Clinical Drug Investigation最新文献

Introduction: Research on the benefits of medical cannabis (MC) is emerging and supports its use as a treatment for post-traumatic stress disorder (PTSD). This study aimed to evaluate the cost effectiveness of MC as an adjunctive therapy for moderate PTSD under varying reimbursement scenarios.

Methods: A cost-utility analysis was conducted from the US payor perspective, using pricing data from the largest multi-state MC producer and established literature on standard PTSD treatments. We analyzed eight MC product types: dried flower, oral solutions, tablets, and edibles, each available in low/moderate (LM) and high-cost formulations. Incremental cost-utility ratios (ICURs) were calculated for these products across reimbursement levels of 100%, 75%, 50%, and 25%. Probabilistic sensitivity analyses with 10,000 Monte Carlo simulations were conducted to assess cost-effectiveness acceptability across willingness-to-pay (WTP) thresholds of $0-$100,000 per quality-adjusted life year (QALY) gained.

Results: Non-flower MC products (edibles, oral solutions, and tablets) consistently demonstrated cost-effectiveness under a WTP threshold of $50,000, even at 100% reimbursement. Dried flower products, while less cost effective due to higher costs, achieved cost effectiveness under 75% or lower reimbursement levels for LM cost formulations. Sensitivity analyses confirmed robust ICURs for non-flower products, with narrower variability compared to dried flower products.

Conclusions: Medical cannabis products, particularly non-flower formulations, represent a cost-effective adjunctive therapy for moderate PTSD under various reimbursement scenarios. This analysis underscores the importance of evidence-based reimbursement policies to improve patient access to cost-effective treatments while ensuring financial sustainability for payors.

Background and objective: Recent research has raised concerns about the association between metformin treatment in patients with diabetes mellitus (DM) and an increased risk of diabetic retinopathy. We sought to investigate this relationship, specifically examining if metformin use affects diabetic retinopathy risk in a dose-dependent manner.

Methods: This study was a secondary data analysis based on a nationwide population database in Taiwan. Patients with new-onset DM, an age of 20 years or older, and a diagnosis of type 2 DM received at any time during 2002-2013 were included in the study. Patients diagnosed with new-onset type 2 DM between 2002 and 2013 were enrolled as the study population. We divided them into two groups: those treated with metformin and those treated with sulfonylureas. A Cox proportional hazards model was employed to estimate the risk of diabetic retinopathy after 5 years of follow-up, including cumulative defined daily dose and intensity of metformin treatment.

Results: A total of 241,231 patients received treatment with metformin, while 152,617 patients were treated with sulfonylureas. Compared with patients treated with sulfonylureas, patients who received metformin treatment, at a cumulative defined daily dose < 30, had a lower risk of diabetic retinopathy (adjusted hazard ratio = 0.77; 95% confidence interval 0.60-0.98). However, those with varying defined daily doses, especially at a higher metformin treatment level (> 25 defined daily dose), had a 2.43 times higher risk of diabetic retinopathy (95% confidence interval 1.37-4.30) compared with patients treated with sulfonylureas.

Conclusions: Patients with DM treated with a lower cumulative dosage of metformin showed beneficial effects that were associated with a lower risk of diabetic retinopathy. In contrast, a higher intensity of metformin use had a greater risk of diabetic retinopathy.

Background: Anti-obesity medications are recommended for patients who do not achieve and maintain weight loss despite lifestyle interventions. S-309309 is a novel oral inhibitor of monoacylglycerol O-acyltransferase 2 being developed as a treatment for obesity.

Objective: The objective of the study was to investigate the safety, clinical pharmacology, pharmacokinetics and pharmacodynamic biomarker of S-309309.

Methods: A phase I, single-center, two-part, randomized, double-blind, placebo-controlled study of S-309309 following oral administration of a single-ascending dose (part 1) and a multiple dose (part 2) in healthy adults with or without obesity was conducted. We also assessed the effect of food on the pharmacokinetics of S-309309 and the effect of S-309309 on electrocardiogram parameters, the pharmacokinetics of midazolam (a cytochrome P450 3A substrate), and the pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition.

Results: In part 1 (N = 50), a single-ascending dose of S-309309 in healthy adults demonstrated dose proportionality and comparable exposure of S-309309 between the fasted and fed states. In part 2 (N = 24), no clinically meaningful difference was observed in the pharmacokinetics of multiple doses between healthy adults with or without obesity. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. The pharmacodynamic biomarker of monoacylglycerol O-acyltransferase 2 inhibition, dicarboxylic acid (18:1), was significantly increased after S-309309 administration in healthy adults with or without obesity. Overall, S-309309 demonstrated acceptable safety and tolerability without any serious adverse events or discontinuations because of adverse events, and did not have a clinically relevant effect on the heart rate or cardiac conduction. An effect on the placebo-corrected change-from-baseline corrected QT interval, corrected for heart rate using the Fridericia method, exceeding 10 ms can be excluded.

Conclusions: S-309309 was well tolerated as single-dose (up to 300 mg) and multiple-dose (50 mg once daily for 14 days) oral administration. The pharmacokinetic characteristics remained unaffected by obesity and food intake. S-309309 did not affect the pharmacokinetics of the cytochrome P450 3A substrate. Overall, S-309309 had an acceptable safety profile and favorable pharmacokinetic and pharmacodynamic characteristics.

Clinical trial registration: NCT05247970, date of registration: 8 February, 2022.

Background and objective: Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy (ET) significantly enhance progression-free survival and overall survival in patients diagnosed with HR+/HER2- metastatic breast cancer (MBC). However, they are highly expensive, and their economic impact has not been fully evaluated. This is a retrospective secondary analysis evaluating the cost effectiveness of these drugs, differentiating between medication-related and non-medication costs from a healthcare perspective.

Methods: We identified 3879 patients diagnosed with MBC who received either CDK4/6i+ET (N = 2137) or ET alone (N = 1742) as first-line treatment between February 2015 and November 2021 using a USA-wide electronic health record-derived de-identified database. SEER-Medicare claims spending data were used to quantify monthly costs as a supplement to the database. Relevant costs included prescribed medications (ET and/or CDK4/6i) and overall other costs. The effectiveness was measured as progression-free duration in months. The incremental cost effectiveness ratio (ICER) analysis was conducted to examine the cost effectiveness of first-line CDK4/6i as compared with first-line ET alone.

Results: For medication costs, CDK4/6i+ET (mean cost: $240,723.7; mean effect: 19.2 months of delayed progression) compared with ET alone (mean cost: $5159.7; mean effect: 16 months without progression) resulted in an ICER of $73,098 per month of delayed progression. For non-medication costs, CDK4/6i+ET (mean cost: $43,656.6) compared with ET alone (mean cost: $66,083.5) resulted in an ICER of - $7178 per month of delayed progression.

Conclusion: The cost of treating HR+/HER2- MBC is driven by the cost of CDK4/6i. Using CDK4/6i+ET reduces non-medication costs compared to ET alone, but these savings are offset by high CDK4/6i medication costs. Lowering the market cost of CDK4/6i or targeting those who can benefit the most could improve the cost effectiveness of CDK4/6i from Medicare perspective.

Purpose: The REDUCE-IT randomized trial demonstrated a cardiovascular benefit of icosapent ethyl (IPE) but also raised potential safety signals for atrial fibrillation (AF) and serious bleeding. We aimed to evaluate the real-world safety of IPE versus mixed omega-3 polyunsaturated fatty acid (OM-3) formulations.

Methods: This retrospective active comparator new-user cohort study compared rates of new-onset AF and major bleeding (MB) among adult new users of IPE versus OM-3 in 2020-2024 US Veterans Affairs data. Daily drug exposure was determined via prescription dispensing dates. AF and MB outcomes were identified via validated algorithms based on the International Statistical Classification of Diseases and Related Health Problems, 10th revision, clinical modification. Confounding was accounted for via nearest-neighbor pairwise propensity score (PS) matching. The PS, constructed via logistic regression, was informed by expert-identified variables meeting the disjunctive cause criterion. Cox regression was used to estimate adjusted hazard ratios (aHRs), interpretable as average treatment effects for the treated.

Results: Cohorts for analyses of AF and MB endpoints included 1927 and 2015 people, respectively, in each of the IPE and OM-3 exposure groups. The median age was 70 years, and the groups exhibited a predominance of white (80%) males (93%). The median follow-up time was 1.29 years per person. Baseline covariates were well balanced by treatment arm after PS matching. Incidence rates for AF were 7.29 versus 7.48 per 100 person-years among new users of IPE versus OM-3. The aHR for AF was 1.15 (95% confidence interval 0.82-1.63). Incidence rates for MB were 3.27 versus 3.35 per 100 person-years among new users of IPE versus OM-3. The aHR for MB was 1.22 (95% confidence interval 0.87-3.02).

Conclusions: Our measures of association were consistent with the null, but we were unable to rule out harms from IPE (vs. OM-3) more modest than a 63% increased rate of AF and threefold increased rate of MB.

Background and objective: There is a significant medical need for improved long-acting local anesthetics to decrease postsurgical pain and reduce postoperative opioid use. While ropivacaine is considered a safer local anesthetic than bupivacaine, no long-acting ropivacaine formulation is currently marketed. Available formulations of bupivacaine show inconsistent pharmacokinetics (PK) among different surgical models, and inconsistency in PK may lead to a reluctance to use the medication owing to fear of local anesthetic systemic toxicity (LAST) or unreliable efficacy. CPL-01 is a novel extended-release formulation of ropivacaine. This analysis used existing published literature to compare the PK of CPL-01 and liposomal bupivacaine (LB) across five surgical models.

Methods: Published results of LB PK were used to construct dose-normalized curves in total knee arthroscopy, hemorrhoidectomy, and bunionectomy after a 200 mg dose, which were compared with a 200 mg dose of CPL-01 in abdominoplasty, herniorrhaphy, and bunionectomy.

Results: The shape of the CPL-01 systemic concentration curves was consistent across multiple surgical models; however, in LB it was not. The median time to peak concentration (T_max) of CPL-01 was 8-12 h and the median T_max of LB varied from < 1 to 36 h. CPL-01 showed tighter ranges in average peak concentration (C_max) compared with average concentration (C_avg) ratios (less "swing") throughout 72 h, suggesting a more predictable and consistent release over time compared with the biphasic release in LB, with two distinct T_max peaks.

Conclusions: CPL-01 demonstrates a more predictable and consistent release of ropivacaine over time, in contrast to LB's erratic and biphasic release of bupivacaine. If approved, the predictability of CPL-01 PK may give physicians greater confidence in more consistent efficacy and less fear of inadvertent LAST.

Background: Primary percutaneous coronary intervention (PPCI) and fibrinolytic or thrombolytic therapy are common treatments for ST-elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention is more effective than thrombolytic therapy, but fibrinolytic therapy is still a preferable option for patients with limited access to healthcare. Alteplase is a tissue plasminogen activator (tPA) used to treat acute myocardial infarction, acute ischemic stroke, and pulmonary embolism.

Objective: This study aims to compare the efficacy and safety of Altelyse (bio-similar Alteplase, Arena Life Science Company, Tehran, IRAN) versus the brand name Actilyse^® (Boehringer Ingelheim, GERMANY) in patients with STEMI.

Methods: In this phase 3, double-blind, randomized trial, we assigned patients with STEMI to receive Altelyse or Actilyse, an intravenous bolus of 15 mg followed by an infusion of 0.75 mg/kg over 30 min (with a maximum dose of 50 mg) and continued with 0.50 mg/kg over 60 min (with a maximum dose of 35 mg). The primary endpoint was total ST-segment resolution (STR) in all leads with ST-segment elevations after 90 min of receiving fibrinolytic therapy.

Results: A total of 153 STEMI patients received Actilyse (79 patients) or Altelyse (74 patients). The mean total STR in all leads with ST elevation after 90 min was - 45.89 ± 32.92% and - 37.11 ± 35.28% in the Altelyse and Actilyse groups, respectively (the mean difference [95% confidence interval]: - 8.77 [- 19.92, 2.36]; p-value for non-inferiority: 0.0004).

Conclusions: Among patients with STEMI, Altelyse was non-inferior to Actilyse with respect to STR after 90 min.

Trial registry: Trial Registration Number, Date: IRCT20190729044366N1, 2019-05-25.