Hwang S, et al. Yonsei Med J. 2024 Feb;65(2):89-97. https://doi.org/10.3349/ymj.2022.0539

Objective: Combination therapy with rosuvastatin and ezetimibe is generally administered to patients with high cardiovascular risk. The objective of this study was to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the interaction between rosuvastatin and ezetimibe that incorporates enterohepatic recirculation (EHC). Methods: Concentration–time data were obtained from a two-part, open-label, multiple-dose crossover, drug interaction study. In total, 50 healthy male subjects received both monotherapy and co-therapy (Part A: rosuvastatin and co-therapy; Part B: ezetimibe and co-therapy). Rosuvastatin (20 mg) or ezetimibe (10 mg) were administered once daily for 7 days as monotherapy or co-therapy. Plasma concentrations were measured for PK analysis until 72 h post-dose at steady state. The changes in low-density lipoprotein cholesterol (LDL-C) levels from baseline to steady state at 24 h after the last administration were measured. A population PK/PD model incorporating EHC was developed using Monolix 2024R1. Covariate effects were explored, and the final model was evaluated through goodness-of-fit diagnostics and visual predictive checks. Model-based simulations were conducted to compare the LDL-C lowering effects of monotherapy and co-therapy. Results: A population PK/PD model was established using a two-compartment model for rosuvastatin and a four-compartment model for ezetimibe incorporating EHC via intermittent gallbladder emptying. No significant PK interaction was observed. An indirect response PD model reflected the independent LDL-C lowering effects of both drugs. Simulations showed LDL-C reductions of − 51.0% (rosuvastatin), − 25.3% (ezetimibe), and − 60.7% (co-therapy), supporting the additive efficacy of co-therapy. EHC increased the exposure of total ezetimibe with limited LDL-C lowering effects. Conclusion: The overall PK interaction between rosuvastatin and total ezetimibe was not significant. The developed PK/PD model incorporating EHC successfully described the independent LDL-C lowering effects. These findings support the additive benefit of co-therapy of rosuvastatin and ezetimibe and may guide future research toward personalized lipid-lowering strategies.

Metabolic abnormalities, such as preexisting diabetes or hyperglycemia or hypoglycemia during hospitalization aggravated the severity of COVID-19. We evaluated whether diabetes history, hyperglycemia before and during extracorporeal membrane oxygenation (ECMO) support, and hypoglycemia were risk factors for mortality in patients with COVID-19. This study included data on 195 patients with COVID-19, who were aged ≥19 years and were treated with ECMO. The proportion of patients with diabetes history among nonsurvivors was higher than that among survivors. Univariate Cox regression analysis showed that in-hospital mortality after ECMO support was associated with diabetes history, renal replacement therapy (RRT), and body mass index (BMI) < 18.5 kg/m². Glucose at admission >200 mg/dL and glucose levels before ventilator >200 mg/dL were not associated with in-hospital mortality. However, glucose levels before ECMO >200 mg/dL and minimal glucose levels during hospitalization 200 mg/dL before ECMO and minimal glucose 200 mg/dL before ECMO and minimal glucose level <70 mg/dL during hospitalization were risk factors for in-hospital mortality among COVID-19 patients who underwent ECMO.

Background: Alcohol withdrawal is widely recognized as a trigger for acute symptomatic seizures among individuals with chronic alcohol consumption. While most alcohol withdrawal seizures occur shortly after cessation, chronic alcohol consumption can be associated with the development of epilepsy, necessitating anti‐epileptic drug (AED) therapy. This study aimed to investigate the clinical characteristics, seizure recurrence, and epilepsy development in patients with alcohol‐related seizures and to identify prognostic factors for epilepsy.Methods: In a retrospective analysis at Ewha Womans University Mokdong Hospital, 206 patients with alcohol‐related seizures were examined and 15 were excluded due to preexisting epilepsy. Demographic and clinical data, including alcohol withdrawal duration, seizure recurrence, types, and comorbidities, were investigated. Logistic regression models were used to analyze the risk factors for seizure recurrence and epilepsy development. The performance of the final models was evaluated based on the area under the receiver operating characteristic curve (AUC) and validated using calibration plots and leave‐one‐out cross‐validation.Results: Of the 191 patients (146 males; mean age 48.3 ± 12.1 years) with alcohol‐related seizures, 99 patients (51.8%) experienced seizure recurrence and 79 patients (41.4%) developed epilepsy. Factors associated with seizure recurrence included alcohol consumption levels, occurrence of focal impaired awareness seizure, anxiety, and headache. The number of recurrent seizures, semiology, status epilepticus, electroencephalogram findings, and brain imaging findings was associated with epilepsy development. The predictive models showed strong diagnostic performance, with AUCs of 0.833 for seizure recurrence and 0.939 for epilepsy development.Conclusion: High alcohol consumption and specific clinical and diagnostic features are significant predictors of seizure recurrence and the development of epilepsy among patients with alcohol‐related seizures. These findings underscore the importance of early identification and intervention to prevent seizure recurrence and the onset of epilepsy, emphasizing the importance of AED treatment in managing these conditions.

Background: The role of biologics and small molecules in coronavirus disease 2019 (COVID-19) risk remains unclear. Therefore, we aimed to evaluate COVID-19 risk among patients with systemic autoimmune diseases treated with biologics or small molecules using the population-based cohort in Korea. Methods: We compared COVID-19 risk in 46 639 patients treated with biologics or small molecules (biologics group) to a 1:2 propensity score–matched (PSM) group of 86 980 controls (nonbiologics group). We matched the groups based on age, sex, type of autoimmune disease, Charlson Comorbidity Index, concurrent medications, and pre-COVID-19 vaccine doses. Results: After PSM, the biologics group exhibited a significantly higher COVID-19 risk (adjusted odds ratio [aOR], 1.20 [95% confidence interval {CI}, 1.08–1.34]) than the nonbiologics group. Subgroup analysis revealed a significant increase in COVID-19 risk in the biologics group that received suboptimal vaccines (aOR, 1.20 [95% CI, 1.08–1.34]). However, under optimal vaccine administration (3–4 doses), the risk of COVID-19 did not differ significantly between the biologics and nonbiologics groups (aOR, 1.22 [95% CI, .74–2.00]). Furthermore, COVID-19 risk significantly increased in patients with anti–tumor necrosis factor agents (aOR, 1.20 [95% CI, 1.05–1.36]), tofacitinib (aOR, 1.76 [95% CI, 1.15–2.71]), and abatacept (aOR, 1.98 [95% CI, 1.11–3.50]), compared with nonusers. Conclusions: Among patients with systemic autoimmune diseases, the risk of COVID-19 was significantly higher in those taking biologics or small molecules than in those not taking biologics. When receiving suboptimal COVID-19 vaccination, the risk of COVID-19 significantly increased in the biologics compared to the nonbiologics group, but it was mitigated through optimal vaccinations.

Han Ah Lee, Na Ryung Choi, Chung Gyo Seo, Hyungmi An, Jae Yoon Jeong, Hwi Young Kim. Gut and Liver -0001;0:. https://doi.org/10.5009/gnl260081