Therapeutic Drug Monitoring最新文献

{"title":"Development and Validation of a High-Performance Liquid Chromatography-Ultraviolet Spectrometry Method for Ampicillin and Its Application in Routine Therapeutic Drug Monitoring of Intensive Care Patients.","authors":"Benedict Morath, Linda Schultes, Otto Roman Frey, Anka Christa Röhr, Hannes Christow, Torsten Hoppe-Tichy, Alexander Brinkmann, Ute Chiriac","doi":"10.1097/FTD.0000000000001253","DOIUrl":"10.1097/FTD.0000000000001253","url":null,"abstract":"<p><strong>Background: </strong>Ampicillin/sulbactam, a combination of a β-lactam and β-lactamase inhibitor, is widely used in clinical settings. However, therapeutic drug monitoring (TDM) of ampicillin is not commonly performed, particularly in intensive care units (ICUs). The purpose of this study was to develop and validate a rapid and cost-effective high-performance liquid chromatography (HPLC)-ultraviolet spectrometry method to quantify ampicillin in human serum and evaluate its clinical application in ICU patients.</p><p><strong>Methods: </strong>Sample cleanup included a protein precipitation protocol, followed by chromatographic separation on a C18 reverse-phase HPLC column within 12.5 minutes using gradient elution of the mobile phase. The assay was validated according to the German Society of Toxicology and Forensic Chemistry criteria. Clinical applications involved the retrospective analysis of TDM data from ICU patients receiving continuous infusion of ampicillin/sulbactam, including the attainment of target ranges and individual predicted and observed pharmacokinetics.</p><p><strong>Results: </strong>The method was robust, with linear relations between the peak area responses and drug concentrations in the range of 2-128 mg/L. The coefficient of variation for precision and the bias for accuracy (both interday and intraday) were less than 10%. Clinical application revealed variable pharmacokinetics of ampicillin in ICU patients (clearance of 0.5-31.2 L/h). TDM-guided dose adjustments achieved good therapeutic drug exposure, with 92.9% of the samples being within the optimal (16-32 mg/L) or quasioptimal (8-48 mg/L) range.</p><p><strong>Conclusions: </strong>This method provides a practical solution for the routine TDM of ampicillin, facilitating individualized dosing strategies to ensure adequate therapeutic drug exposure. Given its simplicity, cost-effectiveness, and clinical relevance, HPLC-ultraviolet spectrometry holds promise for broad implementation in hospital pharmacies and clinical laboratories.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"370-377"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unbound Ceftriaxone Concentrations in Plasma Measured Using Ultrafiltration Versus Equilibrium Dialysis.","authors":"Matthias Gijsen, Dorian Vanneste, Pieter Annaert, Yves Debaveye, Joost Wauters, Isabel Spriet","doi":"10.1097/FTD.0000000000001294","DOIUrl":"10.1097/FTD.0000000000001294","url":null,"abstract":"<p><strong>Background: </strong>Ceftriaxone is a first-line beta-lactam antibiotic used in diverse clinical settings. Owing to pharmacokinetic alterations, ceftriaxone therapeutic drug monitoring is currently recommended for patients in the intensive care unit. Ultrafiltration is typically used to measure unbound ceftriaxone concentrations, as it is less costly and time-consuming compared with equilibrium dialysis. However, the reference method, equilibrium dialysis, has not been compared with equilibrium dialysis for ceftriaxone to measure the unbound ceftriaxone concentrations. Therefore, unbound ceftriaxone fractions measured by ultrafiltration versus equilibrium dialysis were compared in patients in the intensive care unit.</p><p><strong>Methods: </strong>Total and unbound ceftriaxone plasma fractions were measured by ultrafiltration (9500 g at 37°C for 30 minutes) and equilibrium dialysis (12 kDa, 37°C for 4 hours) in 32 plasma samples from 28 patients who were critically ill collected during a previous prospective pharmacokinetic study. Passing-Bablok regression and Bland-Altman analyses were performed to evaluate the agreements between both methods.</p><p><strong>Results: </strong>The median (range) total ceftriaxone plasma concentration was 108.6 (5.2-233) mg/L. The median unbound concentration measured by equilibrium dialysis and ultrafiltration was 14.5 (0.7-52.9) and 23.3 (0.9-79.2) mg/L, respectively, showing a significant difference. Passing-Bablok regression analysis revealed significant proportional and systematic bias. This result was confirmed by Bland-Altman analysis, with a mean relative bias of 43.3% and wide agreement limits (-21% to 108%).</p><p><strong>Conclusions: </strong>Ultrafiltration substantially overestimates the unbound ceftriaxone fraction compared with equilibrium dialysis at 37°C. It is important to report methodological details and consider this information when interpreting unbound fractions of ceftriaxone and other drugs. These findings may impact the therapeutic drug monitoring of ceftriaxone.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"427-432"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Augmented Renal Clearance and Febrile Neutropenia on Initial Trough Level and Clearance of Teicoplanin.","authors":"Nozomi Kondo, Ryota Tanaka, Ryosuke Tatsuta, Haruka Tsushita, Takehiro Hashimoto, Kazufumi Hiramatsu, Hiroki Itoh","doi":"10.1097/FTD.0000000000001320","DOIUrl":"10.1097/FTD.0000000000001320","url":null,"abstract":"<p><strong>Background: </strong>Augmented renal clearance (ARC) and febrile neutropenia (FN) increase drug clearance primarily through glomerular filtration. In this study, we evaluated the influence of ARC and FN on dose-normalized trough concentration (C/D) and/or clearance of teicoplanin (TEIC) by comparing C/D between patients with ARC and non-ARC, and C/D and clearance between patients with FN and non-FN.</p><p><strong>Methods: </strong>This retrospective, single-center, observational cohort study enrolled 309 patients who received intravenous injections of TEIC between July 2016 and September 2021. Of the 94 patients who met the selection criteria, 25 satisfied the ARC definition, and 31 satisfied the FN definition. Using the Chronic Kidney Disease Epidemiology Collaboration formula, ARC was defined as an estimated glomerular filtration rate of 96.5 mL/min/1.73 m 2 or higher. FN was defined as an axillary temperature 37.5°C or higher and neutrophil count of less than 500/μL. TEIC clearance was estimated using a population pharmacokinetic model for adult Japanese patients with Bayesian estimation.</p><p><strong>Results: </strong>Compared with the non-ARC group (n = 69), the ARC group (n = 25) had a significantly lower first trough concentration ( P = 0.014) and lower C/D ( P = 0.009). By contrast, the FN (n = 31) and non-FN (n = 63) groups did not differ significantly in the first trough concentration, C/D, or clearance ( P = 0.294, 0.945, and 0.337, respectively). Forced-entry multiple regression analysis identified ARC as the only independent factor associated with C/D ( P = 0.001).</p><p><strong>Conclusions: </strong>A higher TEIC loading dose may be required for patients with ARC, regardless of the presence or absence of FN.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"385-392"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Approach for Improving the Detection and Quantitation of Buprenorphine and Its Metabolites in Maternal and Neonatal Hair.","authors":"Osama Y Alshogran, Wenchen Zhao, Elizabeth E Krans, Steve Caritis, Imam H Shaik, Raman Venkataramanan","doi":"10.1097/FTD.0000000000001291","DOIUrl":"10.1097/FTD.0000000000001291","url":null,"abstract":"<p><strong>Background: </strong>Buprenorphine (BUP) use is prevalent in pregnant women with opioid use disorder (OUD). Drug monitoring during pregnancy is critical for optimizing dosing regimen and achieving the desired clinical outcomes. Hair can be used as a critical biological matrix for monitoring long-term exposure to drugs. The aim of this study was to optimize the methodology used to quantify BUP and its metabolites in hair samples.</p><p><strong>Methods: </strong>Conditions for hair sample processing (ie, hair washing, incubation temperature, and extraction time) were optimized to maximize extraction recovery. The LC-MS/MS strategy employed here used 4 deuterated internal standards for quantifying BUP and its major metabolites [norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-G), and norbuprenorphine-glucuronide (NBUP-G)] in human hair samples. The optimized conditions were used to measure BUP and its metabolites in hair samples of 5 women undergoing OUD treatment and their neonates.</p><p><strong>Results: </strong>Unwashed hair samples processed by shaking with acetonitrile for 24 hours at 37 °C showed higher BUP (36%) and NBUP (67%) recovery, compared with those processed by incubation at room temperature. The standard curves showed excellent linearity over 0.05-100 ng/mL for BUP and NBUP and 0.1-200 ng/mL for BUP-G and NBUP-G. The assay was partially validated for reproducibility and accuracy and was successfully used for measuring BUP and metabolites in aforementioned hair samples. BUP was identified in all hair samples, while BUP-G was not. BUP was the primary analyte in maternal hair (median: 38.3 pg/mg; 25-75 percentile: 17-152.4 pg/mg), while NBUP-G was predominant in neonatal hair (median: 28.6 pg/mg; 25%-75% percentile: 1.9-112.8 pg/mg).</p><p><strong>Conclusions: </strong>The methodology used for quantifying BUP and its metabolites in hair samples of maternal female patients and their neonates is simple, accurate, and reproducible. The developed method may be useful for measuring fetal exposure to BUP during gestation.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"413-420"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and Pharmacodynamic Assessment of Valganciclovir in Infants With Congenital Cytomegalovirus Infection.","authors":"Kotaro Itohara, Kazuhiro Yamamoto, Shunsuke Fujinaka, Mari Hashimoto, Naoki Tamura, Yumi Kitahiro, Tomohiro Omura, Kazumichi Fujioka, Ikuko Yano","doi":"10.1097/FTD.0000000000001257","DOIUrl":"10.1097/FTD.0000000000001257","url":null,"abstract":"<p><strong>Background: </strong>Valganciclovir (VGCV) is administered at a dose of 16 mg/kg 2 times daily for 6 months to treat symptomatic congenital cytomegalovirus (CMV) infections. During the treatment period, approximately 20% of the patients developed grade 3 or higher neutropenia. Currently, information on the pharmacokinetics and pharmacodynamics of ganciclovir, an active metabolite of VGCV, in infants is limited. In the current study, the relationship between ganciclovir concentration and neutropenia was investigated, and a population pharmacokinetic (PPK) model of ganciclovir in infants with symptomatic congenital CMV infection was developed.</p><p><strong>Methods: </strong>Japanese infants who were prescribed oral VGCV for symptomatic congenital CMV infections between July 2017 and January 2021 were included. The relationship between the observed trough ganciclovir concentrations and neutrophil counts was examined. PPK analysis was performed to evaluate the covariates affecting the pharmacokinetics of ganciclovir.</p><p><strong>Results: </strong>Twenty-seven ganciclovir serum samples from 8 patients were analyzed. A moderate negative correlation was observed between the observed trough ganciclovir concentration and neutrophil count. PPK model analysis showed that postmenstrual age (PMA) affected the total body clearance of ganciclovir after correcting for the empirical allometric scaling of body weight. Based on PMA and body weight, a nomogram to achieve the target area under the concentration-time curve from 0 to 24 hours of 40-60 mcg·h·mL -1 of ganciclovir was calculated.</p><p><strong>Conclusions: </strong>The relationship between neutrophil count and ganciclovir trough concentration in infants was clarified. The PPK model showed that the dose of VGCV should be reduced in patients with a low PMA to achieve target exposure.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 3","pages":"393-399"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Plasma Cabozantinib Concentration With Treatment Response and Adverse Events in Japanese Patients With Advanced Renal Cell Carcinoma.","authors":"Shinichi Maruyama, Hiroaki Kobayashi, Tatsuru Hiraga, Tadatsugu Anno, Tansei Sanjo, Masashi Arai, Masaru Ishida, Hiroshi Kanno, Masaru Kato","doi":"10.1097/FTD.0000000000001254","DOIUrl":"10.1097/FTD.0000000000001254","url":null,"abstract":"<p><strong>Background: </strong>Cabozantinib is highly effective against advanced renal cell carcinoma (RCC). However, approximately 60% of the patients require a dose reduction due to severe adverse events. Although associations between trough concentrations of cabozantinib and its efficacy and safety have been reported in other countries, reports on Japanese patients are unavailable. Therefore, we investigated the association of cabozantinib trough concentration with therapeutic efficacy and adverse events in Japanese patients with RCC and evaluated the usefulness of therapeutic drug monitoring.</p><p><strong>Methods: </strong>In this prospective observational study, we measured the trough concentrations of cabozantinib in 10 Japanese patients with RCC enrolled between May 2022 and September 2023. The associations of trough concentration with treatment response, as determined by RECIST 1.1, and the occurrence of grade 2 or higher adverse events were assessed.</p><p><strong>Results: </strong>Trough concentration was higher in patients with controlled cancer than in those with progressive cancer (1024 ± 352 versus 457 ± 216 ng/mL, P = 0.035). In addition, patients with grade 2 or higher adverse events showed a significantly higher trough concentration than those without (1560 ± 513 versus 807 ± 319 ng/mL, P = 0.032). In particular, grade 2 or higher dysgeusia, anorexia, fatigue, and dyspepsia significantly correlated with trough concentrations.</p><p><strong>Conclusions: </strong>This is the first clinical study to demonstrate a correlation between cabozantinib trough concentration, therapeutic efficacy, and adverse events in Japanese patients with RCC. The therapeutic drug monitoring of cabozantinib could be useful for improving therapeutic efficacy and avoiding serious adverse events.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"400-406"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142112233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Polymorphisms Play an Important Role in the Drug Interaction Between Posaconazole and Tacrolimus in Renal Transplant Patients.","authors":"Nan Hu, Mengmeng Guan, Bin Gu, Xuping Yang, Qing Qian, Di Zhao, Hui Xue, Jingting Jiang","doi":"10.1097/FTD.0000000000001272","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001272","url":null,"abstract":"<p><strong>Background: </strong>Posaconazole (POSA), a second-generation triazole antifungal drug, inhibits CYP3A and P-glycoprotein. Here, the interaction between POSA and tacrolimus (TAC) in patients undergoing early renal transplantation was studied.</p><p><strong>Methods: </strong>Twenty-two renal transplant recipients who received POSA as antifungal therapy were studied. The following indicators were analyzed statistically: the blood concentration (C), dose (D), and concentration-dose ratio (C/D) of TAC before and after introducing POSA; the change of C/D (ΔC/D) after starting POSA; the genotypes of CYP3A5*3, ABCB1 3435, ABCB1 1236, and POR*28; other routine clinical indicators.</p><p><strong>Results: </strong>After starting POSA, the C, D, and C/D values of TAC were 1.29, 0.57, and 2.74 times the original values, respectively. A linear correlation was observed between the plasma levels of POSA and ΔC/D. The CYP3A5*3 gene polymorphism showed a significant impact on C, D, and C/D of TAC; however, it did not affect the ΔC/D. Polymorphism of the ABCB1 3435 gene had a significant effect on ΔC/D, and patients with the CC genotype in ABCB1 3435 had significantly lower ΔC/D than the CT/TT patients.</p><p><strong>Conclusions: </strong>In renal transplant patients, considerable interindividual variability was observed in the drug interactions between POSA and TAC. The genotypes of CYP3A5*3 and ABCB1 3435 and the plasma level of POSA had strong impact on the interaction between POSA and TAC.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 3","pages":"330-336"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the Accuracy and Clinical Utility of AFIAS-10 Point of Care Versus Enzyme-Linked Immunosorbent Assay in Therapeutic Drug Monitoring of Infliximab and Adalimumab.","authors":"Carles Iniesta-Navalón, Manuel Ríos-Saorín, Rebeca Añez-Castaño, Lorena Rentero-Redondo, Patricia Ortíz-Fernandez, Elena Marín-Armero Martínez, Elena Urbieta-Sanz","doi":"10.1097/FTD.0000000000001269","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001269","url":null,"abstract":"<p><strong>Background: </strong>New point-of-care (POC) techniques offer rapid results and address some of the limitations of traditional enzyme-linked immunosorbent assay (ELISA) methods, such as lengthy processing times and delays in therapeutic decision making. It is crucial to evaluate the comparability of POC assays with established ELISA methods to ensure accuracy and reliability in therapeutic drug monitoring. This study aimed to evaluate the analytical performance and clinical utility of the AFIAS-10 POC assay compared with the Promonitor ELISA for quantifying serum concentrations of infliximab (IFX) and adalimumab (ADA) and detecting antidrug antibodies (ATIs and ATAs).</p><p><strong>Methods: </strong>A prospective study was conducted from October 2023 to April 2024, including 225 samples from patients with immune-mediated diseases. The samples were analyzed using both AFIAS-10 POC and Promonitor ELISA assays. To assess the agreement between the 2 methods in terms of quantification, Bland-Altman analysis was performed by examining the mean difference and establishing limits of agreement.</p><p><strong>Results: </strong>The Pearson correlation coefficient indicated strong correlations for IFX (r = 0.932) and ADA (r = 0.967) between the 2 assays. The mean difference between POC and ELISA for IFX was -0.78 mcg/mL and for ADA was 1.54 mcg/mL, respectively. The POC assay tended to underestimate IFX concentrations and overestimate ADA concentrations compared with ELISA.</p><p><strong>Conclusions: </strong>The AFIAS-10 POC assay demonstrated good correlation and concordance with the ELISA method for the quantification of IFX and ADA, as well as for detecting anti-IFX and anti-ADA antibodies. However, this correlation was notably lower at higher drug concentrations.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 3","pages":"346-352"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lacosamide Pharmacokinetics and Retention in Japanese Patients With Epilepsy: A Retrospective Study on the Influence of Age, Comedications, and Cytochrome P450 2C19 Polymorphism.","authors":"Yoshiaki Yamamoto, Yuka Shiratani, Takuji Nishida, Naotaka Usui, Yoshiyuki Kagawa, Yukitoshi Takahashi, Katsumi Imai","doi":"10.1097/FTD.0000000000001278","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001278","url":null,"abstract":"<p><strong>Background: </strong>This retrospective study aimed to identify the genetic and nongenetic factors that influence serum lacosamide (LCM) concentrations and evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on the long-term retention rate of LCM.</p><p><strong>Methods: </strong>We analyzed serum samples from 1901 Japanese patients with epilepsy and compared the concentration-to-dose (CD) ratio of LCM among 4 age groups (preschool children, 1-5 years; primary school children, 6-11 years; adolescents, 12-17 years; and adults, ≥18 years). In addition, we performed CYP2C19 genotyping using real-time polymerase chain reaction in 302 patients and classified them into 3 groups: extensive metabolizers (EM: CYP2C19*1/*1), intermediate metabolizers (IM: CYP2C19*1/*2 or *1/*3), and poor metabolizers (PM: CYP2C19*2/*2, *3/*3, or *2/*3). We compared the LCM retention rates between the non-PM (EM and IM) and PM groups using the Kaplan-Meier method.</p><p><strong>Results: </strong>The adult group had the highest mean CD ratio, which was 33.7%, 21.9%, and 7.3% higher than that of preschool children, school children, and adolescents, respectively. The use of enzyme-inducing antiseizure medications (ASMs; ie, phenytoin, phenobarbital, or carbamazepine) reduced the CD ratio by 34.0% in preschool children, 27.3% in primary school children, 24.3% in adolescents, and 27.4% in adults. In adults, the mean CD ratios were 17.7% and 49.0% higher in the IM and PM groups, respectively, than in the EM group. The 3-year retention rate of LCM was higher in the non-PM group than in the PM group (881 vs. 728 days; log-rank test, P < 0.05).</p><p><strong>Conclusions: </strong>Age and the concomitant use of enzyme-inducing ASMs influence LCM pharmacokinetics. In addition, patients with the PM phenotype have a high LCM CD ratio, which may decrease treatment retention. Therapeutic drug monitoring for LCM is a clinically useful method for evaluating pharmacokinetics in individual patients and optimizing the dose of LCM.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 3","pages":"407-412"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision Dosing of Intravenous Tocilizumab: Development of Pharmacokinetic Model-Derived Tapering Strategies for Patients With Rheumatoid Arthritis.","authors":"Femke Hooijberg, Stefan P H van den Berg, Zohra Layegh, Maureen Leeuw, Ori Elkayam, Annick de Vries, Mike Nurmohamed, Theo Rispens, Thomas P C Dorlo, Gertjan Wolbink","doi":"10.1097/FTD.0000000000001258","DOIUrl":"10.1097/FTD.0000000000001258","url":null,"abstract":"<p><strong>Background: </strong>Tocilizumab targets the interleukin-6 receptor, and dosing is complex owing to its nonlinear clearance related to target binding. Therefore, tapering tocilizumab requires a different approach than that of tumor necrosis factor inhibitors (TNFi). This study aimed to identify these differences and enable personalized treatment of rheumatoid arthritis (RA) beyond TNFi therapy.</p><p><strong>Methods: </strong>A population pharmacokinetic model of intravenous tocilizumab was developed using data from a randomized controlled trial of dose tapering in patients with RA. Subsequent population-level Monte Carlo and individual Bayesian simulations were performed to create tapering strategies involving dose reduction and interval extension. The target trough concentration of tocilizumab was 5 mg/L. Finally, the drug savings were compared between the 2 methods.</p><p><strong>Results: </strong>The pharmacokinetic of tocilizumab was described with a 2-compartment model with parallel linear (CL 0.20 L/d) and nonlinear (V M 5.2 mg/d, K M 0.19 mg/L) elimination. The linear clearance rate and central volume of distribution increased with lean body mass, and men exhibited higher clearance rates than women. The simulated concentration-time profiles demonstrated that, owing to nonlinear clearance, drug concentrations decreased more than dose-proportionally with lower doses. Tapering based on an individual Bayesian approach emerged as the most promising strategy, yielding a 39% reduction in drug use across virtual populations.</p><p><strong>Conclusions: </strong>Tapering strategies were developed for intravenous tocilizumab, offering potential application in patients with RA who have reached low disease activity or remission, pending clinical validation. The developed strategies demonstrate that the tapering of tocilizumab should be approached more carefully and in smaller steps than that of TNFi.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"337-345"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}