Translational and Clinical Pharmacology最新文献

{"title":"Lessons from a multicenter clinical trial with an approved wearable electrocardiogram: issues and practical considerations.","authors":"Ki Young Huh,&nbsp;Sae Im Jeong,&nbsp;Hyounggyoon Yoo,&nbsp;Meihua Piao,&nbsp;Hyeongju Ryu,&nbsp;Heejin Kim,&nbsp;Young-Ran Yoon,&nbsp;Sook Jin Seong,&nbsp;SeungHwan Lee,&nbsp;Kyung Hwan Kim","doi":"10.12793/tcp.2022.30.e7","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e7","url":null,"abstract":"<p><p>Although wearable electrocardiograms (ECGs) are being increasingly applied in clinical settings, validation methods have not been standardized. As an exploratory evaluation, we performed a multicenter clinical trial implementing an approved wearable patch ECG. Healthy male adults were enrolled in 2 study centers. The approved ECGs were deployed for 6 hours, and pulse rates were measured independently with conventional pulse oximetry at selected time points for correlation analyses. The transmission status of the data was evaluated by heart rates and classified into valid, invalid, and missing. A total of 55 subjects (40 in center 1 and 15 in center 2) completed the study. Overall, 77.40% of heart rates were within the valid range. Invalid and missing data accounted for 1.42% and 21.23%, respectively. There were significant differences in valid and missing data between centers. The proportion of missing data in center 1 (24.77%) was more than twice center 2 (11.77%). Heart rates measured by the wearable ECG and conventional pulse oximetry showed a poor correlation (intraclass correlation coefficient = 0.0454). In conclusion, we evaluated the multicenter feasibility of implementing wearable ECGs. The results suggest that systems to mitigate multicenter discrepancies and remove artifacts should be implemented prior to performing a clinical trial.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT05182684.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 2","pages":"87-98"},"PeriodicalIF":0.9,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f9/91/tcp-30-87.PMC9253449.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40480174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioanalytical methods for the detection of duloxetine and thioctic acid in plasma using ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS).","authors":"Zhuodu Wei,&nbsp;Hyeon-Cheol Jeong,&nbsp;Ye-Ji Kang,&nbsp;Jaesang Jang,&nbsp;Myoung-Hwan Kim,&nbsp;Kwang-Hee Shin","doi":"10.12793/tcp.2022.30.e10","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e10","url":null,"abstract":"<p><p>Duloxetine and thioctic acid (TA) are standard drugs for treating diabetic neuropathy, a primary complication associated with diabetes. In this study, ultra performance liquid chromatography coupled with tandem mass spectrometry methods was successfully developed and validated for quantifying duloxetine and TA in biological samples. The protein precipitation method was used to extract duloxetine, TA and their internal standards from beagle dog plasma. A Hypersil Gold C18 column (150 × 2.1 mm, 1.9 μm) was used for the experiment. Isocratic elution with 0.1% formic acid in acetonitrile (A) and 0.1% formic acid (B) was used for duloxetine, whereas a gradient elution with 0.03% acetic acid (A) and acetonitrile (B) was used for TA. The validated parameters included linearity, sensitivity, accuracy, precision, selectivity, matrix effect, stability, and recovery under different conditions. The linear ranges of the calibration curves for duloxetine and TA were 5-800 ng/mL and 5-1,000 ng/mL, respectively. An intra- and inter-run precision of ± 15% can be observed in all quality control samples. These methods were successfully used for pharmacokinetics (PKs) studies in beagle dogs to compare PK differences in a fixed-dose combination including duloxetine and TA and co-administration of the 2 drugs.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 2","pages":"99-111"},"PeriodicalIF":0.9,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a4/f7/tcp-30-99.PMC9253451.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40480175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative pharmacokinetics between two tablets of tramadol 37.5 mg/acetaminophen 325 mg and one tablet of tramadol 75 mg/acetaminophen 650 mg for extended-release fixed-dose combination.","authors":"Hyun Chul Kim,&nbsp;Deok Yong Yoon,&nbsp;SeungHwan Lee,&nbsp;In-Jin Jang,&nbsp;Jang Hee Hong,&nbsp;JaeWoo Kim","doi":"10.12793/tcp.2022.30.e12","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e12","url":null,"abstract":"<p><p>An extended-release (ER) fixed-dose combination (FDC) of tramadol 37.5 mg/acetaminophen 325 mg was developed due to the demand for varying dosages. This study aimed to evaluate the pharmacokinetics (PKs) for two tablets of the new developed tramadol 37.5 mg/acetaminophen 325 mg ER FDC (DW-0920, Wontran Semi ER^®) as test formulation compared to one tablet of the tramadol 75 mg/acetaminophen 650 mg ER FDC (DW-0919, Wontran ER^®) as reference formulation. A randomized, open-label, 2-way crossover study was conducted in 30 healthy subjects. Subjects were orally administered one of 2 formulations followed by an alternate formulation with a 7-day washout period. Blood samples were collected up to 36 hours post-dose. Plasma concentrations of tramadol and acetaminophen were determined using a validated high-performance liquid chromatography with tandem mass spectrometric method. The geometric mean ratios (GMRs) and their 90% confidence intervals (90% CIs) of test formulation to reference formulation were calculated for the maximum plasma concentration (C_max) and the area under the plasma concentration-time curve from zero to the last measurable time point (AUC_last). The PK profiles of 2 formulations were comparable. The GMRs (90% CI) of C_max and AUC_last for tramadol were 1.086 (1.047-1.127) and 1.008 (0.975-1.042), respectively. The corresponding values for acetaminophen were 0.956 (0.897-1.019) and 0.986 (0.961-1.011), respectively. All the values were within the bioequivalence range of 0.80-1.25. Two tablets of DW-0920 were comparable to one tablet of DW-0919. The DW-0920 may be used for optimal pharmacotherapy for pain control with a lower dose.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT01606059.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 2","pages":"112-119"},"PeriodicalIF":0.9,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/78/30/tcp-30-112.PMC9253448.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40480176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stability of acetylsalicylic acid in human blood collected using volumetric absorptive microsampling (VAMS) under various drying conditions","authors":"S. Moon, Song Han, Y. Kwak, Min-Gul Kim","doi":"10.12793/tcp.2022.30.e5","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e5","url":null,"abstract":"Acetylsalicylic acid (ASA) is one of the most commonly used medications in global market, with a risk of intoxication in certain patients. However, monitoring blood drug concentration often requires frequent hospital visits; hence there is an unmet need to increase patient-centricity by conducting blood sampling at home. Volumetric absorptive microsampling (VAMS) is a device that allows collection of homogenous and accurate volume of blood without venipuncture, and can be utilized by patients who are not in hospital settings; but because ASA is prone to hydrolysis and stabilizing reagents cannot be added to VAMS samples, a way to improve sample stability must be developed. The objective of this study was to identify the cause of instability with ASA samples collected by VAMS, and to evaluate ways to improve sample stability. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used for analysis of ASA concentration in whole blood. Samples collected with VAMS were kept under different drying conditions (desiccator, pressurized, nitrogen gas and household vacuum sealer) and were compared to the control samples collected by conventional venous sampling. The recovery of ASA was about 31% of the control when VAMS sample was dried at room temperature, whereas VAMS samples under humidity controlled conditions showed more than 85% of recovery. Our results suggest that adequate level of humidity control was critical to ensure sample stability of ASA, and this humidity control could also be achieved at home using household vacuum sealer, thus enabling patient-centric clinical trials to be conducted.","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 1","pages":"57 - 69"},"PeriodicalIF":0.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45261362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of food effects on the pharmacokinetics of Pelargonium sidoides and Coptis with each bioactive compound berberine and epicatechin after a single oral dose of an expectorant and antitussive agent UI026 in healthy subjects","authors":"Y. Park, W.‐T. Jung, Eunsol Yang, Kyu-Yeol Nam, Woo-Ri Bong, Jaehee Kim, Kyu Yeon Kim, SeungHwan Lee, Joo-Youn Cho, J. Hong, JaeWoo Kim","doi":"10.12793/tcp.2022.30.e3","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e3","url":null,"abstract":"UI026 is an expectorant and antitussive agent which is a new combination of Pelargonium sidoides extract and Coptis extract. The bioactive compounds of Pelargonium sidoides and Coptis extracts were identified as epicatechin and berberine, respectively. This study evaluated the effect of food on the pharmacokinetics (PKs) and safety of UI026. A randomized, open-label, single-dose, 2-treatment, parallel study in 12 healthy male subjects was performed. Subjects received a single oral dose of UI026 (27 mL of syrup) under a fed or fasted condition according to their randomly assigned treatment. Blood samples for the PK analysis were obtained up to 24 hours post-dose for berberine and 12 hours post-dose for epicatechin. The PK parameters were calculated by non-compartmental analysis. In the fed condition, the mean maximum plasma concentration (Cmax) and mean area under the plasma concentration-time curve from time zero to the last observed time point (AUClast) for berberine were approximately 33% and 67% lower, respectively, compared with the fasted condition, both showing statistically significant difference. For epicatechin, the mean Cmax and mean AUClast were about 29% and 45% lower, respectively, compared to the fasting condition, neither of which showed a statistically significant difference. There were no drug-related adverse events. This finding suggests that food affects the systemic exposure and bioavailability of berberine and epicatechin. Trial Registration Clinical Research Information Service Identifier: KCT0003451","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 1","pages":"49 - 56"},"PeriodicalIF":0.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44078894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of international guidelines for early-phase clinical trials of cellular and gene therapy products.","authors":"Wonsuk Shin, Min-Gul Kim, Anhye Kim","doi":"10.12793/tcp.2022.30.e2","DOIUrl":"10.12793/tcp.2022.30.e2","url":null,"abstract":"<p><p>Cellular and gene therapies (CGT) are promising fields that are bringing significant clinical benefits to patients by directly targeting the underlying cause of disease. In line with this trend, regulatory agencies in every country have been making efforts to accelerate CGT product development. For acceleration, it is necessary to increase the efficiency of clinical trials, thus the early-phase clinical trials for CGT products should be elaborate and productive. The guidelines of international regulatory agencies were compared and analyzed to examine the considerations for the design of early-phase CGT products. The guidelines described a safety evaluation, preliminary evidence of effectiveness gathering, dose exploration, and a feasibility assessment as common objectives of early-phase clinical trials for CGT products. In addition, the considerations for the design of early-phase CGT products included pretreatment effects and problems in the manufacturing and administration process. The guidelines also covered selection of a study population, control group/blinding, and dose/regimen planning. There were differences in the degree of detail, description, and the scope of the content covered by each guideline. The guideline published by FDA was the most specific. However, when compared with the previous guidelines for designing early-phase clinical trials for small molecules and biologics, the current guidelines need to be revised to suggest more detailed and practical principles and rules.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 1","pages":"13-23"},"PeriodicalIF":1.1,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48245953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically-based pharmacokinetic modeling of nafamostat to support dose selection for treatment of pediatric patients with COVID-19","authors":"Yong-Soon Cho, Jae-Gook Shin","doi":"10.12793/tcp.2022.30.e4","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e4","url":null,"abstract":"Pediatric patients with coronavirus disease 2019 (COVID-19) are increasing, and severe cases such as multisystem inflammatory syndrome are being reported. Nafamostat, a repurposing drug, is currently being explored for the treatment of COVID-19 in adults. However, the data supporting its exposure in pediatrics remains scarce. Physiologically-based pharmacokinetic (PBPK) modeling enables the prediction of drug exposure in pediatrics based on ontogeny of metabolic enzymes and age dependent anatomical and physiological changes. The study aimed to establish a PBPK model of nafamostat in adults, then scale the adult PBPK model to children for predicting pediatric exposures of nafamostat and an optimal weight-based nafamostat dose in pediatric population. The developed model adequately described adult exposure data in healthy volunteers following i.v. administration with three doses (10, 20, and 40 mg). Scaling adult PBPK models to five pediatric groups predicted that as age advances from neonate to adult, the exposure of nafamostat slightly increased from neonate to infant, steadily decreased from infant to child, and then increased from child to adult after the administration of 0.2 mg/kg/h for 14 days, a dosing regimen being conducted in a clinical trial for COVID-19. Based on the fold change of predicted area under the curve for the respective pediatric group over those of adults, weight-based dosages for each pediatric group may be suggested. The novel PBPK model described in this study may be useful to investigate nafamostat pharmacokinetics in a pediatric subgroup further.","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 1","pages":"24 - 36"},"PeriodicalIF":0.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43668467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of metabolizing enzyme-mediated clinical drug interactions using in vitro information","authors":"Suein Choi, D. Yim, S. Bae","doi":"10.12793/tcp.2022.30.e6","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e6","url":null,"abstract":"Evaluation of drug interactions is an essential step in the new drug development process. Regulatory agencies, including U.S. Food and Drug Administrations and European Medicines Agency, have been published documents containing guidelines to evaluate potential drug interactions. Here, we have streamlined in vitro experiments to assess metabolizing enzyme-mediated drug interactions and provided an overview of the overall process to evaluate potential clinical drug interactions using in vitro data. An experimental approach is presented when an investigational drug (ID) is either a victim or a perpetrator, respectively, and the general procedure to obtain in vitro drug interaction parameters is also described. With the in vitro inhibitory and/or inductive parameters of the ID, basic, static, and/or dynamic models were used to evaluate potential clinical drug interactions. In addition to basic and static models which assume the most conservative conditions, such as the concentration of perpetrators as Cmax, dynamic models including physiologically-based pharmacokinetic models take into account changes in in vivo concentrations and metabolizing enzyme levels over time.","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 1","pages":"1 - 12"},"PeriodicalIF":0.9,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41566557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrafast liquid chromatography-tandem mass spectrometry determination of donepezil in human plasma: application to a bioequivalence study","authors":"Yan-Wen Huang, L. Ding, Yuan-Ming Chen, Wei-Chen Lin, Fei Lin, Yunsheng Hsieh","doi":"10.12793/tcp.2022.30.e1","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e1","url":null,"abstract":"A liquid chromatography equipped with tandem mass spectrometric method using multi-stage flow rates was developed for the determination of donepezil in human plasma to support a randomized, crossover bioequivalence (BE) study in which healthy volunteers each received a single oral dose of the reference and test formulations of 10 mg donepezil hydrochloride. This integrated liquid chromatography with tandem mass spectrometry (LC-MS/MS) system with electrospray ionization and a deuterium-labeled internal standard (IS) were employed for the positive multiple-reaction-monitoring (MRM) analyses. The baseline separation using a high-resolution monolithic column under gradient and flexible flowrate conditions between donepezil and multiple interfering peaks from the extracted quality control, calibration standard and study plasma samples following simple protein precipitation extraction procedures was accomplished within 1.5 minutes. The ultrafast monolithic column performance in terms of chromatographic separation efficiency, peak asymmetry and resolution and retention time reproducibility was found to be sustainable. The linear dynamic range was detected over a concentration range of 0.2–50 ng/mL. The intra- and inter-day assay accuracy and precision were within 15% for the analyte in individual biological fluids. A positive correlation coefficient (r) greater than 0.995 for donepezil concentrations in study plasma samplers measured by the proposed and the other validated LC-MS/MS methods in support of a bioequivalence study was observed.","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 1","pages":"37 - 48"},"PeriodicalIF":0.9,"publicationDate":"2022-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48894358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical development and trial operations in COVID-19 era.","authors":"Seong Choon Choe","doi":"10.12793/tcp.2021.29.e23","DOIUrl":"https://doi.org/10.12793/tcp.2021.29.e23","url":null,"abstract":"Coronavirus disease 2019 (COVID-19) pandemic affects worldwide and various aspects of human life, including drug developments and clinical trials. Especially in trial operations, there are significant impacts from 2020 to 2021. According to the Arkivum report [1], ‘TMF futures 2021: good data within the age of digital transformation,’ 41% of latest clinical trials in 2020 were delayed or placed on hold indefinitely because of the COVID-19 pandemic, 41% of those delayed trials will now be run in 2021, 65% of the life sciences sector say they will still run clinical trials remotely after the pandemic, 57% of the sciences organizations say the price of running a trial has increased since the pandemic began and 49% of the sciences organizations say the time to finish a clinical trial has increased since the pandemic started. We need to review the trends and possible changes during and after the COVID-19 pandemic reviewing the various reports from biopharmaceutical consulting companies and contract research organizations (CROs).","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"29 4","pages":"181-185"},"PeriodicalIF":0.9,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/77/e3/tcp-29-181.PMC8718356.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39816366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}