Clinical Drug Investigation最新文献

Background and objective: Spinal muscular atrophy (SMA) is a genetic disorder with limited treatment options. It is crucial to have a comprehensive understanding of drug safety in order to make informed clinical drug selections for patients with SMA. Assessing the safety profiles of therapeutic drugs for SMA has been challenging due to the limited number of patients included in clinical trials. This study aims to investigate and compare the potential safety concerns associated with three leading SMA therapeutic drugs: nusinersen, risdiplam, and onasemnogene abeparvovec.

Methods: The FDA Adverse Event Reporting System database was used to analyze drug safety, and a case (SMA drug)/noncase (all other drugs in the database) approach was employed to estimate safety signals through disproportionality analysis and reporting odds ratio (ROR). Veen analysis was conducted to compare and select the idiosyncratic adverse events (AEs) associated with each drug.

Results: The study included 5324 cases of nusinersen, 1184 cases of risdiplam, and 1277 cases of onasemnogene abeparvovec. Venn analysis revealed 27 common AEs among the three drugs, including cardiac, gastrointestinal, metabolism, musculoskeletal, renal, respiratory disorders, and infections. Additionally, 196 AEs exclusively found in nusinersen included post lumbar puncture syndrome [ROR (95% CI) = 6120.91 (5057.01-7408.64), n = 372], procedural pain [ROR (95% CI) = 54.86 (48.13-62.54), n = 234], idiopathic intracranial hypertension [ROR (95% CI) = 6.12 (2.29-16.33), n = 4], and hypokalemia [ROR (95% CI) = 2.02 (1.24-3.31), n = 16]. Additionally, transient deafness was identified as an unexpected and rare, yet severe, AE for nusinersen [ROR (95% CI) = 23.32 (8.71-62.44), n = 4]. Risdiplam exhibited 50 AEs exclusively, with notable idiosyncratic AEs including diarrhea [ROR (95% CI) = 4.55 (3.79-5.46), n = 121], fatigue [ROR (95% CI) = 2.03 (1.6-2.57), n = 70], photosensitivity reaction [ROR (95% CI) = 9.50 (4.25-21.13), n = 6], rash [ROR (95% CI) = 1.90 (1.36-2.67), n = 34], and [ROR (95% CI) = 4.3 (1.93-9.58), n = 6] in comparison with the other two drugs. Moreover, ileus [ROR (95% CI) = 11.11 (4.14-29.51), n = 4], gastrointestinal hemorrhage [ROR (95% CI) = 2.55 (1.15-5.69), n = 6], and hypoglycemic unconsciousness [ROR (95% CI) = 153.58 (62.98-374.54), n = 5] were rare but severe AEs associated with risdiplam. Onasemnogene abeparvovec had 143 exclusively identified AEs, with significant high signals for troponin I increase [ROR (95% CI) = 627.1 (492.2-798.99), n = 78], troponin T increase [ROR (95% CI) = 233.98 (153.29-357.15), n = 23], blood lactate dehydrogenase increase [ROR (95% CI) = 39.81 (28.88-54.87), n = 38], and transaminases increase [ROR (95% CI) = 36.88 (29.24-46.52), n = 73].

Conclusions: This study highlights the importance of monitoring injection-related injuries and transient deafness events i

Background and objective: There is a considerable survival benefit of alpelisib in patients with PIK3CA-mutated, hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC), yet the financial burden may limit its use. Therefore, this study evaluated the cost-effectiveness of alpelisib plus fulvestrant in patients with PIK3CA-mutated, HR+/HER2- ABC in the USA.

Methods: A Markov model was constructed to simulate the progression of PIK3CA-mutated, HR+/HER2- ABC. Efficacy and safety data were derived from the SOLAR-1 trial. A parametric survival model was used to explore the long-term effect. From a US payer perspective, only direct medical costs were considered. The cost data were estimated based on local pricing and relevant literature. The health outcomes were expressed in quality-adjusted life years (QALYs). Model stability was assessed using one-way sensitivity analysis and probability sensitivity analysis. Subgroup analyses were performed to explore cost-effectiveness outcomes for patients with different clinical characteristics.

Results: The QALY increased by 0.28 with alpelisib plus fulvestrant with an additional cost of $94,345.87 compared with placebo plus fulvestrant, leading to an incremental cost-effectiveness ratio (ICER) of $340,153.30/QALY gained. Sensitivity analyses suggested that the model is most sensitive to the price of alpelisib. At a willingness-to-pay (WTP) threshold of $150,000/QALY, alpelisib plus fulvestrant was cost effective when the cost of alpelisib was less than $71 per 300 mg (36.5 % of the original price), whereas this cost would be less than $168 per 300 mg (86.5 % of the original price) at a WTP threshold of $300,000/QALY. In addition, alpelisib + fulvestrant was not cost effective in all subgroups compared with placebo + fulvestrant at the WTP threshold of $150,000/QALY. In contrast, at the WTP threshold of $300,000/QALY, alpelisib + fulvestrant was cost effective in nearly all subgroups except for endocrine-sensitive patients.

Conclusion: At current drug prices, alpelisib plus fulvestrant is not cost effective for patients with PIK3CA-mutated, HR+/HER2- ABC from a US payer perspective. Given the considerable progression-free survival (PFS) and overall survival (OS) benefits observed with alpelisib in this setting, further discussion and negotiation of the price of alpelisib are warranted to provide more favorable economic outcomes and thereby increase the value of the alpelisib plus fulvestrant regimen in patients.

Background: Dipeptidyl peptidase-4 inhibitors have limited efficacy in improving glycemic control for obese Japanese patients with type 2 diabetes mellitus. Sodium-glucose co-transporter 2 inhibitors are recommended for use in patients with type 2 diabetes with obesity. Nevertheless, there has been no previously published study on the effect of switching from dipeptidyl peptidase-4 inhibitors to sodium-glucose co-transporter 2 inhibitors on the systemic and organic effects in obese Japanese patients with type 2 diabetes.

Objectives: We evaluated the efficacy and safety of switching from sitagliptin to ipragliflozin for 24 weeks in obese Japanese patients with inadequately controlled type 2 diabetes.

Methods: Fifty-one obese patients with type 2 diabetes (body mass index > 25 kg/m²) treated with sitagliptin (50 mg) and metformin but with inadequate glycemic control (glycosylated hemoglobin [HbA1c] > 7.5% and < 9.0%) were enrolled. After a 4-week observation period, sitagliptin was switched to ipragliflozin (50 mg) for 24 weeks. The primary outcome was the change in HbA1c from baseline to the end of treatment. The secondary outcomes were changes in clinical characteristics and other biochemical variables.

Results: Fifty-one patients with an average HbA1c of 8.37 ± 0.48% and body mass index of 28.8 ± 3.8 kg/m² were enrolled. Fifty patients completed the study, one patient stopped ipragliflozin at 4 weeks because of the development of hyperosmolar hyperglycemic syndrome. No significant change in HbA1c from baseline to the end of treatment was observed (- 0.02 ± 0.75%). However, fasting plasma glucose was reduced (- 16.2 ± 28.4 mg/dL, p < 0.001), and biochemical variables associated with insulin resistance, oxidative stress, and hepatic and renal functions showed significant improvements. No severe adverse effects were observed, except in the one aforementioned case.

Conclusions: Switching from sitagliptin to ipragliflozin did not alter HbA1c in obese patients with type 2 diabetes, while improving parameters related to organ homeostasis. These data provide novel information useful for selecting oral anti-diabetic agents for patients with type 2 diabetes with obesity, a risk factor for developing various complications of diabetes.

Clinical trial registration: Japan Registry of Clinical Trials identifier: jRCT#031190022.

Background and objectives: Tramadol is a centrally acting analgesic with a lower risk of addiction compared to opioids. Tramadol overdose is becoming a health crisis in Egypt and is associated with serious and severe adverse effects. This study aims to identify clinical and laboratory findings associated with tramadol-induced seizure and serotonin toxicity in adult Egyptian patients with tramadol overdose.

Methods: This prospective study included adult patients admitted for tramadol overdose with or without symptoms of seizure or serotonin toxicity. Basic demographic information, clinical symptoms, laboratory measurements, and plasma tramadol concentrations were collected.

Results: A total of 71 patients (79% males) were included in the study. Seizure occurred in 38% of the subjects and was prevalent in male patients with metabolic acidosis or high tramadol concentrations. Serotonin toxicity occurred in 41% of the subjects and was prevalent in patients with hyperthermia, high pulse rate, and high tramadol levels.

Conclusion: Seizure and serotonin toxicity are severe adverse effects of tramadol overdose that occur in high frequency among young Egyptians. High tramadol concentrations in plasma seem to play a key role in prevalence of seizure and serotonin syndrome in tramadol-intoxicated adult Egyptians.

Background: The use of activated prothrombin complex concentrate (aPCC) to treat direct oral anticoagulant (DOAC)-associated bleeding is off-label and clinical experience is limited.

Objectives: We aimed to assess the efficacy and safety of aPCC in reversing the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding.

Methods: A retrospective cohort study of adult non-randomized patients was conducted at a tertiary referral medical center in the United States (US) to investigate the use of aPCC for the reversal of the anticoagulant effect of apixaban and rivaroxaban in patients presenting with major bleeding. The primary outcome was achieving clinical hemostasis according to prespecified criteria. Safety outcomes included the occurrence of thrombotic events during hospitalization.

Results: A total of 217 patients were included in the study. Intracranial hemorrhage (ICH) was the most common site of bleeding (n = 100, 46.1%), followed by gastrointestinal bleed (n = 87, 40.1%). Clinical hemostasis was achieved in 170 patients (78.3%), and the risk of not achieving hemostasis with ICH-related bleeding was significantly higher than that of non-ICH-related bleeding (2.5, 95% confidence interval [CI] 1.44-4.34; p < 0.001). Eight patients not achieving hemostasis died during hospitalization, all of whom were suffering from ICH, and mortality associated with non-ICH-related bleeding was significantly lower compared with ICH-related bleeding (0.91, 95% CI 0.86-0.97; p < 0.001). Thromboembolic events during hospitalization occurred in one patient (0.5%).

Conclusions: The use of aPCC for the management of apixaban- or rivaroxaban-related major bleeding is effective in most cases and is associated with a low risk of thromboembolism.

Background and objective: Evidence on the economic value of rotavirus vaccines in middle-income countries is limited. We aimed to model the implementation of three vaccines (human rotavirus, live, attenuated, oral vaccine [HRV, 2 doses]; rotavirus vaccine, live, oral, pentavalent [HBRV, 3 doses] and rotavirus vaccine, live attenuated oral, freeze-dried [BRV-PV, 3 doses] presented in 1-dose and 2-dose vials) into the South African National Immunisation Programme.

Methods: Cost and cost-effectiveness analyses were conducted to compare three rotavirus vaccines using a static, deterministic, population model in children aged <5 years in South Africa from country payer and societal perspectives. Deterministic and probabilistic sensitivity analyses were conducted to assess the impact of uncertainty in model inputs.

Results: The human rotavirus, live, attenuated, oral vaccine (HRV) was associated with cost savings versus HBRV from both perspectives, and versus BRV-PV 1-dose vial from the societal perspective. In the cost-effectiveness analysis, HRV was estimated to avoid 1,107 home care rotavirus gastroenteritis (RVGE) events, 247 medical visits, 35 hospitalisations, and 4 RVGE-related deaths versus HBRV and BRV-PV. This translated to 73 quality-adjusted life years gained. HRV was associated with lower costs versus HBRV from both payer (-$3.9M) and societal (-$11.5M) perspectives and versus BRV-PV 1-dose vial from the societal perspective (-$3.8M), dominating those options. HRV was associated with higher costs versus BRV-PV 1-dose vial from the payer perspective and versus BRV-PV 2‑dose vial from both payer and societal perspectives (ICERs: $51,834, $121,171, and $16,717, respectively), exceeding the assumed cost-effectiveness threshold of 0.5 GDP per capita.

Conclusion: Vaccination with a 2-dose schedule of HRV may lead to better health outcomes for children in South Africa compared with the 3-dose schedule rotavirus vaccines.

Background and objective: Quadpill, a single pill containing a quadruple combination of quarter doses of four antihypertensive agents, has been investigated for hypertension treatment. This meta-analysis aims to evaluate the safety and efficacy of quadpill for hypertension management.

Methods: We conducted a systematic review and meta-analysis synthesizing randomized controlled trials evaluating quadpill versus monotherapy or placebo in patients with hypertension, which were retrieved by systematically searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane through 17 February, 2023. Continuous and dichotomous outcomes were pooled using mean difference (MD) and risk ratio (RR) along with confidence interval (CI), using Revman Version 5.4 software. Our protocol has been published in PROSPERO with ID: CRD42023406527.

Results: Four randomized controlled trials with a total of 779 patients were included in our analysis. Quadpill was effective in controlling systolic blood pressure in the short term [4-6 weeks] (RR: - 13.00 with 95% CI [- 17.22, - 8.78], p = 0.00001) and in the long term [12 weeks] (RR: - 6.18 with 95% CI [- 9.35, - 3.01], p = 0.0001). Quadpill was also effective in controlling automated diastolic blood pressure in the short term [4-6 weeks] (MD: - 8.15 with 95% CI [- 9.42, - 6.89], p = 0.00001) and in the long term [12 weeks] (MD: - 6.35 with 95% CI [- 10.37, - 2.33], p = 0.002). Moreover, patients in the quadpill group significantly achieved target blood pressure <140/90 (RR: 1.77 with 95% CI [1.26, 2.51], p = 0.001) compared with the control group.

Conclusions: The quadruple ultra-low-dose combination of antihypertensive drugs (quadpill) was effective and safe for hypertension treatment. However, further large-scale, multicenter, randomized controlled trials are still warranted before endorsement in clinical practice.

Background and objectives: Atezolizumab has demonstrated safety and efficacy in patients with metastatic non-small cell lung cancer (NSCLC) in the IMpower110 trial. The aim of this study was to evaluate the cost-effectiveness of atezolizumab as the first-line treatment for patients with unresectable advanced NSCLC, including programmed cell death ligand-1 (PD-L1)-positive probability testing, from the perspective of healthcare costs in Japan.

Methods: A cost-effectiveness analysis model for atezolizumab, including PD-L1-positive probability testing, was used to construct a partitioned survival model with three health states. To assess the robustness, a probabilistic sensitivity analysis (PSA) was conducted. The acceptable probability was defined as the probability of willingness-to-pay (WTP) over the incremental cost-effectiveness ratio (ICER). Multiple repetitions at WTP thresholds were calculated by continuously reducing the atezolizumab price.

Results: The ICER per quality-adjusted life year (QALY) for atezolizumab therapy only for patients with high PD-L1 expression compared to platinum-based chemotherapy for all patients was 31,975,792 yen per QALY. This is higher than the WTP threshold of 15,000,000 yen. If the cost of atezolizumab were reduced to 54% of the original cost (563,917 yen), the strategy of using atezolizumab for patients with high PD-L1 could become more cost-effective.

Conclusions: The results indicated that atezolizumab was not cost-effective compared to platinum-based chemotherapy as a first-line treatment for patients with unresectable advanced NSCLC. However, we suggest that the price of atezolizumab should be reduced to 54% of the original cost to meet the WTP threshold of 15,000,000 yen per QALY.