Translational and Clinical Pharmacology最新文献

This paper aims to elucidate the characteristics of healthy volunteers in Korea and Japan. Clinical trials can be divided into Phases 1 through 4 based on the stage of research. Unlike other phase, Phase 1 trials administer new drugs to healthy volunteers. Although Phase 1 trials are the first stage of drug administration to humans, without therapeutic purposes. Healthy volunteers must have no history of diseases that could affect the study and must have normal physical measurements. They are also defined as individuals who understand the study and can voluntarily consent to participate. Also, it is crucial to conduct them ethically. To date, there has been insufficient research on the Phase 1 clinical trials in Korea and Japan, and in-depth analysis of the perceptions and the motivations. This study enrolled healthy volunteers in Korea and Japan to conduct surveys related to demographic information and their perception.

Zastaprazan (JP-1366) is a new potassium-competitive acid blocker being developed for treating gastrointestinal reflux disease. It is an orally administered small molecule that inhibits gastric H+ and K+-ATPases differently from proton pump inhibitors, which act quickly and have dose-dependent effects on acid secretion. Celecoxib, a selective cyclooxygenase 2 inhibitor, will likely be used with zastaprazan in clinical settings and trials. The objective of current physiologically based pharmacokinetic (PBPK) modeling study is to predict drug-drug interaction (DDI) risk between zastaprazan (perpetrator) and celecoxib (victim). A human PBPK model for zastaprazan was built using experimental physicochemical properties and in silico predictions. The model was optimized with clinical pharmacokinetic (PK) data from a phase 1 study (Protocol No. JP-1366-105). The PBPK model for celecoxib was constructed using the data from previous studies and in silico predictions. The final PBPK model encompassing zastaprazan and celecoxib was used to quantitatively predicted DDI risks in humans. The final PBPK models accurately predicted zastaprazan's PK profiles after single dose in human, and it also well predicted plasma celecoxib concentrations over time. At doses of 20 mg of zastaprazan citrate (JAQBO^® tablet) and 200 mg of celecoxib, multiple oral doses of zastaprazan every 24 hours for 7 days did not increase celecoxib's area under the curve (AUC) and maximum plasma concentration (C_max), with ratios of 1 in both AUC and C_max, indicating no effect of zastaprazan on celecoxib's PK. The PBPK modeling approach provides scientific predictions of DDIs between zastaprazan and celecoxib, guiding future clinical development.

Tuberculosis (TB) remains one of the leading causes of infectious disease-related deaths worldwide. Model-informed precision dosing-based therapeutic drug monitoring (TDM) is a promising strategy to optimize anti-TB drugs doses based on pharmacokinetic (PK) profiles of patients. However, this approach requires significant time and trained personnel to interpret the results. To address this limitation, we developed and utilized an automated, web-based TDM platform that simplifies implementation and enhances accessibility, ultimately aiming to improve treatment outcomes. The system incorporates population PK models for both first- and second-line anti-TB drugs, integrating clinical data including demographics, NAT2 genotype and drug concentrations from limited sampling strategies. Bayesian forecasting is used to estimate individual PK parameters and simulate optimized dosing regimens. Clinicians can use the platform to automatically generate the individual concentration-time curve plot that compares a patient's exposure with population level references, along with a table displaying the estimated individual PK parameters. If the dose adjustment is needed, users may input alternative regimens and run the simulation to predict the corresponding PK metrics. These features enable users to visualize predicted outcomes, compare exposures against therapeutic targets, and support optimal dose selection. The system produces downloadable reports containing patient specific data, PK parameter values, graphical PK profiles, and pharmacogenomic interpretations with minimal user input. This automated web-based platform enhances the time-efficiency and accessibility of TDM, making it a practical tool for personalized TB therapy. It is especially valuable in resource-limited settings where expert support is limited, by supporting clinical decision making and improving patient outcomes.

The combination therapy of low-dose rosuvastatin and ezetimibe has shown similar efficacy in decreasing low-density lipoprotein cholesterol (LDL-C) compared to high-dose rosuvastatin monotherapy. This study aimed to compare the pharmacokinetics (PKs) between the fixed-dose combination (FDC) of rosuvastatin/ezetimibe 2.5/10 mg and the co-administration of individual formulations. A randomized, open-label, single-dose, 2-sequence, 2-period, crossover study was conducted in healthy volunteers. Subjects were randomized in each sequence and received a single dose of the FDC of rosuvastatin/ezetimibe 2.5/10 mg or the co-administration of individual formulations in each period with a 14-day washout. Serial blood samples for PK analysis were collected up to 48 hours post-dose for rosuvastatin and 72 hours post-dose for ezetimibe. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the FDC to the co-administration for maximum plasma concentration (C_max) and area under the curve from zero to the last measurable time point (AUC_last) were calculated. Forty-seven subjects were randomized, and 41 subjects completed the study. The GMRs (90% CIs) of C_max and AUC_last for rosuvastatin were 0.9789 (0.9020-1.0622) and 0.9741 (0.9105-1.0422). The corresponding values were 1.0419 (0.9219-1.1776) and 0.9983 (0.9522-1.0465) for total ezetimibe, and 1.0396 (0.9087-1.1893) and 0.9743 (0.8997-1.0550) for free ezetimibe, respectively. All the values were within the conventional bioequivalence criteria of 0.8 to 1.25. In conclusion, the FDC of rosuvastatin/ezetimibe 2.5/10 mg showed comparable PK with the co-administration of individual formulations.

Trial registration: Clinical Research Information Service Identifier: KCT0009254.

Vancomycin is widely used as a prophylactic antibiotic for ventricular assist device (VAD) implantation to prevent infections, the most common complication. As vancomycin is renally eliminated, an accurate renal function estimation is essential. However, it has been reported that creatinine-based models inaccurately estimate renal function in VAD recipients, and cystatin C could alleviate the limitation. This study analyzed the association between renal function estimation methods and vancomycin trough concentrations in VAD recipients. Clinical data of VAD recipients who received prophylactic vancomycin at Seoul National University Hospital between 2014 and 2023 were retrospectively analyzed. Recipients were categorized into high trough (> 15 mg/dL) or non-high trough (≤ 15 mg/dL) groups based on the 1st vancomycin trough concentration after surgery. The estimated glomerular filtration rates (eGFRs) based on creatinine alone (eGFR_Cr), combined with cystatin C (eGFR_Cr-Cys-C), and their differences (eGFR_diff) were compared between the 2 groups. The association between the eGFRs and vancomycin trough concentrations was evaluated using Pearson's method. Among the 20 recipients, 13 were the high trough group and 7 were the non-high trough group. The high trough group had a significantly higher eGFR_diff than non-high trough group (8.9 vs. -5.1 mL/min/1.73 m², p = 0.0265), while other eGFRs were comparable. Among the three eGFR estimates, eGFR_diff showed the strongest correlation (r = 0.41) with the first measured vancomycin trough levels. In conclusion, creatinine-based eGFR might not fully capture vancomycin pharmacokinetics in VAD recipients. The difference between eGFR_Cr and eGFR_Cr-Cys-C is associated with vancomycin trough concentration in VAD recipients.

Methotrexate (MTX), a folate antagonist, is commonly administered at low doses for the treatment of Crohn's disease (CD). Anti-inflammatory effects of MTX are facilitated by its intracellular conversion to MTX polyglutamates (MTX-PGs). Because plasma-based monitoring of therapeutic response does not accurately reflect the therapeutic efficacy of MTX, quantifying intracellular MTX-PGs, potential biomarkers of the MTX response, is crucial. However, it is challenging to routinely monitor intracellular MTX metabolites in patients with CD due to the low concentrations of MTX-PGs. Therefore, quantitating MTX-PGs in clinical samples with a high-sensitivity method is necessary. We established a high-sensitivity method to quantify three MTX-PGs using perchloric acid deproteinization followed by high-performance liquid chromatography-tandem mass spectrometry. Calibration curves were generated using human red blood cells as biological matrix. This method was applied to analyze MTX-PGs in red blood cells (RBCs) from patients with CD undergoing MTX therapy. The method achieved a lower limit of quantification of 1 ng/mL for individual MTX-PGs. A nine-point calibration curve covering 1-400 ng/mL showed excellent linearity. Precision (relative standard deviation < 15%) and accuracy (93.41-109.37%) were satisfactory in both intra- and inter-day assays. Plasma MTX levels were not significantly correlated with any individual RBC MTX-PG level (p = 0.998, 0.640, and 0.587, respectively). The lack of correlation supports our conclusion that plasma MTX levels may not reliably represent intracellular accumulation. The developed quantitative method provides a useful tool to improve our understanding of MTX metabolism and may facilitate therapeutic drug monitoring in MTX therapy.

This study analyzed clinical laboratory test results of healthy Korean volunteers screened for Phase 1 clinical trials at Chungnam National University Hospital. Data from 53 trials conducted between 2019 and 2023 were extracted from the Clinical Data Warehouse and included tests such as white blood cell count, hemoglobin, aspartate aminotransferase, alanine aminotransferase, and creatinine. The study aimed to evaluate whether current ranges for "not clinically significant (NCS)" values need modification. Results showed that NCS values often varied between studies, with temporary deviations from normal ranges being common among healthy volunteers, especially those engaged in activities such as heavy weight training or recent dietary excess. Comparative pharmacokinetics and bioequivalence studies made up the majority of trials. The analysis highlighted discrepancies in laboratory criteria application, with implications for screening failure rates. The findings suggest that stricter guidelines might exclude otherwise eligible participants unnecessarily. Establishing consistent NCS criteria could optimize screening and reduce variability across clinical sites. This is the first study to provide insights into clinical lab results for healthy Korean volunteers, emphasizing the need for tailored NCS guidelines in Phase 1 trials.

The χ² distribution is commonly used for estimating confidence interval (CI) for variance. However, the validity of the CIs from this method is highly dependent on the assumption that the population follows a normal distribution. Additionally, the Wald CI used in this method does not account for the asymmetry. To address this limitation and provide more accurate interval estimates, especially with relatively small sample sizes, a likelihood interval (LI) approach was adopted. The Likelihood-Based Interval R software package was developed to implement this approach. We conducted a simulation to compare 3 methods for interval estimation of variance in a single group, using the luteinizing hormone () data available with the default R installation and random small sample sizes of 10, 20, and 30 from a standard normal distribution: the conventional χ² interval method, the LI method, and the likelihood-based confidence interval (LBCI) method. The average width (standard deviation) of the CIs from the simulation with data was 0.2582 (0.0534) for LBCI, 0.2604 (0.0538) for LI, and 0.2667 (0.0551) for CI, indicating that LBCI produced the narrowest CIs. The interval coverage was 95.24% for CI, 95.38% for LBCI, and 95.45% for LI. In simulations with small sample sizes, LBCI and LI exhibited narrower widths than CI, while the coverage was similar. Therefore, LBCI or LI for variance estimation can be considered a more efficient option than the conventional method.

The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are well-established treatment options for dyslipidemia. For patients not meeting low-density lipoprotein cholesterol targets with monotherapy, combination therapy with another lipid-lowering agent including ezetimibe, is recommended. This study compared the pharmacokinetics (PKs) and safety of a fixed-dose combination (FDC) of atorvastatin/ezetimibe 5 mg/10 mg with the individual components in healthy Korean subjects. A randomized, open-label, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 60 healthy subjects. An FDC of atorvastatin/ezetimibe 5 mg/10 mg or the corresponding individual components was administered in the first period, and the alternative in the second period after a 14-day washout. Serial blood samples were collected up to 72 hours post-dose to calculate PK parameters such as maximum plasma concentration (C_max) and the area under the plasma concentration-time curve to the last measurable concentration (AUC_last). The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of the C_max and AUC_last for the atorvastatin and total ezetimibe were estimated compared to the individual components. Adverse events (AEs) and other safety variables were monitored to evaluate safety and tolerability profile. Sixty subjects were enrolled and 58 subjects completed the study. For atorvastatin, the GMRs (90% CIs) for C_max and AUC_last were 1.18 (1.04-1.33) and 1.04 (1.00-1.08), respectively, and the corresponding values were 1.37 (1.26-1.50) and 0.98 (0.93-1.03) for total ezetimibe. No clinically significant treatment-emergent AEs were observed with either formulations. The FDC of atorvastatin/ezetimibe 5 mg/10 mg was safe and showed similar exposure to those of the individual components.

Trial registration: ClinicalTrials.gov Identifier: NCT05202405.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder often associated with obesity and elevated cardiovascular risks. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become integral to T2DM management due to their clinical benefits of glucose regulation and weight loss. However, their subcutaneous administration presents challenges to patient adherence, limiting their widespread use. Oral semaglutide (Rybelsus^®), the first oral GLP-1 RA approved for T2DM, addresses these challenges through an innovative co-formulation with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which enhances gastric absorption and stability. This review provides a comprehensive overview of the clinical development of oral semaglutide, with a focus on early-phase trials. Phase 1 studies investigated pharmacokinetics, pharmacodynamics, safety, and dose-response relationships, demonstrating a dose-dependent reduction in hemoglobin A_1c (HbA_1c) and body weight with an acceptable safety profile. Additionally, pharmacological evaluations of interactions with food, dosing condition, disease states, and concomitant medications supported the determination of an optimal dosing regimen for further clinical studies. Phase 2 dose-finding trials confirmed significant HbA_1c and weight reductions comparable to subcutaneous semaglutide, which guided dose selection for phase 3 trials. Phase 3 trials, including the Peptide InnOvatioN for Early diabEtes tReatment program, demonstrated significant reductions in HbA_1c, weight loss, and cardiovascular safety, positioning oral semaglutide as a transformative option in diabetes care. The study highlights comprehensive clinical strategies and provides an insight into the future development of oral GLP-1 RAs and other oral peptide drugs.