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Pharmaceuticals
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Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis
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Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: 31 July 2026 | Viewed by 4531

Special Issue Editors

Dr. Ivana Cizmarova

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Guest Editor
1. Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University Bratislava, Odbojarov 10, 832 32 Bratislava, Slovakia
2. Toxicological and Antidoping Center, Faculty of Pharmacy, Comenius University Bratislava, Odbojarov 10, 832 32 Bratislava, Slovakia
Interests: CE-MS/MS; LC-MS/MS; green analytical methods; method development; therapeutic drug monitoring; bioanalytical method validation; antibiotics; Janus kinase inhibitors; pharmacokinetics
Dr. Juraj Piestansky

E-Mail Website
Guest Editor
1. Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
2. Department of Galenic Pharmacy, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
3. Toxicological and Antidoping Center, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
Interests: capillary electrophoresis; liquid chromatography; mass spectrometry; biologics; therapeutic drug monitoring; bioanalysis; quality control; therapeutic peptides
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Therapeutic Drug Monitoring (TDM) is an essential part of modern pharmacotherapy, allowing for the individualization of drug dosing through the measurement of drug concentrations in biological matrices such as blood, plasma, or saliva. It is particularly important for medications with a narrow therapeutic window, high interindividual variability, or a risk of significant toxicity. In recent years, advances in analytical technologies have greatly enhanced the precision, sensitivity, and speed of TDM workflows.

This Special Issue welcomes a wide range of contributions that reflect the interdisciplinary nature of TDM. We are especially interested in studies focused on the development and validation of analytical methods, innovative sample preparation strategies, and bioanalytical challenges. Equally, we invite submissions addressing pharmacokinetic and pharmacodynamic modeling, individualized dosing strategies, and the application of TDM in special patient populations. Research exploring how TDM supports personalized and precision medicine is particularly encouraged.

By bringing together pharmaceutical scientists, clinicians, and analytical chemists, this Special Issue aims to provide a comprehensive overview of current trends and innovations in TDM, and to showcase its impact on safer and more effective drug therapy.

Dr. Ivana Cizmarova
Dr. Juraj Piestansky
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Therapeutic Drug Monitoring (TDM)
  • bioanalytical method development
  • LC-MS/MS
  • sample preparation
  • method validation
  • pharmacokinetics
  • pharmacodynamics
  • individualized dosing
  • precision medicine
  • clinical applications

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Published Papers (6 papers)

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Research

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15 pages, 1611 KB  
Article
Minimally Invasive Therapeutic Drug Monitoring of Immunosuppressants in Children with Kidney Diseases: Validation of Fingerstick Sampling Using LC-MS/MS
by Marika Ishii, Jun Aoyagi, Natsuka Kimura, Masanori Kurosaki, Tomomi Maru, Kazuya Tanimoto, Mitsuaki Yoshino, Takane Ito, Takahiro Kanai, Hitoshi Osaka, Ryozo Nagai and Kenichi Aizawa
Pharmaceuticals 2026, 19(4), 630; https://doi.org/10.3390/ph19040630 - 16 Apr 2026
Viewed by 179
Abstract
Background/Objectives: Therapeutic drug monitoring (TDM) of immunosuppressants is essential in treating pediatric kidney diseases; however, repeated venipuncture is burdensome in children. We evaluated whether minimally invasive fingerstick capillary sampling combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS) provides results analytically comparable to those [...] Read more.
Background/Objectives: Therapeutic drug monitoring (TDM) of immunosuppressants is essential in treating pediatric kidney diseases; however, repeated venipuncture is burdensome in children. We evaluated whether minimally invasive fingerstick capillary sampling combined with liquid chromatography–tandem mass spectrometry (LC-MS/MS) provides results analytically comparable to those of conventional venous sampling. Methods: Capillary whole blood (2.8 µL) was collected via fingersticks from pediatric patients receiving mycophenolate mofetil, with or without tacrolimus (TAC) or cyclosporine A (CsA). Drug concentrations were quantified using a previously validated simultaneous LC-MS/MS method and compared with conventional venous sampling using linear regression and Bland–Altman analyses. Results: Seventy-four paired samples from 21 patients were analyzed. Strong correlations were observed between capillary and venous samples for mycophenolic acid (MPA), TAC, and CsA (R2 > 0.90). Hematocrit correction improved agreement for MPA. Bland–Altman analyses demonstrated acceptable bias across analytes. Conclusions: Fingerstick-based microvolume sampling combined with LC-MS/MS provides analytically reliable immunosuppressant quantification in pediatric patients. Although larger clinical validation is required, this minimally invasive approach may reduce procedural burden and may support future outpatient or home-based TDM strategies. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis)
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17 pages, 1425 KB  
Article
A Simple Dual-Track HPLC-UV Methodology for Monitoring Primary Antiarrhythmic Drugs and Their Active Metabolites in Serum
by Paweł K. Kunicki, Wioleta Drózd and Jakub Meszka
Pharmaceuticals 2026, 19(3), 406; https://doi.org/10.3390/ph19030406 - 1 Mar 2026
Viewed by 405
Abstract
Objectives: The aim of the work was to present a method for routine determination of antiarrhythmic drugs, propafenone (PPF), its two metabolites, 5-hydroxypropafenone (5OHPPF) and N-depropylpropafenone (NDPPF), mexiletine (MEX), amiodarone (AD) and desethylamiodarone (DEAD) in serum. Methods: A simple isocratic HPLC-UV system with [...] Read more.
Objectives: The aim of the work was to present a method for routine determination of antiarrhythmic drugs, propafenone (PPF), its two metabolites, 5-hydroxypropafenone (5OHPPF) and N-depropylpropafenone (NDPPF), mexiletine (MEX), amiodarone (AD) and desethylamiodarone (DEAD) in serum. Methods: A simple isocratic HPLC-UV system with a manual injector was applied. The separations were performed at ambient temperature on Supelcosil LC-CN column (150 × 4.6 mm, 5 μm). Two analytical procedures (A and B) were used: (A) for AD and (B) for PPF/MEX. The mobile phase for (A) was a mixture of: CH3OH:CH3CN:H2O:0.5M KH2PO4 (200:100:194:6 v/v + 0.1 mL 85% H3PO4 per 500 mL). The slightly acidified serum sample was extracted with hexane and the analytes were detected at 240 nm. The mobile phase for (B) was a mixture of: CH3CN:H2O:0.5M KH2PO4 (185:310:5 v/v + 0.1 mL 85% H3PO4 per 500 mL). The alkalized serum sample was extracted with diisopropyl ether, then back extracted into 0.01M HCl and finally the analytes were detected at 210 nm. Results: The method was calibrated with adequate selectivity and specificity in the range of 20–4000 ng/mL for AD, DEAD and MEX, 10–4000 ng/mL for PPF and 10–500 ng/mL for 5OHPPF and NDPPF. For all analytes, precision and accuracy fulfilled EMA requirements, i.e., ≤15% (≤20% for LLOQ), ensuring the reliability of the measurements. Conclusions: The method can be suitable for laboratories equipped with basic HPLC apparatus as an economical alternative to the LC-MS/MS technique. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis)
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17 pages, 3128 KB  
Article
Strategies to Overcome Hematocrit and Volume Bias in Dried Blood Spot Analysis
by Panagiotis-Dimitrios Mingas, Matjaž Cirar, Iztok Grabnar, David Drobne and Tomaž Vovk
Pharmaceuticals 2026, 19(3), 403; https://doi.org/10.3390/ph19030403 - 1 Mar 2026
Viewed by 583
Abstract
Background/Objectives: Dried blood spot (DBS) sampling, a technique for collecting capillary blood samples, is widely used in therapeutic drug monitoring, pharmacokinetic and toxicology research, newborn screening, and population health because it enables simple, non-invasive sampling across large cohorts. However, it presents several [...] Read more.
Background/Objectives: Dried blood spot (DBS) sampling, a technique for collecting capillary blood samples, is widely used in therapeutic drug monitoring, pharmacokinetic and toxicology research, newborn screening, and population health because it enables simple, non-invasive sampling across large cohorts. However, it presents several challenges, mainly due to the effect of hematocrit (HCT), which can influence the quantification of analytes. Methods: A combination of methods was developed to estimate the HCT and blood volume in DBS samples. Image analysis and hemoglobin (Hb) quantification using UV-VIS spectrometry were used for HCT estimation, and conductivity was used to determine blood volume. DBS samples from five donors were prepared with HCT between 0.2 and 0.6 and were used to prepare calibrators and quality control samples. The developed methods were applied to 23 samples obtained from ten adult patients with inflammatory bowel disease. Results: The methods for HCT determination using image analysis or Hb measurements were linear (r2 > 0.994), with acceptable accuracy (90.3–102.2%) and precision (<7.4%). Moreover, the conductivity method was linear (r2 = 0.999) and enabled accurate (96.8–100%) and precise (<5.65%) determination of blood volume in DBS samples. All three methods were in good agreement with the reference values in patient samples. Finally, strategies to correct HCT- and volume-related bias in DBS samples were proposed for analytes with different blood cell-to-plasma partition coefficients. Conclusions: We accurately and precisely estimated HCT in DBS samples using image analysis and Hb determination, and the volume of blood in DBS using conductivity measurement. We evaluated different approaches and derived an optimal procedure for HCT-bias correction. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis)
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17 pages, 1628 KB  
Article
Method-Comparison Validation of a Novel Capillary Blood Collection Kit, True Dose® TD-EPI, for Therapeutic Drug Monitoring of Epirubicin
by Serena De Chiara, Nektarios Komninos, Oscar P. B. Wiklander, Per Rydberg and Elham Hedayati
Pharmaceuticals 2026, 19(2), 226; https://doi.org/10.3390/ph19020226 - 28 Jan 2026
Viewed by 616
Abstract
Background: Therapeutic drug monitoring (TDM) is a promising strategy to personalize chemotherapy dosing, especially for agents with narrow therapeutic indices such as epirubicin. However, widespread adoption is hindered by logistical challenges associated with venous blood sampling and centralized laboratory workflows. Objective: This study [...] Read more.
Background: Therapeutic drug monitoring (TDM) is a promising strategy to personalize chemotherapy dosing, especially for agents with narrow therapeutic indices such as epirubicin. However, widespread adoption is hindered by logistical challenges associated with venous blood sampling and centralized laboratory workflows. Objective: This study aimed to perform a method-comparison validation of the True Dose® TD-EPI microsampling kit by verifying analytical agreement between capillary and venous epirubicin measurements in real patient samples. The study focuses on analytical performance and does not constitute validation of the whole decentralized workflow, including unsupervised patient self-sampling. Methods: 13 patients with early-stage breast cancer receiving the first cycle of neoadjuvant or adjuvant epirubicin were enrolled. Capillary samples were collected using the finalized TD-EPI kit (Cap-TD) at 2.5 h (n = 13) and/or 48 h (n = 10) post-infusion and stored at room temperature for 72 h before analysis. Matched venous samples were analyzed using both conventional protein precipitation (“Traditional”) and a modified lab-based True Dose workflow (Lab-TD). Epirubicin concentrations were quantified via validated liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results: Cap-TD concentrations showed strong agreement with Traditional venous values (r = 0.953), with minimal bias (mean difference = 0.013 μM) in Bland–Altman analysis. Passing–Bablok regression confirmed analytical equivalence. Intra-assay variability remained within ICH M10 guidelines (CV ≤ 15%), and recovery was unaffected by 72 h ambient storage. Lab-TD results closely matched Traditional workflows, supporting reproducibility. Conclusions: The TD-EPI kit enables accurate decentralized monitoring of epirubicin, eliminating the need for venous access, cold-chain logistics, or in-clinic sampling. These findings support its integration into personalized oncology care and future applications in home-based TDM. Trial Registration: This study is part of an approved protocol registered in the EU Clinical Trials Register (EUCT Number 2024-514818-12-00; EudraCT Number 2017-000641-44; registration date: 15 June 2017). Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis)
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21 pages, 1797 KB  
Article
Volumetric Absorptive Microsampling of Saliva for Pharmacokinetic Evaluation of Mycophenolic Acid and Its Glucuronide Metabolite in Pediatric Renal Transplant Recipients: Bioanalytical Method Validation and Clinical Feasibility Evaluation
by Arkadiusz Kocur, Joanna Sobiak, Agnieszka Czajkowska, Jacek Rubik and Tomasz Pawiński
Pharmaceuticals 2025, 18(11), 1744; https://doi.org/10.3390/ph18111744 - 17 Nov 2025
Viewed by 758
Abstract
Background: Mycophenolic acid (MPA) is frequently used in pediatric renal transplantation as part of immunosuppressive therapy, yet therapeutic drug monitoring (TDM) remains challenging. Accurate monitoring is essential due to MPA’s narrow therapeutic window, variable pharmacokinetics, and high protein binding. This study examined whether [...] Read more.
Background: Mycophenolic acid (MPA) is frequently used in pediatric renal transplantation as part of immunosuppressive therapy, yet therapeutic drug monitoring (TDM) remains challenging. Accurate monitoring is essential due to MPA’s narrow therapeutic window, variable pharmacokinetics, and high protein binding. This study examined whether saliva could serve as a non-invasive alternative to plasma for measuring MPA exposure. Methods and Results: Concentrations of MPA and its primary glucuronide metabolite (MPAG) were determined in plasma, capillary blood, plasma ultrafiltrate, wet saliva, and dried saliva collected using volumetric absorptive microsampling (VAMS). A novel LC–MS/MS method for quantifying MPA and MPAG in dried saliva collected with the Mitra™ device was developed and validated within a 1–700 μg/L calibration range, demonstrating robust analytical performance. Dried and wet saliva showed high correlation (r = 0.99 and 0.98 for MPA and MPAG, respectively). However, both salivary matrices—dried saliva collected with Mitra™ (vsMPA, vsMPAG) and wet saliva (sMPA, sMPAG)—exhibited poor correlation with unbound (fMPA, fMPAG) and total plasma concentrations (tMPA, tMPAG). A modest, yet positive, correlation was observed between the measured concentrations for the following pairs: sMPA versus fMPA (r = 0.376, p = 0.1036), sMPA versus tMPA (r = 0.305, p = 0.1904), sMPAG versus fMPAG (r = 0.205, p = 0.3851), and sMPAG versus tMPAG (r = 0.472, p = 0.0012). Pharmacokinetic parameters supported these findings, highlighting discrepancies between saliva and plasma. Conclusions: From a clinical perspective, saliva sampling—although minimally invasive and patient-friendly—does not offer a reliable substitute for plasma in routine TDM of MPA and MPAG. Capillary blood collected through VAMS remains a promising alternative for long-term monitoring of pediatric patients; however, several considerations still need to be addressed. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis)
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Review

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31 pages, 751 KB  
Review
Artificial Intelligence and Predictive Modelling for Precision Dosing of Immunosuppressants in Kidney Transplantation
by Sholpan Altynova, Timur Saliev, Aruzhan Asanova, Zhanna Kozybayeva, Saltanat Rakhimzhanova and Aidos Bolatov
Pharmaceuticals 2026, 19(1), 165; https://doi.org/10.3390/ph19010165 - 16 Jan 2026
Cited by 1 | Viewed by 1086
Abstract
Optimizing immunosuppressant dosing presents significant challenges in kidney transplantation due to narrow therapeutic ranges and considerable inter-patient pharmacokinetic differences. Emerging strategies for precision dosing, encompassing Bayesian population pharmacokinetic models, pharmacogenomic integration, and artificial intelligence algorithms, aim to enhance drug monitoring by moving beyond [...] Read more.
Optimizing immunosuppressant dosing presents significant challenges in kidney transplantation due to narrow therapeutic ranges and considerable inter-patient pharmacokinetic differences. Emerging strategies for precision dosing, encompassing Bayesian population pharmacokinetic models, pharmacogenomic integration, and artificial intelligence algorithms, aim to enhance drug monitoring by moving beyond traditional trough-based approaches. This review critically assesses available evidence for predictive dosing models targeting immunosuppressants, including calcineurin inhibitors, antimetabolites, and mTOR inhibitors in kidney transplant patients. Available observational and simulation studies demonstrate substantial methodological diversity, with Bayesian PopPK-guided strategies showing 15–35% better target exposure achievement compared to trough-based monitoring. The absence of pooled estimates precludes a precise summary effect size, and evidence from randomized controlled trials remains limited. Machine learning models, particularly for tacrolimus, frequently reduced prediction error relative to traditional regression approaches, but substantial heterogeneity in study design, outcome definitions, and external validation limits quantitative synthesis. Hybrid Bayesian–AI frameworks and explainable AI tools show conceptual promise but are largely supported by proof-of-concept studies rather than reproducible clinical implementations. Overall, Bayesian pharmacokinetic modelling represents the most mature and clinically interpretable approach for precision dosing in transplantation, whereas AI-driven and hybrid systems remain investigational. Key gaps include the need for standardized reporting, rigorous risk-of-bias assessment, prospective validation, and clearer regulatory and implementation pathways to support safe and equitable clinical adoption. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring: Techniques and Applications in Pharmaceutical Analysis)
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