Clinical Pharmacology & Therapeutics最新文献

Disproportionality analyses suggested a cardiovascular risk signal for romosozumab, while statistically significant associations were not found in the real-world database studies. Therefore, a larger comparative study was necessary to examine this signal. This study aimed to compare the cardiovascular risks of romosozumab with those of teriparatide in the overall population and in groups with a history of major adverse cardiovascular events (MACE). A new user cohort study was conducted using Japan’s national claims database. Patients aged ≥ 40 years who initiated romosozumab or teriparatide between March 2019 and March 2023 were analyzed. A multivariable Cox proportional hazards model was used to estimate the adjusted hazard ratio (aHR) for MACE. Subgroup analyses were conducted based on MACE history. A total of 251,219 romosozumab and 500,445 teriparatide users were analyzed (most common age group was 80–89 years for both drugs; men: 9.33% for romosozumab and 14.14% for teriparatide). MACE occurred in 1853 romosozumab and 3427 teriparatide users, with incidence rates of 1.09 and 1.22 per 100 person-years, respectively. The aHR (95% confidence interval [CI]) for romosozumab compared with teriparatide was 1.00 (0.94–1.06). In subgroup analyses based on MACE history, the aHRs (95% CI) for no history, for the one-year period leading up to t₀, and for more than 1 year before t₀ were 1.01 (0.95–1.08), 0.93 (0.72–1.21), and 1.00 (0.85–1.18), respectively. In conclusion, no statistically significant difference in MACE risk was observed between romosozumab and teriparatide in Japan’s national claims database, regardless of MACE history.

Cheng, S., Al-Kofahi, M., Leeder, J.S. and Brown, J.T. (2024), Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder. Clin Pharmacol Ther, 115: 1033-1043. https://doi.org/10.1002/cpt.3155.

In the article cited above, affiliations for the first two authors were published in the incorrect order. The correct order is shown below; we regret this error.

Shen Cheng^1,5; Mahmoud Al-Kofahi^1,4; J. Steven Leeder²; Jacob T. Brown³

¹Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA

²Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Department of Pediatrics, Children’s Mercy Kansas City, and University of Missouri-Kansas City, Kansas City, Missouri, USA

³Department of Pharmacy Practice and Pharmaceutical Sciences, University of Minnesota College of Pharmacy, Duluth, Minnesota, USA

⁴Present address: Gilead Sciences, Inc. Forest City, California, USA

⁵Present address: Metrum Research Group, Tariffville, Connecticut, USA

Traditional drug-food interaction studies of oral anticancer agents have a high patient burden. A patient-friendly alternative approach to studying food effects could be the use of stable isotopically labeled microtracers. A prospective, single-center, open-label, crossover, food effect study with the microtracer ²H₆-alectinib was conducted in patients with ALK-positive, non-small cell lung cancer treated with 600 mg alectinib bidaily. On occasion 1 (fed state), patients received 100 μg ²H₆-alectinib in addition to their usual dose of alectinib and a standardized Dutch breakfast (320–392 kcal and 7.5–7.8 g fat). On occasion 2 (fasted state), patients received ²H₆-alectinib and alectinib after overnight fasting. Pharmacokinetic (PK) samples were collected up to 8 hours after intake of ²H₆-alectinib. The effect of food on relative bioavailability (F) and mean transit time of ²H₆-alectinib was assessed by population PK modeling. Differences in area under the plasma concentration-time curve (AUC) and maximum concentration (C_max) between fed and fasted states were estimated by simulations. MTT in the fed state was 3.14 hours (relative standard error (RSE): 16.0%). MTT and F in the fasted state were 28% (RSE: 20.5%) and 35% (RSE: 12.4%) lower, respectively, compared to the fed state. The geometric mean ratio (fed vs. fasted) of AUC and C_max was 1.52 (90% confidence interval (CI): 1.25–1.89) and 1.42 (90% CI: 1.16–1.76), respectively. These results showed that the intake of a Dutch breakfast leads to a higher total exposure of alectinib. More importantly, the feasibility of a microtracer food effect study to reduce patient burden was demonstrated.

Pediatric drug development has achieved remarkable success in the last 20 years with over 1,000 products studied in pediatric patients. This success has been driven in part by an increased understanding of pediatric disease processes. The aspect that has been largely overlooked is the potential adverse effect of new drugs on pediatric developmental processes. The realization of this risk comes with the understanding that we could not predict another thalidomide worldwide tragedy even 70 years later.

The global prevalence and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), are steadily rising, making them the most common chronic liver diseases worldwide. However, therapeutic options for MAFLD are currently limited. Glucolipid dysregulation drives MAFLD pathogenesis through intertwined glucose metabolic imbalance and lipid accumulation. Patients with type 2 diabetes mellitus (T2DM) are particularly prone to developing MASH and are at a higher risk of progressing to cirrhosis and hepatocellular carcinoma. The coexistence of MAFLD and T2DM correlates with clinical prognosis and elevates the risk of extrahepatic complications. Given the close association between MAFLD and T2DM, glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have been approved for the treatment of T2DM and obesity, were the first to be investigated in patients with MAFLD/MASH. Recently, beyond GLP-1RAs, novel combination agents integrating glucose-dependent insulinotropic peptide receptor (GIPR) and/or glucagon receptor (GCR) agonists have also been explored. A large number of phase II randomized clinical trials have demonstrated significant improvements in body weight, insulin resistance, and liver parameters. Thus, GLP-1RAs and dual/triple agonists are promising for MAFLD/MASH, especially in those with obesity or T2DM. This study explores mechanisms and clinical evidence of incretin-based therapies for MAFLD by targeting its core pathogenesis—glucolipid disorders. With growing evidence, it also forecasts the broad clinical prospects on MAFLD treatment.

This study investigated real-world edoxaban concentrations across different dosing regimens, with a specific focus on patients who met the inclusion criteria of low-dose edoxaban for the Elder Care Atrial Fibrillation (ELDERCARE-AF) trial. Patients with atrial fibrillation receiving edoxaban were enrolled to measure trough concentrations. The levels were compared with the expected therapeutic range (12–43 ng/mL) to define low or high concentrations. Data on ischemic stroke and systemic thromboembolism (SSE), and major bleeding, were collected prospectively. In total, 402 patients (77.2 ± 10.6 years; 52.2% men) were included. The SSE incidence was 1.22 (0.56–2.31) per 100 person years and was significantly associated with low edoxaban concentration (aHR, 4.13 [1.08–15.82]). Among patients meeting the ELDERCARE-AF criteria (n = 160), the use of the 15-mg regimen (ELDER-15 mg, n = 46) vs. the 30-mg regimen (ELDER-30 mg, n = 114) (aOR, 7.65 [2.92–20.09]), higher creatinine clearance (CrCL) (aOR, 1.05 [1.01–1.08]) and lower CHA₂DS₂-VA score (aOR, 0.69 [0.51, 0.95]) were significantly associated with low concentrations. In the ELDER-15 mg group, patients with CrCL > 50 mL/min had more than 50% probability of exhibiting low drug concentrations. The incidence of SSE was numerically higher in the ELDER-15 mg group than the ELDER-30 mg group (2.34 [0.06–13.02] vs. 1.55 [0.32–4.52]), while major bleeding rates were similar (4.67 [0.57–16.89] vs. 5.15 [2.47–9.48]). In conclusion, low edoxaban concentrations have been associated with thromboembolic events. Among ELDERCARE-AF-eligible patients, the 15-mg regimen results in underexposure to edoxaban, particularly when the CrCL exceeded 50 mL/min.

Vascular leakage and its associated phenomena vasodilation and endothelial activation are pathophysiological features of various diseases. Multiple drug candidates targeting these phenomena are in development, necessitating translational models to demonstrate proof-of-pharmacology and proof-of-mechanism in early-phase clinical trials. This single-center experimental study evaluated the intradermal lipopolysaccharide (id LPS) challenge model as a tool to induce and characterize vascular leakage in healthy participants. Eight participants (male:female = 4:4) received id LPS in the volar forearms, followed by serial pharmacodynamic assessments, including imaging and suction blister induction up to 9 hours after injection. Id LPS administration resulted in significant increases in skin perfusion (P < 0.0001), erythema (P = 0.0013), and skin volume (P = 0.0008), indicating initial stages of inflammation and fluid extravasation. Blister fluid analysis revealed elevated extravascular concentrations of albumin (P = 0.0011), total protein (P < 0.0001), and neutrophils (P = 0.0342), supporting the presence of vascular leakage. Moreover, the expression of endothelial activation markers VCAM-1 (P = 0.0015), ICAM-1 (P = 0.0004), ITGB1 (P = 0.01), and E-selectin (P = 0.0218) increased significantly. Disruption of endothelial cell–cell integrity was supported by increased expression of VE-cadherin (P = 0.0002) in blister fluid. These findings support the applicability of the id LPS model for the induction of vascular leakage in humans. This model holds potential as a translational tool for evaluating the pharmacodynamic responses of vascular leakage-targeting drugs in early clinical development.