was considered, and a deterministic one-way sensitivity analysis was performed to evaluate the uncertainty over the main parameters.

Results: Over the period considered, 2582 patients with stage II-IIIA eNSCLC (7th edition of the TNM [tumour, node, metastases] classification) after resection and chemotherapy were estimated annually. Of these, 720 (27.9%) were potentially eligible to receive atezolizumab according to the approved indication. Overall, the model estimated 2556 recurrences for the eligible patients, which generated an economic burden of €11.02 million yearly. The introduction of atezolizumab could avoid 720 recurrences (111 locoregional and 609 metastatic), resulting in a direct healthcare cost reduction of €3.11 million annually from the perspective of the Italian NHS. One-way sensitivity analysis showed moderate base-case changes, especially due to drug costs in the metastatic settings.

Conclusions: Recurrences are common among patients with eNSCLC and are associated with a remarkable increase in total direct costs. It appears that adjuvant atezolizumab would prevent a relevant number of events, with potential savings in recurrence-related costs from the perspective of the NHS in Italy.

Background and objectives: In clinical practice, granulocyte colony-stimulating factor (G-CSF) is often used to lower infection risk and avoid poor outcomes from chemotherapy dose reduction or delay. Efbemalenograstim alfa (also known as F-627) is a non-pegylated but long-acting (once-per-cycle) recombinant human granulocyte colony-stimulating factor (rhG-CSF) compared with pegfilgrastim. This study was designed to obtain pharmacokinetic (PK)/pharmacodynamic (PD), safety, and tolerability data for F-627 in healthy Chinese participants.

Methods: This was a single-center, open-label phase I clinical study involving 24 healthy Chinese volunteers (sex ratio = 1:1). All the participants were administered a single subcutaneous injection of 20 mg F-627 into the abdomen.

Results: In this study, 15 (62.5%) participants reported 28 treatment-related adverse events. PK/PD data showed that after a single 20 mg subcutaneous (SC) F-627 abdominal injection in healthy Chinese participants, serum concentrations peaked at 36 h post dose, while the absolute neutrophil count (ANC) peaked at 96 h. After peaking, F-627 serum levels decreased rapidly to low concentrations by 120 h, while ANC declined gradually to near baseline by day 15. Similar trends in serum concentration and ANC kinetics were seen between sex.

Conclusions: This phase I study showed that 20 mg F-627 was well tolerated and exhibited a favorable safety profile in a healthy Chinese population. The PK and PD data correlated well and were consistent across sex.

Trial registration: This trial was registered at the Chinese Clinical Trial Registry (chictr.org.cn) on 10 September 2024 (registration ID: ChiCTR2400089548).