Translational and Clinical Pharmacology最新文献

{"title":"Building and analyzing machine learning-based warfarin dose prediction models using scikit-learn.","authors":"Sangzin Ahn","doi":"10.12793/tcp.2022.30.e22","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e22","url":null,"abstract":"<p><p>For personalized drug dosing, prediction models may be utilized to overcome the inter-individual variability. Multiple linear regression has been used as a conventional method to model the relationship between patient features and optimal drug dose. However, linear regression cannot capture non-linear relationships and may be adversely affected by non-normal distribution and collinearity of data. To overcome this hurdle, machine learning models have been extensively adapted in drug dose prediction. In this tutorial, random forest and neural network models will be trained in tandem with a multiple linear regression model on the International Warfarin Pharmacogenetics Consortium dataset using the scikit-learn python library. Subsequent model analyses including performance comparison, permutation feature importance computation and partial dependence plotting will be demonstrated. The basic methods of model training and analysis discussed in this article may be implemented in drug dose-related studies.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 4","pages":"172-181"},"PeriodicalIF":0.9,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/67/ea/tcp-30-172.PMC9810489.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10524379","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":"Melatonin and melatonergic drugs in sleep disorders.","authors":"Hyung Ki Kim, Kwang Ik Yang","doi":"10.12793/tcp.2022.30.e21","DOIUrl":"10.12793/tcp.2022.30.e21","url":null,"abstract":"<p><p>Melatonin is an endogenous chronobiological regulator secreted mainly from the pineal gland, which has been used as a dietary supplement in the treatment of sleep problems, including insomnia, parasomnia, and circadian rhythm sleep disorders. However, the short half-life and rapid metabolism of melatonin limit its suitability as a drug. There are many melatonergic drugs used in the treatment of sleep disorders and several drugs are under investigation for approval. Ramelteon was the first melatonergic agonist approved as hypnotic agent by U.S. Food and Drug Administration for the treatment of insomnia. It exhibits higher selective affinity for melatonin 1a (MT₁) receptor than melatonin 1b (MT₂) receptor. This selectivity suggests that it targets sleep onset with no significant adverse effect or dependency. Agomelatin, naphtahalenic compound, act as a potent MT₁/MT₂ melatonergic receptor agonist and serotonergic receptor antagonist was approved for treatment of depression in 2009. This dual action drug is the first melatonergic agent used in depression. Another melatonergic agonist, tasimelteon has high affinity for the MT₁/MT₂ receptors in humans. It was approved for the treatment of non-24 hours sleep-wake rhythm disorder. The newly developed melatonin and melatonergic drugs have the potential to be used extensively in various clinical situations and substitute the old benzodiazepine and its derivatives in the treatment of insomnia. However, the efficacy and safety of newly developed melatonergic drugs should be elucidated through long-term clinical trials.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 4","pages":"163-171"},"PeriodicalIF":1.1,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ba/b0/tcp-30-163.PMC9810491.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10524380","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 randomized, open-label, single-dose, two-way crossover study to assess the pharmacokinetics between two tablets of fixed-dose combination formulation with raloxifene and cholecalciferol and concomitant administration of each agents in healthy male volunteers.","authors":"Hae Won Lee,&nbsp;Woo Youl Kang,&nbsp;Mi-Ri Gwon,&nbsp;Eun Jung Choi,&nbsp;Eun Hee Kim,&nbsp;Kyunghee Cho,&nbsp;Bakhwan Lee,&nbsp;Sook Jin Seong,&nbsp;Young-Ran Yoon","doi":"10.12793/tcp.2022.30.e13","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e13","url":null,"abstract":"<p><p>A new fixed-dose combination (FDC) formulation of raloxifene 60 mg and cholecalciferol 800 IU was developed to improve the medication compliance and overall efficacy of raloxifene treatment in postmenopausal osteoporosis patients. The aim of this study was to compare the pharmacokinetics between two tablets of FDC formulation of raloxifene/cholecalciferol and the two products administered concomitantly at respective doses. This randomized, open-label, single-dose, two-treatment, two-way crossover study included 46 volunteers. During each treatment period, subjects received the test formulation (FDC formulation containing raloxifene and cholecalciferol) or the reference formulation (co-administration of raloxifene and cholecalciferol), with a 14-d washout period. Serial blood samples were collected periodically over 96 hours after drug intake. In total, 46 subjects completed the study. The geometric mean ratios and its 90% confidence intervals of the FDC to the single agents for the area under the concentration-time curve from zero to the last quantifiable time point and the maximum plasma concentration met the regulatory criteria for bioequivalence: 1.1364 (1.0584-1.2201) and 1.1010 (0.9945-1.2188) for raloxifene and 1.0266 (0.9591-1.0989) and 1.0354 (0.9816-1.0921) for baseline-corrected cholecalciferol, respectively. Both formulations were well tolerated. No significant differences was observed in the incidence of adverse events between the two treatments. It was concluded that two tablets of the newly developed FDC formulation of raloxifene and cholecalciferol and the corresponding two agents administered concomitantly at respective doses were bioequivalent.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT03010267.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 3","pages":"136-144"},"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/58/82/tcp-30-136.PMC9532856.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33543632","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":"Incorporation of real-world data to a clinical trial: use of external controls.","authors":"Tae-Eun Kim,&nbsp;Sang-In Park,&nbsp;Kwang-Hee Shin","doi":"10.12793/tcp.2022.30.e14","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e14","url":null,"abstract":"<p><p>As real-world data (RWD) becomes more available and the methodology for handling RWD evolves, the use of RWD in drug development and drug approval is drawing interest. One of the ways RWD can be applied to a clinical trial is using an external control, a cohort of patients established separately serving as a control group for the clinical trial's treatment group. Although external controls have the possibility of bias as a result of differences in baseline characteristics between the external control and experimental groups, selecting an appropriate data source and ensuring comparability through proper handling of the data can increase the utility of external controls, raising the efficiency of drug development. This article discusses several topics relevant to using external controls in clinical trials, including the definition of external control, the selection of data sources, the strategy ensuring comparability, current regulatory circumstances, and future directions.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 3","pages":"121-128"},"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/0b/8b/tcp-30-121.PMC9532857.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33543633","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":"Implementation of Miettinen-Nurminen score method with or without stratification in R.","authors":"Moon Hee Lee, Kyun-Seop Bae","doi":"10.12793/tcp.2022.30.e16","DOIUrl":"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":"30 3","pages":"155-162"},"PeriodicalIF":1.5,"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":"Considerations for clinical evaluation of the effects of bariatric surgery on the pharmacokinetics of orally administered drugs.","authors":"Sungyeun Bae,&nbsp;JungJin Oh,&nbsp;Ildae Song,&nbsp;Kyung-Sang Yu,&nbsp;SeungHwan Lee","doi":"10.12793/tcp.2022.30.e15","DOIUrl":"https://doi.org/10.12793/tcp.2022.30.e15","url":null,"abstract":"<p><p>Obesity has been a growing worldwide concern, and surgical intervention including bariatric surgery is considered as one of the options for treatment. However, there still is controversy over the change in pharmacokinetics (PKs) of drugs after the surgery. To investigate the potential covariates that can influence the area under the curve (AUC) and maximum plasma concentration (C_max), the design of previous studies was reviewed based on pre-determined eligibility criteria. Each study calculated the ratios of the AUC and C_max before and after bariatric surgery. These studies investigated whether the PK parameters were affected by the time after the surgery or by the type of control group. The ratio of the AUC calculated in the early and late follow-up period was similar across Roux-en Y gastric bypass patients. No significant difference in the PK parameters was found between the pre-surgical patients and matched healthy subjects. However, certain control groups could be preferable depending on the purpose of the clinical trial. Although C_max was inconsistent compared to the AUC, insufficient sampling of the time points may have caused such an inconsistency. This is the first article exploring the appropriate methodology in designing clinical studies for changes in the PK characteristics of orally administered drugs in patients with bariatric surgery.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"30 3","pages":"145-154"},"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/63/78/tcp-30-145.PMC9532855.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33515605","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":"30 3","pages":"129-135"},"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":"30 2","pages":"75-82"},"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":"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":"30 2","pages":"71-74"},"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":"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":"30 2","pages":"83-86"},"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}