Translational and Clinical Pharmacology最新文献

{"title":"Response surface analyses of antihypertensive effects of angiotensin receptor blockers and amlodipine or hydrochlorothiazide combination therapy in patients with essential hypertension.","authors":"Minhee Cho,&nbsp;Eunsook Oh,&nbsp;Byungjin Ahn,&nbsp;MoonTae Yoon","doi":"10.12793/tcp.2023.31.e15","DOIUrl":"10.12793/tcp.2023.31.e15","url":null,"abstract":"<p><p>While previous studies have examined the dose-response characteristics of certain antihypertensive drugs alone or in combination, response surface analysis for combination therapies involving angiotensin receptor blockers (ARBs) and either amlodipine (AML) or hydrochlorothiazide (HCT) has not been explored, particularly in the context of low-dose combinations. The objectives of present study were to generate useful dose-response information for the combination of ARB/AML or ARB/HCT and to predict the blood pressure lowering effects of combination therapies compared to monotherapies. We reviewed the New Drug Application data of combination drugs of ARB/AML and ARB/HCT. Data on systolic blood pressure (SBP), from studies conducted using a factorial dose-response design over a period of 8-12 weeks, were used. The placebo-subtracted SBP change was used for analysis. Response surface analyses of the collected data were conducted using a polynomial regression model. For ARB/AML combination, the quadratic polynomial regression model containing two linear terms, two quadratic terms, and one interaction term was best fitted to the naïve pooled data. Meanwhile, for ARB/HCT combination, the best-fitted model was a quadratic model that included two linear terms and two quadratic terms. The 1/2-dose combination of these medications, compared to each monotherapy, resulted in predicted SBP reductions that were 8-30% greater. The ratio of the estimated antihypertensive effects of the combination to the expected additive effects of each component ranged from 82% to 100% of the expected effect. These results can provide a rationale for developing lower-dose combinations of ARB/AML or ARB/HCT and assist in designing clinical trials.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 3","pages":"154-166"},"PeriodicalIF":0.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e5/9d/tcp-31-154.PMC10551747.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41141031","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":"Transforming clinical trials: the emerging roles of large language models.","authors":"Jong-Lyul Ghim, Sangzin Ahn","doi":"10.12793/tcp.2023.31.e16","DOIUrl":"10.12793/tcp.2023.31.e16","url":null,"abstract":"<p><p>Clinical trials are essential for medical research, but they often face challenges in matching patients to trials and planning. Large language models (LLMs) offer a promising solution, signaling a transformative shift in the field of clinical trials. This review explores the multifaceted applications of LLMs within clinical trials, focusing on five main areas expected to be implemented in the near future: enhancing patient-trial matching, streamlining clinical trial planning, analyzing free text narratives for coding and classification, assisting in technical writing tasks, and providing cognizant consent via LLM-powered chatbots. While the application of LLMs is promising, it poses challenges such as accuracy validation and legal concerns. The convergence of LLMs with clinical trials has the potential to revolutionize the efficiency of clinical trials, paving the way for innovative methodologies and enhancing patient engagement. However, this development requires careful consideration and investment to overcome potential hurdles.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 3","pages":"131-138"},"PeriodicalIF":2.4,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ab/70/tcp-31-131.PMC10551746.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41140566","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":"Effects of rifampin coadministration on the pharmacokinetics of digoxin: a real-world data approach.","authors":"JungJin Oh,&nbsp;Byungwook Kim,&nbsp;SeungHwan Lee","doi":"10.12793/tcp.2023.31.e13","DOIUrl":"10.12793/tcp.2023.31.e13","url":null,"abstract":"<p><p>Digoxin, a cardiac glycoside, is commonly prescribed to treat heart failure and atrial fibrillation. Because digoxin acts as a substrate of P-glycoprotein (P-gp), its blood concentration may be reduced by P-gp inducers such as rifampin. To assess the real-world implications of this drug-drug interaction, a retrospective analysis was carried out on the Clinical Data Warehouse at Seoul National University Hospital between 2012 and 2017. Eleven patients who received both digoxin and rifampin with satisfying the inclusion/exclusion criteria were identified. The C_trough values of digoxin monotherapy were compared to those of the combination therapy with rifampin. Results demonstrated that the systemic exposure of orally administered digoxin decreased by 40% with the concurrent use of rifampin. Clinicians should be aware of potential drug interactions between digoxin and rifampin, as adjustments to digoxin dosage might be necessary for patients receiving rifampin or other P-gp inducer drugs.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 3","pages":"148-153"},"PeriodicalIF":0.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4a/fd/tcp-31-148.PMC10551748.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41152438","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":"Quantification of OATP1B1 endogenous metabolites coproporphyrin I and III in human urine.","authors":"Yeonseo Jang,&nbsp;Jihyun Kang,&nbsp;Sejung Hwang,&nbsp;Jae-Yong Chung,&nbsp;Joo-Youn Cho","doi":"10.12793/tcp.2023.31.e12","DOIUrl":"10.12793/tcp.2023.31.e12","url":null,"abstract":"<p><p>Coproporphyrin (CP)-I and CP-III are the markers of organic anion-transporting polypeptides' (OATPs) activities, and they are porphyrin metabolites that originate from heme synthesis. Furthermore, CP-I and CP-III, which are OATP1B endogenous metabolites, have gradually attracted the attention of scientists and researchers in recent years. Previous studies have also observed CP-I and CP-III levels as clinical biomarkers for predicting OATP1B inhibition in drug-drug interaction studies. To establish an accurate ultra-high performance liquid chromatography-mass spectrometry method for the quantitation of CP-I and CP-III, we reviewed previous methodological publications and applied them to a clinical pharmacology study using a human urine matrix. We used 13.25 M formic acid as a working solution for internal standards (CP-I ¹⁵N₄ and CP-III d₈) to avoid isobaric interference. The calibration curve showed good linearity in the range of 1-100 ng/mL, with a correlation coefficient (<i>R²</i>) higher than 0.996 in each validation batch. Both the between-run and within-run assays achieved good precision and accuracy, and we found that both CP-I and CP-III were stable in the pre-study validation. The method exhibited suitable dilution integrity, allowing for the re-analysis of samples with concentrations exceeding the upper limit of quantification through dilution. Overall, the application of the described method in a clinical study revealed that it can be utilized effectively to monitor drug-drug interactions mediated by OATP1B.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 3","pages":"139-147"},"PeriodicalIF":0.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/65/46/tcp-31-139.PMC10551744.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155409","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":"What goes in the regulatory clinical pharmacology package for an oncolytic virus?","authors":"Sun Young Yum,&nbsp;Kyungho Jang,&nbsp;Francine Attié de Castro,&nbsp;Amandine Manon","doi":"10.12793/tcp.2023.31.e14","DOIUrl":"10.12793/tcp.2023.31.e14","url":null,"abstract":"OVs are natural or genetically modified viruses designed to selectively replicate in tumor cells, resulting in tumor cell lysis, that is, a direct oncolytic effect. The destruction of tumor cells leads to the release of viral particles (VPs) that infect surrounding tumor cells and release tumor-derived antigens, which are presented to T-cells. This process results in a cascade of adaptive immune responses (e.g., T-cell activation, memory, migration, infiltration, and T-cell mediated tumor death) leading to a systemic antitumor immune response. OV replication and amplification after administration into the tumor cells are major determinants of tumor eradication [1,2]. The paper aims to guide the readers through the conceptual framework of OV drug development in the current regulatory environment.","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 3","pages":"125-130"},"PeriodicalIF":0.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/6b/0e/tcp-31-125.PMC10551745.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41154209","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":"Safety and pharmacokinetic comparison between fenofibric acid 135 mg capsule and 110 mg enteric-coated tablet in healthy volunteers.","authors":"Yu-Bin Seo,&nbsp;Jae Hoon Kim,&nbsp;Ji Hye Song,&nbsp;WonTae Jung,&nbsp;Kyu-Yeol Nam,&nbsp;Nyung Kim,&nbsp;Youn-Woong Choi,&nbsp;SangMin Cho,&nbsp;Do-Hyung Ki,&nbsp;Hye Jung Lee,&nbsp;JungHa Moon,&nbsp;SeungSeob Lee,&nbsp;JaeHee Kim,&nbsp;Jang Hee Hong,&nbsp;Jung Sunwoo,&nbsp;Jin-Gyu Jung","doi":"10.12793/tcp.2023.31.e7","DOIUrl":"https://doi.org/10.12793/tcp.2023.31.e7","url":null,"abstract":"<p><p>This study aimed to compare the pharmacokinetic (PK) and safety profiles of 2 fenofibric acid formulations under fasting and fed conditions. The reference was a 135 mg capsule, while the test was a 110 mg enteric-coated tablet. This randomized, open-label, two-sequence, two-period crossover phase 1 clinical trial was conducted in healthy Korean men. Sixty participants were enrolled in each of the fasting and feeding groups. Blood samples were collected 72 hours after drug administration. PK parameters were calculated using a non-compartmental method with Phoenix WinNonlin^®. A total of 53 and 51 participants from the fasting and feeding groups, respectively, completed the study. The geometric mean ratio and 90% confidence intervals of the maximum concentration (C_max) and area under the concentration-time curve to the last measurable plasma concentration were 0.9195 (0.8795-0.9614) and 0.8630 (0.8472-0.8791) in the fasting study and 1.0926 (1.0102-1.1818) and 0.9998 (0.9675-1.0332) in the fed study, respectively. The time to reach C_max of the enteric-coated tablet compared to that of the capsule was extended by 1 and 3 hours under fasting and fed conditions, respectively. In conclusion, enteric-coated tablets have a higher bioavailability than capsules. In addition, the enteric-coated tablet was smaller than the capsule, making it easier for patients to swallow.</p><p><strong>Trial registration: </strong>Clinical Research Information Service Identifier: KCT0007177, KCT0003304.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 2","pages":"95-104"},"PeriodicalIF":0.9,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5c/ea/tcp-31-95.PMC10333648.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10192784","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":"Fed and fasted bioequivalence assessment of two formulations of extended-release fixed-dose combination dapagliflozin/metformin (10/1,000 mg) tablets in healthy subjects.","authors":"Hae Won Lee,&nbsp;Woo Youl Kang,&nbsp;Ji Seo Park,&nbsp;Jae Hwa Lee,&nbsp;Mi-Ri Gwon,&nbsp;Dong Heon Yang,&nbsp;Eun Hee Kim,&nbsp;Soo-Jin Park,&nbsp;Young-Ran Yoon,&nbsp;Sook Jin Seong","doi":"10.12793/tcp.2023.31.e10","DOIUrl":"https://doi.org/10.12793/tcp.2023.31.e10","url":null,"abstract":"<p><p>Two open-label, randomized, two-period crossover studies were conducted to investigate the pharmacokinetic (PK) properties, safety, and bioequivalence of the test formulation (KD4004), a new fixed-dose combination (FDC) formulation of dapagliflozin and metformin extended release (XR) tablets, relative to the reference formulation (10 mg dapagliflozin/1,000 mg metformin XR FDC tablet) in healthy subjects under fasting (Part A) and fed (Part B) conditions. After giving the dose, serial blood samples were collected for a period of 48 hours. Primary PK parameters (AUC_0-t and C_max) were used to assess bioequivalence between two dapagliflozin/metformin XR (10/1,000 mg) FDC formulations under fed and fasting conditions. Safety and tolerability were also evaluated. Part A and Part B were completed by 32 and 37 subjects, respectively. Bioequivalence of the two FDC formulations of dapagliflozin and metformin XR tablets was established in both the fasted and the fed conditions as the 90% confidence interval of the ratios of adjusted geometric means for AUC_0-t and C_max were contained within the predefined range of 0.800-1.250 bioequivalence criteria. Single-dose administration of dapagliflozin and metformin XR was safe and well tolerated as the two FDC formulations. In conclusion, both FDC formulations of dapagliflozin and metformin XR tablets were bioequivalent in fed and fasted subjects. All treatments were well tolerated.</p><p><strong>Trial registration: </strong>Clinical Research Information Service Identifier: KCT0004026.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 2","pages":"105-113"},"PeriodicalIF":0.9,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8e/9d/tcp-31-105.PMC10333646.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9816599","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":"Likelihood interval for nonlinear regression.","authors":"Moon Hee Lee,&nbsp;Kyun-Seop Bae","doi":"10.12793/tcp.2023.31.e8","DOIUrl":"https://doi.org/10.12793/tcp.2023.31.e8","url":null,"abstract":"<p><p>Wald confidence interval has been used as the conventional method of interval estimation for the parameters in nonlinear models. Because Wald confidence interval is symmetric around the point estimate, it does not reflect the asymmetry of the likelihood profile in nonlinear regression. In contrast, a likelihood interval is estimated directly from the likelihood profile and does reflect the shape of the likelihood profile. However, the lack of software for the estimation of likelihood intervals and visualization of likelihood profiles posed an obstacle to the use of likelihood intervals in nonlinear models. There was a need for software implementation to tackle these tasks. Likelihood interval estimation and likelihood profile plotting for nonlinear models had not been previously implemented in R software. This article describes the implementation of likelihood interval estimation and likelihood profile plotting in the wnl R software package. To demonstrate the usage of implemented functions, an example of fitting a nonlinear pharmacokinetic model to concentration-time data is presented.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 2","pages":"85-94"},"PeriodicalIF":0.9,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e7/83/tcp-31-85.PMC10333647.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10192786","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 review of the Bayesian approach with the MCMC and the HMC as a competitor of classical likelihood statistics for pharmacometricians.","authors":"Kyungmee Choi","doi":"10.12793/tcp.2023.31.e9","DOIUrl":"10.12793/tcp.2023.31.e9","url":null,"abstract":"<p><p>This article reviews the Bayesian inference with the Monte Carlo Markov Chain (MCMC) and the Hamiltonian Monte Carlo (HMC) samplers as a competitor of the classical likelihood statistical inference for pharmacometricians. The MCMC and the HMC samplers have greatly contributed to realization of the Bayesian methods with minimal requirement of mathematical theory. They do not require any closed form of the posterior density nor linear approximation of complex nonlinear models in high dimension even with non-conjugate priors. The HMC even weakens the dependency of the chain and improves computational efficiency. Pharmacometrics is one of great beneficiaries since they use complex multivariate multilevel nonlinear mixed effects models based on the restricted maximum likelihood estimation. Comprehension of the Bayesian approach will help pharmacometricians to access the data analysis more conveniently.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 2","pages":"69-84"},"PeriodicalIF":2.4,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/0d/tcp-31-69.PMC10333649.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10192780","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":"Evaluation of pharmacokinetic drug-drug interaction between tegoprazan and clarithromycin in healthy subjects.","authors":"Minkyung Oh,&nbsp;Heechan Lee,&nbsp;Seokuee Kim,&nbsp;Bongtae Kim,&nbsp;Geun Seog Song,&nbsp;Jae-Gook Shin,&nbsp;Jong-Lyul Ghim","doi":"10.12793/tcp.2023.31.e11","DOIUrl":"https://doi.org/10.12793/tcp.2023.31.e11","url":null,"abstract":"<p><p>Tegoprazan is a novel potassium-competitive acid blocker that treats gastric acid-related diseases. Clarithromycin was widely used as one of various regimens for eradicating <i>Helicobacter pylori</i>. This study compared the pharmacokinetic and safety profile of tegoprazan and clarithromycin between combination therapy and monotherapy to evaluate the potential drug-drug interaction. An open-label, randomized, 6-sequence, 3-period crossover study was conducted in 24 healthy subjects. According to the assigned sequence, the subject was administered the assigned treatment during 5 days in each period. PK parameters of tegoprazan and clarithromycin administered in combination were compared with those of the respective monotherapies. The co-administration of tegoprazan with clarithromycin increased maximum steady-state plasma concentration (C_ss,max) and area under the plasma concentration-time curve in dosing interval at steady-state (AUC_ss,tau) of tegoprazan (1.6-fold in C_ss,max and 2.5-fold in AUC_ss,tau) and M1 (2.0-fold in C_ss,max, 2.5-fold in AUC_ss,tau) than tegoprazan alone. The C_ss,max and AUC_ss,tau of 14-hydroxyclarithromycin increased 1.8- and 2.0-fold in co-administration, respectively. The AUC_ss.tau of clarithromycin was slightly increased in co-administration, but C_ss,max was not changed. Combination of tegoprazan and clarithromycin and those of the respective monotherapies were tolerated in 24 healthy subjects. There may exist drug interaction that lead to reciprocal increase in plasma drug concentrations when tegoprazan and clarithromycin were administrated in combination and no safety concerns were raised. It is suggested that an in-depth analysis of the concentration-response relationship is necessary to determine whether these concentration changes warrant clinical action.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT02052336.</p>","PeriodicalId":23288,"journal":{"name":"Translational and Clinical Pharmacology","volume":"31 2","pages":"114-123"},"PeriodicalIF":0.9,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a1/80/tcp-31-114.PMC10333645.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10192782","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}