Clinical Drug Investigation最新文献

Background and objectives: Pembrolizumab has been approved for the immunotherapy of programmed death ligand 1 (PD-L1)-positive triple-negative breast cancer (TNBC) based on the KEYNOTE-355 trial. However, cost-effectiveness evidence is limited. The purpose of this study was to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy alone for patients with PD-L1-positive inoperable or metastatic TNBC from a Japanese healthcare perspective.

Methods: The cost-effectiveness analysis was performed for pembrolizumab, of which the drug price was determined at 214,498 Japanese yen (JPY), or 1631 US dollars (USD) (1 USD = 131.5 JPY) for KEYTRUDA^® (100 mg), using a partition survival model based on the KEYNOTE-355 trial subgroup analysis in Japan. The comparison was made using quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way deterministic and probabilistic sensitivity analyses (PSA), which evaluate the impact of parameter uncertainty, were performed to assess the robustness and calculate the acceptable probability, defined as the probability of the ICER being below the willingness-to-pay (WTP).

Results: Pembrolizumab plus chemotherapy provided an additional 0.676 QALYs at an incremental cost of 8,503,072 JPY. The ICER for pembrolizumab plus chemotherapy compared with conventional chemotherapy was 12,577,178 JPY (95,644 USD) per QALY. The ICER per QALY was below the willingness-to-pay threshold of 15,000,000 JPY. PSAs revealed that the acceptable probability was 83.9% at 15,000,000 JPY.

Conclusions: The pembrolizumab plus chemotherapy is likely to be a cost-effective option compared with conventional chemotherapy for patients with PD-L1-positive inoperable or metastatic TNBC in a Japanese medical environment from a healthcare system.

Background: Antibody-drug conjugates provide significant advantages in cancer therapy, but their associated ophthalmotoxicity remains insufficiently explored.

Objective: Our objective was to determine the prevalence and risk of ophthalmotoxicity in patients receiving antibody-drug conjugates.

Methods: We conducted a systematic search in MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov for phase II or III randomized clinical trials reporting ocular adverse events linked to antibody-drug conjugates up to 5 March, 2025. The Cochrane Bias Risk Assessment Tool was used to assess the risk of bias. The primary outcome was the risk of all-grade ocular adverse events induced by antibody-drug conjugates, measured by the risk ratio (RR) with 95% confidence intervals (CIs).

Results: Thirty-one trials consisting of 18,490 patients were ultimately included. The pooled incidence of all-grade ocular adverse events following antibody-drug conjugate therapy was 10.45% (95% CI 4.51-18.42). Antibody-drug conjugates were linked to a potentially increased risk of ophthalmotoxicity (RR = 1.76, 95% CI 1.25-2.48), particularly with monomethyl auristatin E (RR = 2.73, 95% CI 1.42-5.28) and monomethyl auristatin F (RR = 3.01, 95% CI 2.58-3.52) payloads. Dry eye was the most common ocular manifestation (15.49%, 95% CI 7.66-25.38).

Conclusions: Antibody-drug conjugate therapy has been associated with an elevated risk of ophthalmotoxicity. Further research is needed to explore the influence of antibody-drug conjugate components, disease characteristics, and treatment regimens on ophthalmotoxicity risk.

Clinical trial registration: PROSPERO register name and registration number: Antibody-drug conjugates-related to ocular toxicity: a network meta-analysis and real-world pharmacovigilance study of the FAERS database (CRD42023458065).

Background: Preclinical studies have shown that baclofen may reduce the risk of osteoarthritis through its anti-inflammatory effect.

Objective: We aimed to clarify this association by comparing the risks of osteoarthritis and joint replacement surgery in patients receiving baclofen and tizanidine.

Methods: This retrospective cohort study was conducted on the global TriNetX platform (October 31, 2024). New users of baclofen and tizanidine aged ≥40 years were included in the baclofen and tizanidine group, respectively. The propensity score matching method was used. The primary outcomes were osteoarthritis and joint replacement surgery. The secondary outcomes included all-cause mortality, a composite outcome of osteoarthritis and all-cause mortality, and a composite outcome of joint replacement surgery and all-cause mortality. Cause specific hazard ratios (HRs) with 95% confidence intervals (CIs) of the outcomes were calculated with Cox regression using the TriNetX platform.

Results: Two well-balanced groups containing 68,210 patients each were generated by propensity score matching (age: 57.8 years; female: 55.6% in both groups). Baclofen users had a significantly lower risk of developing osteoarthritis than tizanidine users (HR: 0.965, 95% CI: 0.941 to 0.989). A similar relationship was observed for joint replacement surgery (HR: 0.847, 95% CI: 0.750 to 0.956). However, the composite outcome of osteoarthritis or death had a HR of 1.129 (95% CI: 1.109 to 1.150), and the HR of joint replacement surgery or death was 1.509 (95% CI: 1.463 to 1.556). The HR of death was 1.577 (95% CI: 1.527 to 1.629), suggesting a higher risk of mortality in the baclofen group.

Conclusion: The surviving baclofen users had a lower risk of osteoarthritis and joint replacement surgery compared to surviving tizanidine users. However, baclofen users exhibited a higher risk of mortality than tizanidine users. Future studies are necessary to clarify the impact of baclofen on osteoarthritis and joint replacement surgery while accounting for mortality.

Background: Axatilimab, an anti-colony-stimulating factor 1 receptor (CSF-1R) antibody, blocks colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34) binding to CSF-1R on macrophages and monocytes. Axatilimab has demonstrated efficacy and safety in chronic graft-versus-host disease, and its safety, pharmacokinetics (PK), and pharmacodynamics (PD) were characterized in healthy Western participants.

Objective: The objective of this study was to evaluate the safety, PK, and PD of axatilimab among healthy Japanese men.

Methods: In this double-blind, randomized, dose-escalation study, eligible participants were healthy Japanese men aged 18-55 years, with a body weight of 50-100 kg, a body mass index of 18.0-30.0 kg/m², and no clinically significant findings on screening evaluation (clinical, laboratory, electrocardiogram, and physical exam). Participants were randomized to receive axatilimab or placebo in a 3:1 ratio in a blinded manner. Safety (30 d follow-up; primary endpoint), PK, and PD were evaluated at a clinic in Japan following single-dose infusions of axatilimab 0.3 mg/kg (n = 6), axatilimab 1.0 mg/kg (n = 9), or placebo (n = 5).

Results: Three participants receiving axatilimab experienced a nonserious treatment-emergent adverse event (nasopharyngitis [0.3-mg/kg dose], amylase level increased [1.0-mg/kg dose], and headache [1.0-mg/kg dose]), with no clinically meaningful trends in hematology, urinalysis, physiologic, and most clinical chemistry measures. PK exposure increased with the 1.0 mg/kg versus 0.3 mg/kg dose, with greater than dose-proportional increases in area under the curve. CSF-1 and IL-34 levels had dose-dependent increases following axatilimab infusion. A transient increase in nonclassical monocytes was observed for 8 h following axatilimab infusion and then decreased below baseline until day 8 (0.3 mg/kg) or day 15 (1.0 mg/kg). The inverse effect was observed with classical monocytes. Intermediate monocytes had similar transient increases as nonclassical monocytes.

Conclusions: A single dose of axatilimab 0.3 mg/kg and 1.0 mg/kg was generally well tolerated in healthy Japanese men. Safety, PK, and PD findings were consistent with those observed in healthy Western participants.

Trial registration: Japan Registry for Clinical Trials, jRCT2071220109; 27 February 2023.

Background and objective: Respiratory syncytial virus (RSV) is a major global cause of childhood respiratory infections, globally linked to significant morbidity and mortality, particularly leading in hospitalizations and death among infants below 1 year of age. A cost-effectiveness analysis was conducted to estimate the economically justifiable price (EJP) of nirsevimab, a new prophylaxis strategy protecting all infants against RSV lower respiratory tract infections (LRTIs), compared with a strategy consisting of palivizumab, protecting only high-risk infants and no preventive intervention for others.

Methods: A static decision tree model previously published to evaluate the clinical and economic burden of RSV in Italy was used to determine the EJP of nirsevimab for the prevention of RSV medically attended lower respiratory tract infections (RSV-MA-LRTIs) in all infants experiencing their first RSV season, to become a cost-effective alternative compared with palivizumab only in high-risk infants and no preventive intervention for others. The EJP was estimated considering three different willingness-to-pay (WTP) thresholds. The National Health Service (NHS) perspective was considered in the base-case. Direct costs considered in the analysis were acquisition and administration costs of prophylaxis, costs of managing RSV infection (inpatient and outpatient care, and emergency department visits) and costs of handling complications following hospitalization per RSV event. Indirect costs were evaluated in the scenario analysis as productivity loss due to premature death for RSV infection. A discount rate of 3.0% was applied only to mid-long-term costs and outcomes.

Results: From the NHS perspective, over the first RSV season, nirsevimab in an all-infants population could be a cost-effective approach compared with palivizumab only in high-risk infants, with an EJP equal to €267, €365, and €400 considering a WTP threshold of €0, €22,000, and €30,000 per QALY saved, respectively. Considering only the palivizumab-eligible population, the model estimated that nirsevimab could be a cost-effective approach with an EJP equal to €3,467, €3,633, and €3,694 considering a WTP threshold of €0, €22,000, and €30,000 per QALY saved, respectively.

Conclusions: A prophylaxis strategy against RSV infection targeting all infants with nirsevimab could represent a cost-effective option for both NHS and societal perspectives, and supports the implementation and the equity of RSV prevention for all infants.

Background and objective: The introduction of immune checkpoint inhibitors (ICIs) in oncology presents a critical healthcare policy challenge for resource allocation due to their substantial financial burden. This study assessed the reporting quality of health economic evaluation (HEE) studies of ICIs.

Methods: This study conducted a systematic literature search of four databases (PubMed, EMBASE, Cochrane CENTRAL, and the International HTA Database) for studies published between January 1, 2014 and December 31, 2022. All ICIs approved up to December 31, 2022, in the USA, EU, China, and Japan were included. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards published in 2013 (CHEERS 2013), which is the most widely recognised and implemented reporting guideline for HEE studies. Subgroup analyses were also performed based on the risk of sponsorship bias or citation of CHEERS 2013.

Results: A total of 5368 records were identified, 252 of which were included after full-text review. The study design, setting, and ICIs most frequently observed were cost-effectiveness and cost-utility analyses (63.5%), the USA (46.0%), and pembrolizumab (38.1%), respectively. Of the 24 items of CHEERS 2013, fully reported items were limited, particularly in the Methods section. Setting and location were not reported in 94.4% of the records. Subgroup analyses also revealed insufficient reporting of items in the Methods section, particularly "Setting and location".

Conclusion: Health economic evaluation studies on ICIs between 2014 and 2022 had limited reporting across the 24 items of CHEERS 2013, regardless of sponsorship bias risk or citations. The items on setting and location in the Methods section were particularly underreported, emphasising the need for transparent reporting in HEE studies of ICIs.

Background: Natural biomedicines (NBMs) are frequently used to manage immune-mediated and inflammatory dermatologic diseases (IMIDDs). This systematic review evaluates the efficacy, safety, and clinical relevance of NBMs in IMIDDs, providing an evidence-based analysis to guide dermatologic practice.

Methods: Following PRISMA guidelines, a systematic search was conducted in PubMed, Embase, Medline, and Google Scholar for randomized controlled trials (RCTs) investigating NBMs in IMIDDs from 1990 to 2023. Studies were included if they met predefined eligibility criteria: RCT design, relevant IMIDD condition, NBM intervention, and quantitative outcome measures. Risk of bias was assessed using the Jadad scale. Results were synthesized qualitatively due to heterogeneity in study designs and outcome measures.

Results: Of 1364 records screened, 95 RCTs were included, encompassing 5265 participants across 23 countries. Indigo naturalis, fish oil (⍵-3), and aloe vera demonstrated the most consistent efficacy in managing psoriasis, systemic lupus erythematosus (SLE), atopic dermatitis (AD), and lichen planus (LP). Indigo naturalis significantly improved erythema, scaling, and PASI scores in psoriasis patients. Fish oil showed benefits in SLE disease activity indices and AD severity, while aloe vera demonstrated improvements in SCORAD and LP severity criteria. Most NBMs exhibited favorable safety profiles, although adverse event reporting was inconsistent.

Discussion: While these findings highlight the potential of NBMs in dermatologic care, methodological limitations, including small sample sizes, heterogeneity in study designs, and lack of direct comparisons to conventional therapies, limit definitive conclusions. Additionally, not all natural agents can be easily searched and captured in systematic reviews, which may have restricted the scope of included NBMs. Future research should emphasize high-quality RCTs, standardized outcome measures, and comparative studies against conventional treatments.

Trial registration: The review protocol is registered with Open Science Framework (OSF) ( https://doi.org/10.17605/OSF.IO/UH9XJ ).

Introduction: Penpulimab is a PD-1 monoclonal antibody recommended for treating squamous non-small cell lung cancer (sqNSCLC) in combination with paclitaxel and carboplatin. This study aimed to assess the cost-effectiveness of penpulimab combined with paclitaxel and carboplatin against paclitaxel plus carboplatin as first-line treatment for locally advanced or metastatic sqNSCLC in China.

Methods: A three-state partitioned survival model was constructed using the efficacy outcomes obtained by digitizing the AK105-302 trial and was extrapolated to the lifetime horizon. Data on direct medical costs and utilities was gathered from the literature and commercial databases from the perspective of the Chinese healthcare system. Outcomes included quality-adjusted life years (QALYs), life years (LYs), and the incremental cost-effectiveness ratio (ICER). Sensitivity analysis and scenario analysis were performed to test the model robustness.

Results: The incremental efficacy of penpulimab plus paclitaxel and carboplatin was 0.821 QALYs and 1.176 LYs with an incremental cost of $20,335 compared with paclitaxel plus carboplatin combination therapy. The ICER was $24,778 per QALY, falling below the threshold of three times the per capita gross domestic product of China, a commonly applied benchmark. The results of the one-way sensitivity analysis demonstrated that the ICER values were primarily influenced by the utility of progression-free state and cost of penpulimab. Probabilistic sensitivity analysis showed that penpulimab plus paclitaxel and carboplatin was cost-effective for 98.3% of the cases. Scenario analysis yielded results similar to those of the base-case analysis.

Conclusions: Our analysis suggests that penpulimab plus paclitaxel and carboplatin combination therapy is cost-effective for patients with locally advanced or metastatic sqNSCLC in China.

Background: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, such as fremanezumab, are effective for migraine prevention. However, their effectiveness in treating migraine complicated by medication overuse, remains underexplored.

Objective: This systematic review aims to evaluate the effectiveness of fremanezumab in adults with migraine complicated by medication overuse.

Methods: We systematically searched PubMed and Embase (Ovid) databases for studies on fremanezumab, selecting primary studies that included adults with migraine complicated by medication overuse and reported at least one efficacy outcome. The search was performed in January 2024 and then updated in June 2024. Risk of bias for randomized controlled trials was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, while real-world studies were evaluated using both the ROBINS-I and ROB-ME tools. Data extraction and analysis followed established guidelines.

Results: Our search identified 176 records, of which 2 clinical trials and 7 real-world studies were included. Included studies recruited a total of 1422 adults with migraine complicated by medication overuse. In post hoc analyses from clinical trials, fremanezumab significantly reduced monthly migraine days, days with acute headache medication use, and Headache Impact Test (HIT-6) scores compared to placebo during a 12-week period. The real-world studies reported a reduction in monthly headache days at 6 months, and a high reversion rate from medication overuse headache (MOH) after one year of treatment.

Conclusion: Both post hoc analyses from clinical trials and real-world studies support fremanezumab benefits in reducing migraine frequency, medication use, and headache-related disability in adults with migraine complicated by medication overuse. Given the limited quality of data, further real-world research with standardized reporting criteria is needed to substantiate long-term benefits and establish optimal treatment protocols.