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Pharmaceutics
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Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd...
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Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: 10 October 2024 | Viewed by 5023

Special Issue Editors

Prof. Dr. Barna Vasarhelyi

E-Mail Website
Guest Editor
Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
Interests: pediatrics; biostatistics; laboratory medicine; pharmacogenomics; renal elimination
Special Issues, Collections and Topics in MDPI journals
Dr. Gellért Balázs Karvaly

E-Mail Website
Guest Editor
Department of Laboratory Medicine, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
Interests: therapeutic drug monitoring; liquid chromatography-mass spectrometry; clinical pharmacokinetics; microsampling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The field of therapeutic drug monitoring (TDM) is experiencing a revolution as it is becoming an important supporting tool for clinical decision making in various fields of pharmacotherapy. From the simplified evaluation of drug concentrations collected at the trough or, in certain cases, at other time points following drug administration, based on therapeutic ranges, this field has improved into one with a focus on providing in vivo pharmacokinetic information for the personalized modulation of drug regimens. The introduction of novel analytical and sampling technologies, as well as the availability of modern bioinformatic tools, including artificial intelligence and machine learning, have made important contributions to this rapid development.

This is the second volume of the Special Issue with the goal to mediate state-of-the-art scientific knowledge in the field of pharmacokinetics-based individualized drug therapy based on therapeutic drug monitoring. The aims have not changed: in this volume, contemporary, innovative research focusing on novel approaches to TDM and individualized drug regimens will be published with the perspective of improving patient care. The integration of clinical pharmacokinetic approaches with machine learning or artificial intelligence is of particular interest. Manuscripts enlightening the application of these tools to the assessment of patient adherence, countering adverse effects and events, establishing increased effectiveness and the safety of drug therapy, improving the cost-efficiency of treatments, or identifying patient sub-populations based on TDM, among others, will be considered for publication.

We express our appreciation to the authors of all submitted manuscripts for choosing this Special Issue to share their achievements. We are excited about Volume II, which is now open for the submission of high-quality manuscripts in the fields of therapeutic drug monitoring and pharmacokinetics-based individualized treatments.

Prof. Dr. Barna Vásárhelyi
Dr. Gellért Balázs Karvaly
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 100 words) can be sent to the Editorial Office for announcement on this website.

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. Pharmaceutics 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

  • precision pharmacotherapy
  • population pharmacokinetic modeling probability of target attainment
  • pharmacokinetic–pharmacodynamic index
  • active metabolite
  • adaptive control
  • patient adherence
  • chromatography
  • mass spectrometry
  • microsampling

Published Papers (4 papers)

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Research

11 pages, 726 KiB  
Article
A New Algorithm Integrating Molecular Response, Toxicity, and Plasma Level Measures for Ponatinib Dose Choice in Patients Affected by Chronic Myeloid Leukemia
by Sara Galimberti, Elisabetta Abruzzese, Giacomo Luci, Claudia Baratè, Luigia Luciano, Alessandra Iurlo, Giovanni Caocci, Riccardo Morganti, Fabio Stefanelli and Antonello Di Paolo
Pharmaceutics 2024, 16(3), 383; https://doi.org/10.3390/pharmaceutics16030383 - 11 Mar 2024
Viewed by 695
Abstract
Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. [...] Read more.
Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. The present study was aimed at investigating any possible correlations among ponatinib dose, plasma concentration, molecular response (MR), and tolerability in a real-world setting. Clinical and laboratory records (including MR and drug plasma concentrations) of 32 CML patients treated with ponatinib were harvested and analyzed. Twenty-seven patients (71%) had ponatinib Cmin values > 21.3 ng/mL, but Cmin values > 10.7 ng/mL (considered efficacious in BCR-Abl unmutated patients) were achieved by 80% of the patients receiving ≥30 mg/day and 45% of the subjects treated with 15 mg/day. No significant correlations were identified among clinical efficacy, tolerability, daily dose, and plasma concentration. Notably, patients who underwent dose tapering for tolerability or safety reasons did not experience treatment failure. In a real-world setting, adjustment of ponatinib daily doses lower than those registered may maintain therapeutic efficacy while reducing the risk of vascular events and improving tolerability. Further studies are warranted to confirm the present results in a larger cohort of patients. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)
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14 pages, 1308 KiB  
Article
Meltdose Tacrolimus Population Pharmacokinetics and Limited Sampling Strategy Evaluation in Elderly Kidney Transplant Recipients
by Jasper Kamp, Tom C. Zwart, Soufian Meziyerh, Paul J. M. van der Boog, Esther E. Nijgh, Koen van Duin, Aiko P. J. de Vries and Dirk Jan A. R. Moes
Pharmaceutics 2024, 16(1), 17; https://doi.org/10.3390/pharmaceutics16010017 - 21 Dec 2023
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Abstract
Background: Meltdose tacrolimus (Envarsus®) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose individualization is essential. Relaxation of the upper age limits for kidney transplantations has resulted in larger [...] Read more.
Background: Meltdose tacrolimus (Envarsus®) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose individualization is essential. Relaxation of the upper age limits for kidney transplantations has resulted in larger numbers of elderly patients receiving tacrolimus. However, due to the physiological changes caused by aging, the tacrolimus pharmacokinetics (PK) might be altered. The primary aim was to develop a population PK model in elderly kidney transplant recipients. Secondary aims were the development and evaluation of a limited sampling strategy (LSS) for AUC estimation. Methods: A total of 34 kidney transplant recipients aged ≥65 years, starting on meltdose tacrolimus directly after transplantation, were included. An eight-point whole blood AUC0–24h and an abbreviated dried blood spot (DBS) AUC0–24h were obtained. The PK data were analyzed using nonlinear mixed effect modeling methods. Results: The PK data were best described using a two-compartment model, including three transit compartments and a mixture model for oral absorption. The best three-sample LSS was T = 0, 2, 6 h. The best four-sample LSSs were T = 0, 2, 6, 8 h and T = 0, 1, 6, 8 h. Conclusions: The developed population PK model adequately described the tacrolimus PK data in a population of elderly kidney transplant recipients. In addition, the developed population PK model and LSS showed an adequate estimation of tacrolimus exposure, and may therefore be used to aid in tacrolimus dose individualization. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)
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14 pages, 2544 KiB  
Article
Dynamic Monitoring of Intracellular Tacrolimus and Mycophenolic Acid Therapy in Renal Transplant Recipients Using Magnetic Bead Extraction Combined with LC-MS/MS
by Huan Xu, Yingying Liu, Yinan Zhang, Xinhua Dai, Xueqiao Wang, Haojun Chen, Lin Yan, Xingxin Gong, Jiaxi Yue, Zhengli Wan, Jiwen Fan, Yangjuan Bai, Yao Luo and Yi Li
Pharmaceutics 2023, 15(9), 2318; https://doi.org/10.3390/pharmaceutics15092318 - 14 Sep 2023
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Abstract
Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA concentrations in peripheral blood mononuclear cells (PBMCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) and to evaluate and validate the [...] Read more.
Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA concentrations in peripheral blood mononuclear cells (PBMCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) and to evaluate and validate the performance of the methodology. A prospective follow-up cohort study was conducted to determine whether intracellular concentrations were associated with adverse outcomes in renal transplants. Methods: PBMCs were prepared using the Ficoll separation technique and purified with erythrocyte lysis. The cells were counted using Sysmex XN-3100 and then packaged and frozen according to a 50 µL volume containing 1.0 × 106 cells. TAC and MPA were extracted using MagnaBeads and quantified using an LC-MS/MS platform. The chromatography was run on a reversed-phase Waters Acquity UPLC BEH C18 column (1.7 µm, 50 mm × 2.1 mm) for gradient elution separation with a total run time of 4.5 min and a flow rate of 0.3 mL/min. Mobile phases A and B were water and methanol, respectively, each containing 2 mM ammonium acetate and 0.1% formic acid. Renal transplant recipients receiving TAC and MPA in combination were selected for clinical validation and divided into two groups: a stable group and an adverse outcome group. The concentrations were dynamically monitored at 5, 7, 14, and 21 days (D5, D7, D14, and D21) and 1, 2, 3, and 6 months (M1, M2, M3, and M6) after operation. Results: Method performance validation was performed according to Food and Drug Administration guidelines, showing high specificity and sensitivity. The TAC and MPA calibration curves were linear (r2 = 0.9988 and r2 = 0.9990, respectively). Both intra-day and inter-day imprecision and inaccuracy were less than 15%. Matrix effects and recoveries were satisfactory. The TAC and MPA concentrations in 304 “real” PBMC samples from 47 renal transplant recipients were within the calibration curve range (0.12 to 16.40 ng/mL and 0.20 to 4.72 ng/mL, respectively). There was a weak correlation between PBMC-C0TAC and WB-C0TAC (p < 0.05), but no correlation was found for MPA. The level of immunosuppressive intra-patient variation (IPV) was higher in PBMC at 77.47% (55.06, 97.76%) than in WB at 34.61% (21.90, 49.85%). During the dynamic change in C0TAC, PBMC-C0TAC was in a fluctuating state, and no stable period was found. PBMC-C0TAC did not show a significant difference between the stable and adverse outcome group, but the level of the adverse outcome group was generally higher than that of the stable group. Conclusions: Compared with conventional therapeutic drug monitoring, the proposed rapid and sensitive method can provide more clinically reliable information on drug concentration at an active site, which has the potential to be applied to the clinical monitoring of intracellular immunosuppressive concentration in organ transplantation. However, the application of PBMC-C0TAC in adverse outcomes of renal transplant should be studied further. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)
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19 pages, 524 KiB  
Article
Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial
by Michael Frey, Lukasz Smigielski, Elvira Tini, Stefanie Fekete, Christian Fleischhaker, Christoph Wewetzer, Andreas Karwautz, Christoph U. Correll, Manfred Gerlach, Regina Taurines, Paul L. Plener, Uwe Malzahn, Selina Kornbichler, Laura Weninger, Matthias Brockhaus, Su-Yin Reuter-Dang, Karl Reitzle, Hans Rock, Hartmut Imgart, Peter Heuschmann, Stefan Unterecker, Wolfgang Briegel, Tobias Banaschewski, Jörg M. Fegert, Tobias Hellenschmidt, Michael Kaess, Michael Kölch, Tobias Renner, Christian Rexroth, Susanne Walitza, Gerd Schulte-Körne, Marcel Romanos and Karin Maria Egbertsadd Show full author list remove Hide full author list
Pharmaceutics 2023, 15(9), 2202; https://doi.org/10.3390/pharmaceutics15092202 - 25 Aug 2023
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Abstract
Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic [...] Read more.
Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial (“TDM-VIGIL”), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7–18 years; 24.6% males) was treated with fluoxetine (10–40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208–328 ng/mL (transdiagnostically) and 201.5–306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose–serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)
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