Translational and Clinical Pharmacology最新文献

In recent years, with the experience of the COVID-19 pandemic, countries around the world have realized that improving patient access to new medicines can have a significant impact on public health and economic stability. The aim of this study was to identify new drugs that are urgently needed among those not yet available in South Korea from 2011 to 2020, and to develop strategies to improve access by analyzing the causes of delay. Through a 3-step screening process that included a literature review of new drugs, surveys of domestic clinicians and academics, and consideration of expedited review status by regulatory authorities, 34 out of 244 unreleased new drugs were prioritized for rapid introduction. Reasons for drug delays were investigated through inquiries to the marketing authorization holders of the prioritized drugs and interviews with experts on new drug introductions. Key considerations for market entry include exemption from bridging clinical trials, reimbursement listing, and maximum reimbursement price. For foreign developers without domestic subsidiaries, providing systematic support-such as clear information on Korea's regulatory standards and facilitating reliable partnership matching-could improve access to priority unintroduced new drugs. Based on the results of this study, we propose strategies to facilitate the introduction of priority new drugs in South Korea.

Identifying how trial sites collaborate is essential for multicenter trials. The ways in which collaboration among trial sites is established can vary according to study phase and clinical trial domains. In this study, we employed association rule mining to reveal trial collaboration. We used trial approval data provided by the Ministry of Food and Drug Safety in Korea and organized the trial sites. We collected trial information from 2012 to 2023 and categorized the trials according to study phase and clinical trial domain. We performed association rule mining based on study phase and clinical trial domain. We identified 209 valid trial sites and analyzed 11,107 clinical trials conducted during this period. By study phase, phase 1 trials accounted for the largest number (5,451), followed by phase 3 (2,492), others (1,826), and phase 2 (1,338). We found that phase 1 clinical trials had the highest lift metrics. The mean lift for phase 1 trials was 5.40, which was significantly greater than that of phase 2 (1.68) and phase 3 trials (1.72). Additionally, the network structure for trial collaboration in phase 1 trials was highly condensed, with several trial sites located in Seoul and Gyeonggi-do. Different trial collaboration characteristics were noted among clinical trial domains, with mean and variability of the lift metrics for pediatrics being the highest. In conclusion, association rule mining can identify collaborations among trial sites. Collaboration in phase 1 trials is relatively more exclusive than in other phases, and aspects of collaboration differ among clinical trial domains.

The Comprehensive In Vitro Proarrhythmia Assay (CiPA) evaluates drug-induced torsade de pointes (TdP) risk, with qNet commonly used to classify drugs into low-, intermediate-, and high-risk categories. While most studies focus on single-drug effects, 2-drug fixed-dose combination (FDC) therapy is widely used for cardiovascular disease management. We aimed to develop the CiPA-based methodology to predict adverse effects of FDC therapy. A human ventricular cell model was stimulated under the effects of various drug combinations from twelve well-characterized compounds suggested by CiPA at 1 to 4 maximum plasma concentration, and the qNet_avg biomarker as a function of the ratio of two drugs was used to evaluate the TdP risk of combined compounds. Results showed that high-risk and intermediate-risk drug combinations often yielded lower qNet_avg than individual drugs, suggesting increased TdP risk. Conversely, combinations involving low-risk drugs tended to reduce TdP risk by raising qNet_avg above individual drug levels. Also, we found that the interplay of some major ionic channels caused variations on qNet_avg. These findings highlight the importance of evaluating FDC cardiotoxicity to predict risks that may not appear in single-drug analysis.

Delpazolid is an oxazolidinone-class antibiotic under development for treating diseases caused by antimicrobial-resistant gram-positive bacteria. This study compared the pharmacokinetics (PK) and safety of two formulations of delpazolid 400 mg with distinct excipient compositions: Batch No. 3183817R (test drug) and Batch No. 1650006 (reference drug). A randomized, open-label, single-dose, two-way crossover study was conducted. The participants received a single oral dose of delpazolid 400 mg (test or reference) in each period, with serial blood samples collected up to 12 hours post-dose. The PK parameters of delpazolid were calculated using a noncompartmental method. The geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) of the test drug to the reference drug were estimated for the maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time zero to the last observation (AUC_last). Safety assessments were also conducted. Twenty-four participants completed the study as planned. The PK profiles of delpazolid were similar between the test and reference drugs. The GMRs (90% CIs) of the test to the reference for C_max and AUC_last were 1.1265 (0.8666-1.4644) and 1.0290 (0.9402-1.1261), respectively. The result of AUC_last met the bioequivalence criteria (0.8-1.25), but the 90% CI for C_max exceeded the upper limit of 1.25. Both drugs were safe and well tolerated. The two different delpazolid formulations showed comparable PK and safety profiles, indicating that the test drug is an appropriate alternative to the reference drug.

Trial registration: ClinicalTrials.gov Identifier: NCT04939779.

A hangover is a combination of negative mental and physical symptoms, such as headache, diarrhea, and loss of appetite, that occur after alcohol consumption and can vary depending on individual genetic and environmental factors. To quickly relieve these hangover symptoms, a new hangover relief compound called HK-GCM-H01 has been developed. This compound, HK-GCM-H01, consists of fermented rice germ extracts, yeast extract mixtures, cili extract powder, and concentrated nipafam powder, all of which are known to relieve hangover symptoms. The safety and clinical symptoms of HK-GCM-H01 were evaluated, along with the pharmacokinetic properties of alcohol and acetaldehyde after its administration. This study was conducted on 50 healthy Korean men using a randomized, double-blind, placebo-controlled, single-intake, crossover design. To evaluate clinical symptoms, Acute Hangover Scale and Alcohol Hangover Severity Scale were used, and the pharmacokinetic evaluation parameters included the maximum plasma concentration, the time to peak plasma concentration, the terminal half-life, and the area under the plasma concentration-time curve from X hours to Y hours. A significant reduction in clinical symptoms was observed after alcohol consumption in the group that consumed HK-GCM-H01 with added hangover relief compound, as was a significant decrease in blood exposure to acetaldehyde compared to the placebo group. There were no adverse events or significant changes in liver function indicators reported during the safety evaluation. These findings indicate that HK-GCM-H01 is safe and significantly reduces plasma concentrations of acetaldehyde, the main cause of hangover, suggesting that it improves hangover symptoms.

This study aimed to estimate individual pharmacokinetic (PK) parameters in an obese hemodialysis (HD) patient receiving gentamicin and to assess the impact of obesity on gentamicin clearance (CL). A 53-year-old obese Korean woman underwent HD and received gentamicin. To estimate individual PK parameters, we employed the POSTHOC option using NONMEM^® 7.4.4. A priori model contained HD as a covariate for CL during HD, and creatinine CL (CrCL), normalized by the group mean value from the a priori model, as a covariate for non-HD CL (CLNHD). Individual CLNHD exhibited a substantial reduction from the population CLNHD, with the value corresponding to 36% of the a priori model's population PK (popPK) parameter. The patient's CrCL exceeded the group maximum of the a priori information, suggesting inaccurate renal function representation. After adjusting CrCL to the group mean from the a priori model, the patient's CLNHD was 138% of the population's typical value. The objective function value for each run was 0.53 and -4.49, respectively. The patient's CLNHD was greater than the popPK parameter value but less than the popPK parameter value when estimated using the patient's original CrCL. Meanwhile, another software (Monolix^®; version 2024R1) gave similar results. This study shows the importance of individualized PK parameter estimation, particularly in obese HD patients, and highlights the potential impact of factors including obesity on gentamicin CL.

Due to the forensic aspects of drinking and exposure to toxic substances, more sophisticated quantitative technology is needed to quantify the concentration of ethyl alcohol and acetaldehyde in the blood. In this study, we developed a headspace gas chromatography tandem mass spectrometry method that could simultaneously detect ethyl alcohol and acetaldehyde in human plasma. Through a simple preparation process, ethyl alcohol and acetaldehyde were quickly detected within 4 min, and a lower limit of quantification (LLOQ) (20 and 0.2 µg/mL) was obtained; these results confirmed the suitability of the system. According to Food and Drug Administration guidelines, the linearity (correlation coefficient > 0.9996), intraday and intraday accuracy, precision, and both short- and long-term stability and freeze-thaw stability satisfied the evaluation criteria (within 100.0 ± 15.0% and 20.0% of the LLOQ). Carryover and batch size assessment for the evaluation of the sample influence during analysis also satisfied the evaluation criteria. A valid method was applied to the pharmacokinetics study, and the plasma from 43 subjects after oral administration of the placebo or HK-GCM-H01 was analyzed. The developed analysis method for ethyl alcohol and acetaldehyde in blood could be used in various fields, such as forensics and those requiring precise quantification.

Interethnic differences in the pharmacokinetics of drugs result from a complex interplay of environmental, genetic, and demographic factors. Identifying ethnic differences in pharmacokinetics is challenging due to the multifaceted contributions of the underlying factors. To address these challenges, this paper reviews 9 pharmacokinetic studies meeting the following criteria: (A) Conducted at Seoul National University Hospital from 2013 to 2022 as a single-center study. (B) Pharmacokinetic studies involving both East Asians (Korean, Japanese, or Chinese) and Caucasians. (C) Study drugs were administered orally. (D) Raw data was provided for reanalysis. This retrospective analysis aimed to investigate the existence of ethnic differences in drug exposure and understand the possible factors contributing to these variabilities. Pharmacokinetic, demographic, and clinical laboratory test data were analyzed to assess potential pharmacokinetic differences between East Asians and Caucasians. This assessment involved calculating the geometric mean ratio of dose-normalized area under the time-concentration curve (AUC) and dose- and weight-normalized AUC, along with their 90% confidence intervals. Additionally, pharmacological information, including metabolic pathways, was gathered from the investigational brochure or the respective country's drug label. Among 9 studies, 4 studies demonstrated approximately 1.3 to 1.8 times higher drug exposure in East Asians compared to Caucasians. These drugs were primarily eliminated through hepatic metabolism, with less than 5% excreted unchanged in the urine. Two drugs were metabolized by hepatic cytochrome P450 3A4, one by glutathione S-transferase, and specific metabolic pathways for another drug were not identified. Further research is needed to assess the causes of ethnic variability in these drugs.