Therapeutic Drug Monitoring最新文献

{"title":"Vancomycin Dosing Assessment in a Tunisian Pediatric Population.","authors":"Safa Souissi, Syrine Ben Hammamia, Mouna Ben Sassi, Mouna Daldoul, Hanene El Jebari, Mohamed Zouari, Rim Charfi, Riadh Daghfous, Emna Gaies, Sameh Trabelsi","doi":"10.1097/FTD.0000000000001358","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001358","url":null,"abstract":"<p><strong>Background: </strong>Vancomycin is a glycopeptide antibiotic indicated in patients suffering from infections caused by gram-positive bacteria. Therapeutic drug monitoring is crucial because of its high interindividual variability, especially in pediatric populations. However, validated data guiding vancomycin monitoring in pediatric patients are lacking. This study aimed to assess vancomycin plasma concentrations in a Tunisian pediatric population according to patient's age and administration mode.</p><p><strong>Methods: </strong>A retrospective study was conducted at department of Clinical Pharmacology of National Pharmacovigilance Center. It obtained approval from the Institutional Review Board at Charles Nicolle Hospital in Tunis, Tunisia. Patients included in this study were classified by age. Only vancomycin levels associated with initial doses were evaluated. Continuous and intermittent infusion modes were assessed.</p><p><strong>Results: </strong>The study included 146 patients. Each age group was separately evaluated. Only 11.8% of initial trough concentrations were within the therapeutic range with an average dosage of 38 mg/kg/d. Using the continuous infusion, 29.5% of initial concentrations reached the therapeutic range with an average vancomycin dose of 44 mg/kg/d. Only 20.5% of plasma concentrations during continuous infusion were supratherapeutic, compared with intermittent infusion (29.4%). Infants and children required higher daily doses to achieve therapeutic range. Lower doses were needed for prematurely born neonates.</p><p><strong>Conclusions: </strong>Although numerous studies have evaluated vancomycin prescribing practices in pediatric populations, clinical data validating recent recommendations remain lacking. More personalized dosing approaches, including Area Under the Curve-guided monitoring, should be established.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601696","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 CYP3A4 Methylation on Tacrolimus Pharmacokinetics.","authors":"Karel K M Koudijs, Oumaima Etsouli, Costanza L Vallerga, Dirk Jan A R Moes, Bastian N Ruijter, Jesse J Swen, Minneke J Coenraad, Teun van Gelder","doi":"10.1097/FTD.0000000000001351","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001351","url":null,"abstract":"<p><strong>Background: </strong>Common genetic variants in CYP3A4 together only explain a limited amount of the variability in tacrolimus clearance. This cross-sectional study aimed to explore the extent to which pharmacokinetic variability can be explained by methylation of the CYP3A4 gene.</p><p><strong>Methods: </strong>Residual tissue material from liver biopsies routinely collected 6 months post-transplantation was used. Inclusion criteria were tacrolimus once daily (Advagraf) in a steady state (ie, no dose change in the previous 3 days); assessment of tacrolimus pharmacokinetics within 3 weeks of the biopsy; and no documented episode of rejection for at least 3 months prior. Patients and liver donor tissue were genotyped. Only patients in which the patient and the donor had a genotype that did not express the CYP3A5 protein were included. The liver biopsy tissue material was then analyzed using an Illumina Infinium MethylationEPIC array.</p><p><strong>Results: </strong>Of the 28 patients who met the inclusion criteria, 23 passed the quality control assessment required for the methylation analysis. Increased methylation of 1 of the 10 methylation probes within the CYP3A4 gene region (cg19046783) was positively correlated (Spearman correlation coefficient, 0.52) with the dose-normalized area under the concentration versus time curve (AUC)0-24h (P = 0.01). When quantified using univariate linear regression, this probe explained 18% of the variation in the dose-normalized AUC0-24h. Interestingly, cg19046783 had the lowest mean methylation and highest biological variation.</p><p><strong>Conclusions: </strong>Increased methylation of 1 of the 10 methylation probes within the CYP3A4 gene region (cg19046783) was positively correlated with increased dose-normalized AUC0-24h, which explained 18% of the variation in the dose-normalized AUC0-24h using univariate linear regression.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601695","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 Characterization of Rituximab in Patients with Glomerular Diseases.","authors":"María Larrosa-García, Irene Agraz Pamplona, María Teresa Sanz Martínez, Roxana Paola Bury Macías, Mónica Martínez Gallo, Roger Colobran, Sonia García García, María José Soler, Manuel Hernández González, José Bruno Montoro Ronsano","doi":"10.1097/FTD.0000000000001353","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001353","url":null,"abstract":"<p><strong>Background: </strong>Rituximab is commonly used to treat patients with primary glomerular diseases; however, its pharmacokinetics in this population have not been fully described yet.</p><p><strong>Materials and methods: </strong>This single-center, open-label, uncontrolled clinical trial included adult patients with glomerular diseases who required rituximab treatment (NEFRTX; EudraCT: 2020-000484-23). Patients received 1 or 0.5 g of rituximab on day 1 (and d14 in some cases). Blood and urine samples were collected at days 1, 7, 14, 28, and 45 to measure biochemical parameters (proteinuria, albuminemia, plasma immunoglobulin, and urine immunoglobulin), rituximab, and antidrug antibody concentrations. The gene encoding the neonatal fragment-crystallizable receptor was also characterized. Linear regression and Win-Nonlin 1.1 were used for pharmacokinetic analysis.</p><p><strong>Results: </strong>Thirty-five cases (30 patients) were included in this study. Pharmacokinetic parameters were expressed as mean (SD): maximum plasma concentration, 179.4 (71.8) mcg/mL; volume of distribution, 78.9 (31.4) mL/kg; clearance, 0.30 (0.27) mL/h/kg; half-life (t1/2), 11.6 (5.8) d; elimination rate constant, 0.0036 (0.0030) hour-1; and area under the curve, 117,756.1 (88,228.1) mcg·h/mL. Antidrug antibody was detected on d1 in 3 cases (8.6%) and was negative by d28.Rituximab t1/2 was represented by the formula: t1/2 = A-B·Log (Proteinuria)+C·Albuminemia, where A = 515.1 (128.8-901.3), B = 182.1 (-108.6 to -35.4), and C = 39.5 (-10.9 to 89.9).There were significant differences in rituximab t1/2 based on diagnosis (P = 0.025), early treatment (P = 0.008), proteinuria >2.4g/24h (P < 0.001), plasma immunoglobulin <650 mg/dL (P = 0.048), and detectable urine immunoglobulin (P = 0.018).</p><p><strong>Conclusions: </strong>Albuminemia and proteinuria affect rituximab t1/2 and drug exposure in patients with glomerular diseases. Patients with proteinuria >2.4g/24h may require higher frequent dosing for adequate rituximab exposure. Establishing an optimal dosing regimen in this population remains warranted.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144508386","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":"\"Goofballing\": An Emerging Threat With Clinical Challenges-A Short Communication.","authors":"Guillaume Drevin, Marie Briet, Séverine Ferec, Chadi Abbara","doi":"10.1097/FTD.0000000000001354","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001354","url":null,"abstract":"<p><strong>Background: </strong>The coinjection of methamphetamine and opioids, known as \"goofballing,\" is an emerging practice among people who inject drugs. This combination poses significant clinical challenges due to the opposing pharmacological effects of stimulants and depressants. The increasing prevalence of this practice, particularly in North America, raises significant concerns regarding its impact on public health and patient management.</p><p><strong>Material and methods: </strong>The authors report the case of a 48-year-old man admitted to the intensive care unit with suspected sepsis after intravenous heroin use. During methadone substitution therapy, the patient developed hyperthermia, diffuse myalgia, and mild somnolence. Physical investigation revealed no evidence of infection. Toxicological analyses were conducted on blood and urine samples using targeted and nontargeted screening methods.</p><p><strong>Results: </strong>Toxicological analyses revealed the presence of methamphetamine, amphetamine (a metabolite of methamphetamine), morphine, codeine, methadone, and EDDP in both blood and urine. The presence of 6-acetylmorphine in the urine confirmed recent heroin exposure. No other substances were detected in any sample. The patient was later treated for coinjection of heroin and methamphetamine, which supported the diagnosis of goofballing-induced hyperthermia rather than sepsis.</p><p><strong>Conclusions: </strong>This case highlights the diagnostic challenges associated with the \"goofball\" phenomenon. The coadministration of methamphetamine and heroin can lead to severe atypical toxicological symptoms. Health care providers should be aware of this emerging practice to ensure rapid diagnosis and appropriate management. Public health initiatives should focus on harm reduction strategies to mitigate associated risks.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333926","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":"Optimization of Teicoplanin Dosing Regimen in Adult Patients Using an Externally Evaluated Population Pharmacokinetic Model.","authors":"Xiaojing Li, Qiang Sun, Genzhu Wang, Xiaoying Wang, Baiqian Xing, Zhikun Xun, Zhongdong Li","doi":"10.1097/FTD.0000000000001349","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001349","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to identify population pharmacokinetic models suitable for optimizing individualized teicoplanin dosing regimens in adult Chinese patients.</p><p><strong>Methods: </strong>PubMed and Web of Science were searched for teicoplanin population pharmacokinetic models developed for the general adult population. Patient data used for the external evaluation, including demographics, teicoplanin-related information (administration and blood concentration), and laboratory test values, were collected from the Beijing Electric Power Hospital. External evaluation was performed using the Nonlinear Mixed-Effects Modeling software. Models with excellent predictive abilities were identified, and Monte Carlo simulations were conducted.</p><p><strong>Results: </strong>A total of 66 teicoplanin concentrations used for external evaluation were obtained from 62 patients. The model built by Ogami et al performed excellently, with a bias of -7.56% and inaccuracy of 26.28%. The model consisted of the following parameters: clearance (L/h) = (0.379 + 0.211 × creatinine clearance/100) × (total body weight/70)0.75; volume (V) 1 (L) = 38.2 × (fat-free mass/70); Q (L/h) = 2.42 × (total body weight/70)0.75; V2 (L) = 106 × (fat-free mass/70). The model was subsequently used in Monte Carlo simulations (n = 1000). For general infections (minimum plasma concentration [Cmin] = 10-15 mg/L), the loading dose (LD) and maintenance dose (MD) of teicoplanin should be at least 400 mg to achieve the target concentration. For endocarditis or severe infections, where a target concentration (Cmin = 15-30 mg/L) is required, LD should be at least 800 mg. Alternatively, the LD and MD of teicoplanin should be at least 600 mg to achieve desired therapeutic levels.</p><p><strong>Conclusions: </strong>By combining external evaluations using Nonlinear Mixed-Effects Modeling with Monte Carlo simulations, the model developed by Ogami et al was identified as the most suitable for guiding clinical dosing under different pathophysiological conditions.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289671","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":"The Rational Basis for Personalized Treatment Using Concentration-Guided Dosing.","authors":"Nick Holford, Zvonimir Petric","doi":"10.1097/FTD.0000000000001350","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001350","url":null,"abstract":"<p><strong>Background: </strong>The purpose of the review is to explain and encourage the use of terminology that distinguishes between the steps of measurement and reporting of concentrations, interpretation of the measurements, and subsequent prediction of individualized doses. The principles of concentration-guided dosing (CGD) provide a rational basis for personalized dosing. Existing terminology such as therapeutic drug monitoring (TDM) or model-informed precision dosing (MIPD) may have multiple meanings or be imprecisely defined. A brief history of CGD reveals the evolution of more accurate terminology focused on using concentration observations to provide individual drug dose guidance to clinicians.</p><p><strong>Methods: </strong>Relevant literature was identified using keyword searches such as \"TDM,\" \"therapeutic range,\" \"individualized dosing,\" \"target concentration intervention,\" \"precision dosing,\" \"MIPD,\" and \"personalized dosing.\" Studies were included if they addressed the theoretical basis, clinical implementation, and/or effectiveness of CGD approaches. The findings were synthesized to underscore the relevance of a CGD approach in the context of clinical pharmacology.</p><p><strong>Results: </strong>CGD is commonly implemented using either the therapeutic window approach (TWA) or the target concentration approach (TCA). The dosing approach is often not specified for TDM and MIPD. Clinicians, clinical pharmacologists, and pharmacists have typically been trained to view TWA as the gold standard for personalized dosing.</p><p><strong>Conclusions: </strong>Although many clinicians are well-versed in dosing using TWA, understanding and awareness of the benefits of TCA are still lacking. TCA offers accurate, personalized treatment by guiding the clinical team to use an optimally effective and safe dose for each patient.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259003","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":"Machine Learning Modeling for Predicting Infliximab Pharmacokinetics in Pediatric and Young Adult Patients With Crohn Disease: Leveraging Ensemble Modeling With Synthetic and Real-World Data.","authors":"Kei Irie, Phillip Minar, Jack Reifenberg, Brendan M Boyle, Joshua D Noe, Jeffrey S Hyams, Tomoyuki Mizuno","doi":"10.1097/FTD.0000000000001348","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001348","url":null,"abstract":"<p><strong>Background: </strong>Predicting infliximab pharmacokinetics (PK) is essential for optimizing individualized dosing in pediatric patients with Crohn disease (CD). Machine learning (ML) has emerged as a tool for predicting drug exposure; however, its development typically requires large datasets. This study aimed to develop an ML model for infliximab PK prediction by leveraging population PK model-based synthetic and real-world data.</p><p><strong>Methods: </strong>An initial ML model was trained using the XGBoost algorithm with synthetic infliximab concentration data (n = 560,000) generated from an established pediatric PK model. The prediction errors were assessed using real-world data, including 292 plasma concentrations from 93 pediatric and young adult patients with CD. A second XGBoost model, incorporating clinical features, was used to correct these errors. The performance of the model was evaluated using the root mean square error (RMSE) and mean prediction error (MPE).</p><p><strong>Results: </strong>The first ML model yielded RMSE and MPE values of 6.44 and 1.84 mcg/mL, respectively. The features of the second XGBoost model included the predicted infliximab concentrations, cumulative dose, and dosing interval duration. A 5-fold cross-validation demonstrated improved performance of the ensemble model (RMSE = 4.30 ± 1.09 mcg/mL, MPE = 0.21 ± 0.39 mcg/mL) compared with the initial model and was comparable with the Bayesian approach (RMSE = 4.81 mcg/mL, MPE = -0.67 mcg/mL).</p><p><strong>Conclusions: </strong>This study demonstrated the feasibility of combining synthetic and real-world data to develop an ML-based approach for infliximab PK prediction, potentially enhancing precision dosing in pediatric CD.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216943","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":"Serum Lenvatinib Concentration Monitoring in a Patient With Thyroid Cancer Exhibiting Hand-Foot Syndrome.","authors":"Yusuke Watanabe, Kosuke Doki, Ikuo Sekine, Hisato Hara, Masato Homma","doi":"10.1097/FTD.0000000000001312","DOIUrl":"10.1097/FTD.0000000000001312","url":null,"abstract":"<p><strong>Background: </strong>Hand-foot syndrome (HFS) is a common adverse event associated with lenvatinib treatment. Lenvatinib dose adjustment using therapeutic drug monitoring may be beneficial in the management of HFS, as symptoms improve with dose reduction or treatment interruption. The serum lenvatinib levels were monitored in a patient with lenvatinib-induced HFS.</p><p><strong>Case presentation: </strong>A 74-year-old woman was administered lenvatinib (24 mg/d) for papillary thyroid cancer. Although lenvatinib was withheld several times owing to the occurrence of HFS, the severity of the HFS was controlled to within grade 1 by reducing the dose to 4 mg/d. The lenvatinib dose was subsequently increased to 8 mg/d owing to the progression of lung metastases, resulting in increased HFS severity. The association between serum lenvatinib levels and the severity of HFS was examined in this case: serum lenvatinib levels were higher in grade 2 HFS than in grade 1 HFS (median 42.1 vs. 22.5 ng/mL; P < 0.05).</p><p><strong>Conclusions: </strong>This case's findings suggest that serum lenvatinib concentrations are associated with the severity of lenvatinib-induced HFS and that there may be an overlap between drug concentrations, metastatic suppression, and the grade of HFS.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"323-325"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528009","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":"Nifedipine May Be an Inhibitor of Clozapine Metabolism as Seen in 5 Patients: 2 From a US Double-Blind Study and 3 From a German Therapeutic Drug Monitoring Study.","authors":"Georgios Schoretsanitis, Ekkehard Haen, Hélène Verdoux, Michael Paulzen, Jose de Leon","doi":"10.1097/FTD.0000000000001277","DOIUrl":"10.1097/FTD.0000000000001277","url":null,"abstract":"<p><strong>Background: </strong>Clozapine is the only licensed antipsychotic for treatment-refractory schizophrenia. Therapeutic drug monitoring (TDM) refers to the measurement of clozapine concentration. Clozapine TDM can be used to optimize treatment, particularly by identifying pharmacokinetic interactions between clozapine and comedications.</p><p><strong>Methods: </strong>We identified 5 cases of patients with available clozapine concentrations who were concomitantly receiving nifedipine and clozapine. These cases were drawn from 2 independent datasets: 2 from a double-blind, randomized clinical trial in the United States and 3 from a German TDM naturalistic database. As an index of clozapine clearance, we used the trough-level concentration-to-dose (C/D) ratios to estimate the minimum therapeutic doses. To estimate dose-correction factors for nifedipine treatment, we included only clozapine concentrations at steady state. We divided the clozapine minimum therapeutic doses (MTD) from the on-condition by the off-nifedipine condition.</p><p><strong>Results: </strong>In 4 patients, the ratio of on/off nifedipine for MTD ranged between 0.58 and 0.82. Another patient had no data and had to be compared with published control data (female smoker of African ancestry), providing a correction factor of 0.52 after eliminating 5 concentrations contaminated by the development of obesity.</p><p><strong>Conclusions: </strong>In the absence of access to TDM, when prescribing nifedipine to clozapine-treated patients, we recommend reducing the daily dose of clozapine by one-third because of the weak inhibition of clozapine metabolism. With access to TDM, TDM should guide dosing as unusual patients may need larger dose reductions, as it is possible that in some patients, nifedipine may be a moderate inhibitor requiring halving clozapine dose. Further prospective studies are warranted.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":"47 3","pages":"438-441"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027555","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":"Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Voriconazole for Predicting the Clinical Outcomes of Adult Patients With Invasive Aspergillosis.","authors":"Monchai Duangpraphat, Richard C Wilson, Timothy M Rawson, Wichai Santimaleeworagun, Worapong Nasomsong, Alison H Holmes, Vasin Vasikasin","doi":"10.1097/FTD.0000000000001268","DOIUrl":"10.1097/FTD.0000000000001268","url":null,"abstract":"<p><strong>Background: </strong>Voriconazole is the first-line therapy for invasive aspergillosis (IA). To determine the minimum inhibitory concentration of Aspergillus, a voriconazole pharmacokinetic-pharmacodynamic (PK-PD) model linked to galactomannan response was developed and evaluated, and its clinical correlation for IA treatment was elucidated.</p><p><strong>Methods: </strong>Adult patients with probable or definite IA and at least one serum voriconazole measurement were included. A two-compartment voriconazole PK model was linked to a previously described PD model of galactomannan response. PK and PD parameters were estimated using a nonparametric adaptive grid technique. The relationship between the ratio of voriconazole exposure that induced half-maximum galactomannan response (EC50) and the observed terminal galactomannan concentration was evaluated. The factors associated with the PK-PD parameters and mortality were also determined.</p><p><strong>Results: </strong>Between January 2013 and December 2022, 41 patients were prescribed voriconazole for IA. The 30-day mortality rate was 17%. A high correlation was found for the observed-predicted Bayesian posterior estimates of voriconazole and galactomannan levels. Moreover, a nonlinear relationship was identified between AUC:EC50 and terminal galactomannan. The factors associated with higher AUC:EC50 were intravenous administration and intubation. In the survival analysis, higher EC50 tended to be associated with mortality, higher AUC was significantly associated with increased mortality, and higher AUC:EC50 tended to be associated with higher mortality. After adjusting for the intravenous route, higher AUC and AUC:EC50 were not associated with mortality.</p><p><strong>Conclusions: </strong>Individual EC50 estimation can provide insights into in vivo host and organism responses. Elevated EC50 showed comparable and unfavorable trends to higher minimum inhibitory concentration. Thus, determining EC50 might help guide individualized target serum voriconazole levels.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"378-384"},"PeriodicalIF":2.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508530","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}