Translational and Clinical Pharmacology最新文献

{"title":"Implementation of Miettinen-Nurminen score method with or without stratification in R.","authors":"Moon Hee Lee,&nbsp;Kyun-Seop Bae","doi":"10.12793/tcp.2022.30.e16","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e16","url":null,"abstract":"<p><p>Analysis of a 2 × 2 table for clinical data involves computing the point estimate and confidence interval for risk difference, relative risk, or odds ratio. While point estimates of these comparative parameters are uniquely defined, several statistical methods have been proposed to estimate the confidence interval for each parameter. The Miettinen-Nurminen (MN) score method is expected to be used increasingly over traditional interval estimation methods. The MN score method has not been previously implemented in R software for data with stratification. There is a need for a comprehensive software implementation of the MN score method. This article describes the implementation of the MN score method in the sasLM R software package. To demonstrate the usage of the sasLM functions introduced, recently published clinical data are provided as examples.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.9,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e6/fa/tcp-30-155.PMC9532853.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33543634","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":"How to boost and accelerate new drug development in Korea: business ecosystem perspectives.","authors":"Yoona Choi,&nbsp;Howard Lee","doi":"10.12793/tcp.2022.30.e17","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e17","url":null,"abstract":"Vaccines against the coronavirus disease 2019 (COVID-19) pandemic were developed at an unprecedented speed. For example, tozinameran (Comirnaty®, Pfizer-BioNTech) and elasomeran (Spikevax, Moderna), mRNA vaccines against COVID-19, were granted an emergency use authorization (EUA) by the U.S. Food and Drug Administration within just 10 months since COVID-19 pandemic was declared by the World Health Organization [1]. They were the first COVID-19 vaccines approved by the regulatory authority in the world. Soon after, the regulatory agencies in other countries or regions also granted EUA or full approval to tozinameran and elasomeran as the first vaccines in their territories [1], and people in many of those areas were able to receive the COVID-19 vaccine. Interestingly, these 2 vaccines were both developed by a pharmaceutical company based in the US, i.e., Pfizer (tozinameran) and Moderna (elasomeran) [1].","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":null,"pages":null},"PeriodicalIF":0.9,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4d/41/tcp-30-129.PMC9532854.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33543631","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":"A simple time-to-event model with NONMEM featuring right-censoring.","authors":"Quyen Thi Tran,&nbsp;Jung-Woo Chae,&nbsp;Kyun-Seop Bae,&nbsp;Hwi-Yeol Yun","doi":"10.12793/tcp.2022.30.e8","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e8","url":null,"abstract":"<p><p>In healthcare situations, time-to-event (TTE) data are common outcomes. A parametric approach is often employed to handle TTE data because it is possible to easily visualize different scenarios via simulation. Not all pharmacometricians are familiar with the use of non-linear mixed effects models (NONMEMs) to deal with TTE data. Therefore, this tutorial simply explains how to analyze TTE data using NONMEM. We show how to write the code and evaluate the model. We also provide an example of a hands-on model for training.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":null,"pages":null},"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/58/50/tcp-30-75.PMC9253447.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40480172","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":"Therapeutic drug monitoring on the use of transplacental digoxin in fetal tachyarrhythmia: a case report.","authors":"Sae Im Jeong,&nbsp;Heejae Won,&nbsp;Ildae Song,&nbsp;Jaeseong Oh","doi":"10.12793/tcp.2022.30.e11","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e11","url":null,"abstract":"<p><p>Fetal tachycardia (FT) is a rare disorder and is associated with significant mortality of fetus. Digoxin is one of the antiarrhythmic agents used to treat FT via transplacental therapy. In this report, we describe a therapeutic drug monitoring (TDM) case of digoxin during the treatment of FT. A 40-year-old woman, gravida 2 para 1, hospitalized to control FT as the fetal heart rate (FHR) showed over 200 bpm on ultrasonography at 29 weeks of gestation. She did not have any medical or medication history and showed normal electrolytes level on clinical laboratory test results. For the treatment of FT loading and maintenance dose of intravenous digoxin (loading dose: 0.6 mg; maintenance dose: 0.3 mg every 8 hours) were administered. To monitor the efficacy and safety of the treatment, TDM was conducted with a target maternal serum trough digoxin concentration of 1.0 to 2.0 ng/mL, as well as ultrasonography and maternal electrocardiogram. The observed digoxin serum concentrations were 0.67, 0.83, and 1.05 ng/mL after 1, 2, and 5 days after the initiation of digoxin therapy, respectively. Although the serum digoxin concentrations reached the target range, the FHR did not improve. Therefore, digoxin was discontinued, and oral flecainide therapy was started. The FHR adjusted to the normal range within 2 days from changing treatment and remained stable. TDM of digoxin along with the monitoring of clinical responses can give valuable information for decision-making during the treatment FT.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":null,"pages":null},"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/0e/19/tcp-30-83.PMC9253450.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40480171","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":"FDA initiatives to support dose optimization in oncology drug development: the less may be the better.","authors":"Hanlim Moon","doi":"10.12793/tcp.2022.30.e9","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e9","url":null,"abstract":"When anticancer drugs are developed, the first-time-in-human study is initiated with dose escalation to find the best dose for the subsequent development. In this stage, the assumption of the optimal dose is the maximum tolerated dose (MTD) which was well applied to cytotoxic agents since those drugs show a steep dose-response relationship. The more drug administered, the greater the tumor cell die as far as the human body is tolerated. These days, most new anticancer drugs are targeted agents that inhibit molecular pathways of proliferation in cancer cells or inhibit their death. For these agents, dosing at the MTD is often inappropriate. Higher doses lead to off-target effects: toxicity, dose interruptions, and reduced compliance, while much lower doses result in good tumor response with much lower toxicity and better drug compliance. Nevertheless, most new targeted anticancer agents are still tested in early phase clinical trials to determine the MTD without incremental benefit and that dose is carried forward into late-stage studies. Therefore, some groups of oncologists have suggested the optimal dose of a new anticancer drug would be determined best through a randomized dose-ranging phase II trial [1]. Recently FDA and many stakeholders including Friends of Cancer Research have started to advocate the concept and implementation in the early drug development process [2,3]. In this commentary, issues from conventional dose findings in early phase oncology trials and suggestions and recommendations by Friends of Cancer Research and FDA initiatives with a case of sotorasib are addressed.","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":null,"pages":null},"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/c9/ab/tcp-30-71.PMC9253446.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40480173","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":"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}