Therapeutic Drug Monitoring最新文献

{"title":"The Effect of Age on Antipsychotic Serum Concentration in Males and Females: A Study Based on Therapeutic Drug Monitoring Data From 19,926 Patients.","authors":"Vigdis Solhaug, Ragnhild Birkeland Waade, Espen Molden, Elisabet Størset, Gudrun Høiseth, Marit Tveito","doi":"10.1097/FTD.0000000000001309","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001309","url":null,"abstract":"<p><strong>Background: </strong>Antipsychotic medications are commonly prescribed for older patients; however, documentation on their safety and efficacy in this population is limited. This study aimed to investigate and compare the effect of age on dose-adjusted serum concentrations of 6 commonly used antipsychotic medications in both sexes.</p><p><strong>Methods: </strong>Patients with serum concentration measurements of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, and zuclopenthixol were retrospectively included from a therapeutic drug monitoring service. The primary outcome measure for each antipsychotic was the dose-adjusted serum concentration (C:D ratio), assessed across groups divided by sex and age (18-49 years, 50-74 years, and ≥75 years). The data were analyzed using linear mixed modeling with restricted maximum likelihood estimation.</p><p><strong>Results: </strong>A total of 19,926 patients (53% male) with 74,194 serum concentration measurements were included. For most antipsychotics, the C:D ratios increased significantly with age, with generally larger differences observed in females compared with males. The largest impact of age was observed for risperidone, where C:D ratios in the age groups 50-74 years and ≥75 years were 20% and 81% higher for males, respectively, compared with the reference group (18-49 years). For females, the C:D ratios were 28% and 92% higher, respectively, compared with females aged 18-49 years (all P < 0.001). The smallest impact of age was observed for aripiprazole, with no significant differences in C:D ratios across age groups for males. For females treated with aripiprazole, C:D ratios were 8% and 28% higher in the 50-74 and ≥75 years age groups, respectively, compared with females aged 18-49 years (both P < 0.001).</p><p><strong>Conclusions: </strong>The age-dependent increase in dose-adjusted serum concentrations among males and females varied across different antipsychotics and was highest for risperidone. These findings emphasize the importance of proper monitoring of antipsychotic use in older adults.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492534","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":"A Sensitive Ultrafiltration Plus RP-HPLC-FLD Method to Quantify Total and Free Perampanel Concentrations in the Plasma of Patients With Epilepsy: A Fully Validated Assay With Clinical Application.","authors":"Zhonghua Dong, Peng Wang, Xueyan Cui, Jinjuan Liu, Haiyan Shi, Yilei Yang, Jingya Xu, Qiaoyan Yi","doi":"10.1097/FTD.0000000000001311","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001311","url":null,"abstract":"<p><strong>Background: </strong>Perampanel (PER), a novel antiepileptic drug, exhibits high protein binding. Given the drug's susceptibility to various factors, including drug interactions, and the considerable variability in blood concentrations among individuals, solely measuring the total plasma concentration of PER may not provide comprehensive insights. This study aimed to establish an HPLC-FLD method to quantify both total and free PER in clinical samples.</p><p><strong>Methods: </strong>Analysis of total PER involved a straightforward sample preparation process involving plasma protein precipitation. Plasma samples were ultrafiltered to isolate the free portion of PER. Chromatographic separation was achieved on an InertSustain C18 column at a 1-mL/min flow rate using a gradient of acetonitrile and aqueous sodium acetate buffer at pH 4.4.</p><p><strong>Results: </strong>Calibration curves for total and free PER in plasma exhibited excellent linearity over the concentration ranges of 10-3000 and 0.5-100 ng/mL, respectively. The method was applied to analyze blood samples from patients with epilepsy quantitatively; the total concentration of perampanel in the plasma of the patients was in the range of 90.45-563.39 ng/mL, whereas the free concentration was in the range of 1.82-15.29 ng/mL. The plasma protein binding ratio of perampanel was normally between 97.09% and 99.29% and decreased in cases of hypoproteinemia.</p><p><strong>Conclusions: </strong>The method was rigorously validated for selectivity, accuracy, precision, and stability in accordance with established FDA and EMA guidelines. The developed method enables the rapid and accurate quantification of both total and free PER concentrations in the plasma of patients with epilepsy, offering technical support for its subsequent clinical application.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441949","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":"Predictive Performance of Bayesian Dosing Software for Vancomycin in Intensive Care Unit Patients.","authors":"Gali Bai, Hui Qi, Yaqun Huang, Jiao Zhang, Huiying Zhao, Ruiting Wen, Xiaohong Zhang","doi":"10.1097/FTD.0000000000001310","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001310","url":null,"abstract":"<p><strong>Background: </strong>According to the updated guidelines, Bayesian-derived area under the curve estimation is recommended to guide vancomycin dosing. However, the Bayesian dosing software that facilitates this procedure has not been adequately assessed in intensive care unit (ICU) patients. This study evaluated the performance of 3 commonly used Bayesian software programs in predicting vancomycin concentrations in ICU patients before they could be utilized for personalized dosing in this population.</p><p><strong>Methods: </strong>Retrospective data from adult ICU patients who were administered vancomycin intravenously were obtained to predict serum concentrations a priori (based solely on patient characteristics) or a posteriori (Bayesian forecasting using measured concentrations). The predictive performance was evaluated via bias and precision using relative bias (rBias) and relative root mean squared error, respectively.</p><p><strong>Results: </strong>Data from 139 patients with 284 vancomycin concentrations were evaluated using 3 software programs: SmartDose (He model), Pharmado (Yasuhara model), and PrecisePK (Rodvald and Goti model). All 3 programs showed clinically acceptable bias with the exception of the Goti model of PrecisePK in an a priori estimation (rBias, 27.44%). A relatively low level of precision in terms of relative root mean squared error was observed in all these programs, but with a marked improvement in the a posteriori estimation (27.69%-37.64%) compared with the a priori situation (45.12%-68.59%).</p><p><strong>Conclusions: </strong>Bayesian dosing software is a potential tool for vancomycin dose optimization in ICU patients. Patients with different physiological and pathological features may be referred to specific Bayesian programs.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442037","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":"External Evaluation of Longitudinal Population Pharmacokinetic Models of Vancomycin in Patients With Osteoarticular Infections.","authors":"Van Dong Nguyen, Alice Côté, Amélie Marsot","doi":"10.1097/FTD.0000000000001303","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001303","url":null,"abstract":"<p><strong>Background: </strong>Osteoarticular infections pose a challenge for therapeutic drug monitoring of vancomycin because they often require prolonged treatment. Given the extensive renal elimination of vancomycin, its pharmacokinetic properties are difficult to predict in the later stages of treatment because the risk of nephrotoxicity increases with the duration of treatment. In this study, published longitudinal population pharmacokinetic (popPK) models were externally evaluated in a cohort of patients with osteoarticular infections.</p><p><strong>Methods: </strong>A literature search was performed in PubMed/EMBASE and published reviews. The predictive performance of the selected models was assessed through prediction- and simulation-based diagnostics using NONMEM software. Data were collected during both the retrospective and prospective phases, during which prospectively recruited patients provided additional vancomycin concentrations.</p><p><strong>Results: </strong>The external validation dataset comprised 525 vancomycin concentrations obtained from 73 patients treated for osteoarticular infections at Montréal General Hospital. Two published popPK models that provided different approaches for integrating a longitudinal structure were identified. Both failed to meet the clinically acceptable threshold of imprecision in population predictions. The weighted median absolute prediction error ranged from 34.9% to 48.3% before re-estimation of model parameters and from 33.5% to 35.2% after re-estimation. The re-estimated models tended to underpredict vancomycin concentrations in the later stages of treatment.</p><p><strong>Conclusions: </strong>The 2 evaluated models showed poor predictive performance in our local study population. Further studies should explore new strategies to incorporate a longitudinal component and consider other relevant clinical covariates to develop improved longitudinal popPK models for vancomycin.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399918","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":"Development of a UHPLC-MS/MS Method for the Determination of Omadacycline in Human Plasma.","authors":"Chuang Chen, Yao-Jie Chen, Jing Fu, Yu-Zhen Wang, Sun-Ting Qin, Meng-Yu Kong, Guan-Yang Lin, Xiu-Hua Zhang, Xu-Ben Yu","doi":"10.1097/FTD.0000000000001308","DOIUrl":"10.1097/FTD.0000000000001308","url":null,"abstract":"<p><strong>Abstract: </strong>Omadacycline is a novel aminomethylcycline antibiotic that retains its antibacterial activity against strain-specific efflux pumps and ribosomal protective protein mechanisms of tetracycline resistance. To determine the concentration of omadacycline in human plasma, an ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to provide a basis for therapeutic monitoring of omadacycline in clinical settings. The experimental approach involves using an ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 μm), with a mobile phase of 0.1% aqueous formic acid:acetonitrile (90:10, vol/vol), a flow rate of 0.3 mL·min -1 , a column temperature of 40°C, and an injection volume of 0.1 μL. Protein precipitation was employed as pretreatment, using acetonitrile as the precipitant. Minocycline was used as an internal standard. Omadacycline and internal standard were monitored in positive ion mode with the following mass transition pairs: mass/charge (m/z) = 557.1→ 470.1 for omadacycline, and m/z = 458.3→ 440.9 for IS, respectively. The established method showed a good linearity in the range of 0.01-10 mcg/mL of omadacycline (Y = 0.4603X + 0.0452, r 2 = 0.999), with the lower limit of quantification of 0.01 mcg/mL. Method validation included accuracy, precision, matrix effect, recovery, carryover, dilution integrity, and stability, all of which met the requirements of the US Food and Drug Administration for the validation of bioanalytical methods. This method has been successfully applied to therapeutic drug monitoring in patients.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399917","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":"Eltrombopag-Induced Falsely Elevated Bilirubin Concentrations in Enzymatic and Vanadate Oxidation Assays: Involvement of High Serum Eltrombopag Concentrations.","authors":"Shun Oda, Kosuke Doki, Naoshi Obara, Yoshiharu Suzuki, Shigeru Chiba, Masato Homma","doi":"10.1097/FTD.0000000000001307","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001307","url":null,"abstract":"<p><strong>Background: </strong>The administration of eltrombopag, used to restore low blood count, demonstrates a positive interference of blood bilirubin levels when analyzed through the diazo assay. However, research on bilirubin measurements using other methods is limited. Therefore, using an enzymatic assay, this study aimed to investigate the effect of serum eltrombopag on bilirubin measurements in patients with aplastic anemia. It further assessed the concentration-dependent effect of eltrombopag on bilirubin measurements using enzymatic and vanadate oxidation assays.</p><p><strong>Methods: </strong>Total and conjugated bilirubin concentrations measured using an enzymatic assay and serum eltrombopag concentrations were examined in 227 serum samples collected from 30 patients with aplastic anemia receiving eltrombopag. Eltrombopag-spiked samples were analyzed using the enzymatic and vanadate oxidation assays for total and conjugated bilirubin to determine its concentration-dependent effects.</p><p><strong>Results: </strong>A strong positive correlation was observed between total bilirubin and serum eltrombopag concentrations in patients receiving eltrombopag (r = 0.820). However, the correlation between conjugated bilirubin and serum eltrombopag concentrations was weaker (r = 0.413). In eltrombopag-spiked serum samples, the enzymatic assay showed significant false elevation of total bilirubin concentrations at ≥6.0 mcg/mL; no interference with conjugated bilirubin measurements was observed. The vanadate oxidation assay showed mild positive biases of 0.2 and 0.1 mg/dL for total and conjugated bilirubin concentrations, respectively, at a high eltrombopag concentration (50 mcg/mL).</p><p><strong>Conclusions: </strong>Eltrombopag causes clinically significant concentration-dependent interference in total blood bilirubin, but not in conjugated bilirubin measurements through the enzymatic assay in patients with aplastic anemia. The vanadate oxidation assay may be used as an alternative to measure total blood bilirubin when the eltrombopag concentration is below 50 mcg/mL.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256698","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":"Population Pharmacokinetics of Perampanel in Chinese Pediatric and Adult Patients With Epilepsy.","authors":"Jiayu Yang, Sitian Zhang, Zhigang Zhao, Shenghui Mei, Weixing Feng","doi":"10.1097/FTD.0000000000001296","DOIUrl":"https://doi.org/10.1097/FTD.0000000000001296","url":null,"abstract":"<p><strong>Background: </strong>Perampanel is a promising epilepsy treatment with an innovative mechanism of action. This study was performed to investigate the factors affecting perampanel clearance in a population pharmacokinetic (PPK) model of Chinese pediatric and adult patients with epilepsy.</p><p><strong>Methods: </strong>A total of 135 perampanel plasma concentrations from 125 patients with epilepsy were analyzed using the PPK model with nonlinear mixed-effects modeling. One-compartment and proportional residual models best described the pharmacokinetics of perampanel. Covariate effects on the model parameters were assessed using forward and backward elimination. Goodness-of-fit, bootstrapping, visual predictive checks, and normalized prediction distribution errors were used to evaluate the model. Monte Carlo simulations were conducted to assess the impact of covariate combinations on perampanel plasma concentrations at different dosages.</p><p><strong>Results: </strong>In the final PPK model, body weight (BW), concomitant carbamazepine (CBZ), oxcarbazepine (OXC), and C-reactive protein (CRP) levels significantly influenced perampanel clearance. The interindividual clearance was calculated as follows: 0.84 × (BW/70)0.53 × eCBZ × eOXC × eCRP (CBZ = 0.98, when comedicated with carbamazepine; OXC = 0.43, when comedicated with oxcarbazepine; CRP = -0.69, when CRP >15 mg/L, otherwise = 0). The estimates (relative standard error) for clearance and apparent volume of distribution of the final model were 0.84 L/h (8.75%) and 64.35 L (19.78%), respectively. The model maintained its stability and effectiveness with moderate predictability.</p><p><strong>Conclusions: </strong>BW and CBZ, OXC, and CRP levels may influence perampanel clearance in both pediatric and adult patients with epilepsy according to a population pharmacokinetic model that included real-world data.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189974","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":"Getting Tacrolimus Dosing Right.","authors":"Pierre Marquet","doi":"10.1097/FTD.0000000000001266","DOIUrl":"10.1097/FTD.0000000000001266","url":null,"abstract":"<p><strong>Abstract: </strong>Tacrolimus (TAC) dosing is typically guided by the trough concentration (C0). Yet, significant relationships between TAC C0 and clinical outcomes have seldom been reported or only with adverse events. Large retrospective studies found a moderate correlation between TAC C0 and the area under the curve (AUC), where, for any given C0 value, the AUC varied 3- to 4-fold between patients (and vice versa). However, no randomized controlled trial evaluating the dose adjustment based on TAC AUC has been conducted yet. A few observational studies have shown that the AUC is associated with efficacy and, to a lesser extent, adverse effects. Other studies showed the feasibility of reaching predefined target ranges and reducing underexposure and overexposure. TAC AUC 0-12 h is now most often assessed using Bayesian estimation, but machine learning is a promising approach. Microsampling devices are well accepted by patients and represent a valuable alternative to venous blood sample collection during hospital visits, especially when a limited sampling strategy is required. As AUC monitoring cannot be proposed very frequently, C0 monitoring has to be used in the interim, which has led to fluctuating doses in patients with an AUC/C0 ratio far from the population mean, because of different dose recommendations between the 2 biomarkers. We proposed estimating the individual AUC/C0 ratio and derived individual C0 targets to be used in between or as a replacement for AUC monitoring. Existing technology and evidence are now sufficient to propose AUC monitoring interspersed with individualized-C0 monitoring for all patients with kidney transplants while collecting real-world data to strengthen the evidence.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"41-48"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366631","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":"Toward Analytical Performance Specifications for Immunosuppressive Drug Quantification in Transplantation: An Opinion Article.","authors":"Maria Shipkova, Eberhard Wieland, Ekkerhard Schütz","doi":"10.1097/FTD.0000000000001261","DOIUrl":"10.1097/FTD.0000000000001261","url":null,"abstract":"<p><strong>Background: </strong>Analytical methods require performance that meets the clinical needs. Different approaches for setting up permissible analytical imprecision goals (pCVA%) for drug analyses have been reported. The aim of this study was to calculate the pCV A % for cyclosporine, tacrolimus, everolimus, sirolimus, and mycophenolic acid using 4 alternative approaches, to compare the results and to critically discuss advantages and disadvantages of each model.</p><p><strong>Methods: </strong>The approaches to evaluate pCV A % were (A) based on biological variation observed in routine measurement results between 2022 and 2023 in the authors' laboratory, (B) derived from the terminal elimination half-life and dosing interval of the drugs, and (C and D) explored from the width of the therapeutic ranges (TR) by the 2 methods. For approach A, routine measurement data for cyclosporine and tacrolimus, obtained through liquid chromatography-tandem mass spectrometry and electrochemiluminescence immunoassays, were evaluated separately.</p><p><strong>Results: </strong>The 4 alternative approaches for deriving pCV A % yielded similar results, for cyclosporine and tacrolimus in an analytical method dependent manner. The average pCV A % was 5.2%, 5.6%, 5.1%, 4.8%, and 7.7% for cyclosporine, tacrolimus, everolimus, sirolimus, and mycophenolic acid, respectively. The most challenging goals were those using TR-related approaches, while those using the biological variation approach were most easily achievable. Approach B resulted in more stringent goals for drugs with longer elimination half-lives (eg, everolimus and sirolimus).</p><p><strong>Conclusions: </strong>There is no single ideal approach for setting goals of drug analysis. However, the pCV A % values derived from the various approaches are similar and confirm that a <6% target proposed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology is adequate and realistic in combination with state-of-the-art measurement technologies. In the authors' opinion, approaches based on the width of the TR are preferable, as they represent a common basis for clinical decisions and reflect elements of biological variation and analytics used to establish the TR.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"32-40"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366632","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":"Alternate Sampling Matrices for Therapeutic Drug Monitoring of Immunosuppressants.","authors":"Benedetta C Sallustio","doi":"10.1097/FTD.0000000000001282","DOIUrl":"10.1097/FTD.0000000000001282","url":null,"abstract":"<p><strong>Background: </strong>Immunosuppressant (IS) therapeutic drug monitoring (TDM) relies on measuring mostly pharmacologically inactive erythrocyte-bound and/or plasma protein-bound drug levels. Variations in hematocrit and plasma protein levels complicate interpretation of blood calcineurin inhibitor (CNI) and inhibitors of the molecular target of rapamycin (mTORi) concentrations. Variable binding of mycophenolic acid (MPA) to albumin similarly complicates its TDM in plasma. A different matrix may improve IS concentration-response relationships and better reflect exposures at sites of action.</p><p><strong>Methods: </strong>This review explores the evidence for IS TDM using peripheral blood mononuclear cell (PBMC), graft tissue, and total or unbound plasma concentrations.</p><p><strong>Results: </strong>Tandem mass spectrometry provides the sensitivity for assessing these matrices. But several challenges must be addressed, including minimizing hemolysis during blood collection, preventing IS efflux during PBMC preparation, and determining the need for further purification of the PBMC fraction. Assessing and reducing nonspecific binding during separation of unbound IS are also necessary, especially for lipophilic CNIs/mTORi. Although TDM using PBMC or unbound plasma concentrations may not be feasible due to increased costs, plasma CNI/mTORi levels may be more easily integrated into routine TDM. However, no validated TDM targets currently exist, and published models to adjust blood CNI/mTORi concentrations for hematocrit or to predict PBMC, and total and unbound plasma IS concentrations have yet to be validated in terms of measured concentrations or prediction of clinical outcomes.</p><p><strong>Conclusions: </strong>Even if CNI/mTORi measurements in novel matrices do not become routine, they may help refine pharmacokinetic-pharmacodynamic relationships and improve mathematical models for TDM using whole blood. Notably, there is evidence to support measuring unbound MPA in patients with severe renal dysfunction, hypoalbuminemia, and hyperbilirubinemia, with some proposed TDM targets.</p>","PeriodicalId":23052,"journal":{"name":"Therapeutic Drug Monitoring","volume":" ","pages":"105-117"},"PeriodicalIF":2.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142732764","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}