Research

Jump to: Review

13 pages, 1888 KiB

Open AccessArticle

A Drug Safety Concept (I) to Avoid Polypharmacy Risks in Transplantation by Individual Pharmacotherapy Management in Therapeutic Drug Monitoring of Immunosuppressants

by Ursula Wolf

Pharmaceutics 2023, 15(9), 2300; https://doi.org/10.3390/pharmaceutics15092300 - 10 Sep 2023

Cited by 1 | Viewed by 1324

Abstract

For several, also vital medications, such as immunosuppressants in solid organ and hematopoietic stem cell transplantation, therapeutic drug monitoring (TDM) remains the only strategy for fine-tuning the dosage to the individual patient. Especially in severe clinical complications, the intraindividual condition of the patient [...] Read more.

For several, also vital medications, such as immunosuppressants in solid organ and hematopoietic stem cell transplantation, therapeutic drug monitoring (TDM) remains the only strategy for fine-tuning the dosage to the individual patient. Especially in severe clinical complications, the intraindividual condition of the patient changes abruptly, and in addition, drug-drug interactions (DDIs) can significantly impact exposure, due to concomitant medication alterations. Therefore, a single TDM value can hardly be the sole basis for optimal timely dose adjustment. Moreover, every intraindividually varying situation that affects the drug exposure needs synoptic consideration for the earliest adjustment. To place the TDM value in the context of the patient’s most detailed current condition and concomitant medications, the Individual Pharmacotherapy Management (IPM) was implemented in the posttransplant TDM of calcineurin inhibitors assessed by the in-house laboratory. The first strategic pillar are the defined patient scores from the electronic patient record. In this synopsis, the Summaries of Product Characteristics (SmPCs) of each drug from the updated medication list are reconciled for contraindication, dosing, adverse drug reactions (ADRs), and DDIs, accounting for defined medication scores as a second pillar. In parallel, IPM documents the resulting review of each TDM value chronologically in a separate electronic Excel file throughout each patient’s transplant course. This longitudinal overview provides a further source of information at a glance. Thus, the applied two-arm concept of TDM and IPM ensures an individually tailored immunosuppression in the severely susceptible early phase of transplantation through digital interdisciplinary networking, with instructive and educative recommendations to the attending physicians in real-time. This concept of contextualizing a TDM value to the precise patient’s condition and comedication was established at Halle University Hospital to ensure patient, graft, and drug safety. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Graphical abstract

16 pages, 2675 KiB

Open AccessArticle

Therapeutic Drug Monitoring (TDM) Implementation in Public Hospitals in Greece in 2003 and 2021: A Comparative Analysis of TDM Evolution over the Years

by Gavriela Voulgaridou, Theodora Paraskeva, Georgia Ragia, Natalia Atzemian, Konstantina Portokallidou, George Kolios, Konstantinos Arvanitidis and Vangelis G. Manolopoulos

Pharmaceutics 2023, 15(9), 2181; https://doi.org/10.3390/pharmaceutics15092181 - 23 Aug 2023

Viewed by 2345

Abstract

Therapeutic drug monitoring (TDM) is the clinical practice of measuring drug concentrations. TDM can be used to determine treatment efficacy and to prevent the occurrence or reduce the risk of drug-induced side effects, being, thus, a tool of personalized medicine. Drugs for which [...] Read more.

Therapeutic drug monitoring (TDM) is the clinical practice of measuring drug concentrations. TDM can be used to determine treatment efficacy and to prevent the occurrence or reduce the risk of drug-induced side effects, being, thus, a tool of personalized medicine. Drugs for which TDM is applied should have a narrow therapeutic range and exhibit both significant pharmacokinetic variability and a predefined target concentration range. The aim of our study was to assess the current status of TDM in Greek public hospitals and estimate its progress over the last 20 years. All Greek public hospitals were contacted to provide data and details on the clinical uptake of TDM in Greece for the years 2003 and 2021 through a structured questionnaire. Data from 113 out of 132 Greek hospitals were collected in 2003, whereas for 2021, we have collected data from 98 out of 122 hospitals. Among these, in 2003 and 2021, 64 and 51 hospitals, respectively, performed TDM. Antiepileptics and antibiotics were the most common drug categories monitored in both years. The total number of drug measurement assays decreased from 2003 to 2021 (153,313 ± 7794 vs. 90,065 ± 5698; p = 0.043). In direct comparisons between hospitals where TDM was performed both in 2003 and 2021 (n = 35), the mean number of measurements was found to decrease for most drugs, including carbamazepine (198.8 ± 46.6 vs. 46.6 ± 10.1, p < 0.001), phenytoin (253.6 ± 59 vs. 120 ± 34.3; p = 0.001), amikacin (147.3 ± 65.2 vs. 91.1 ± 71.4; p = 0.033), digoxin (783.2 ± 226.70 vs. 165.9 ± 28.9; p < 0.001), and theophylline (71.5 ± 28.7 vs. 11.9 ± 6.4; p = 0.004). Only for vancomycin, a significant increase in measurements was recorded (206.1 ± 96.1 vs. 789.1 ± 282.8; p = 0.012). In conclusion, our findings show that TDM clinical implementation is losing ground in Greek hospitals. Efforts and initiatives to reverse this trend are urgently needed. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Figure 1

16 pages, 7747 KiB

Open AccessArticle

Gut Microbiota-Mediated Pharmacokinetic Drug–Drug Interactions between Mycophenolic Acid and Trimethoprim-Sulfamethoxazole in Humans

by Nahathai Dukaew, Patcharawadee Thongkumkoon, Nutnicha Sirikaew, Sivamoke Dissook, Wannachai Sakuludomkan, Siripong Tongjai, Parameth Thiennimitr, Mingkwan Na Takuathung, Juthipong Benjanuwattra, Prachya Kongthaweelert and Nut Koonrungsesomboon

Pharmaceutics 2023, 15(6), 1734; https://doi.org/10.3390/pharmaceutics15061734 - 14 Jun 2023

Cited by 1 | Viewed by 1515

Abstract

Mycophenolic acid (MPA) and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed together in certain groups of patients, including solid organ transplant recipients. However, little is known about the pharmacokinetic drug–drug interactions (DDIs) between these two medications. Therefore, the present study aimed to determine the effects [...] Read more.

Mycophenolic acid (MPA) and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed together in certain groups of patients, including solid organ transplant recipients. However, little is known about the pharmacokinetic drug–drug interactions (DDIs) between these two medications. Therefore, the present study aimed to determine the effects of TMP-SMX on MPA pharmacokinetics in humans and to find out the relationship between MPA pharmacokinetics and gut microbiota alteration. This study enrolled 16 healthy volunteers to take a single oral dose of 1000 mg mycophenolate mofetil (MMF), a prodrug of MPA, administered without and with concurrent use of TMP-SMX (320/1600 mg/day) for five days. The pharmacokinetic parameters of MPA and its glucuronide (MPAG) were measured using high-performance liquid chromatography. The composition of gut microbiota in stool samples was profiled using a 16S rRNA metagenomic sequencing technique during pre- and post-TMP-SMX treatment. Relative abundance, bacterial co-occurrence networks, and correlations between bacterial abundance and pharmacokinetic parameters were investigated. The results showed a significant decrease in systemic MPA exposure when TMP-SMX was coadministered with MMF. Analysis of the gut microbiome revealed altered relative abundance of two enriched genera, namely the genus Bacteroides and Faecalibacterium, following TMP-SMX treatment. The relative abundance of the genera Bacteroides, [Eubacterium] coprostanoligenes group, [Eubacterium] eligens group, and Ruminococcus appeared to be significantly correlated with systemic MPA exposure. Coadministration of TMP-SMX with MMF resulted in a reduction in systemic MPA exposure. The pharmacokinetic DDIs between these two drugs were attributed to the effect of TMP-SMX, a broad-spectrum antibiotic, on gut microbiota-mediated MPA metabolism. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Figure 1

14 pages, 924 KiB

Open AccessArticle

Magnetic Solid-Phase Microextraction Protocol Based on Didodecyldimethylammonium Bromide-Functionalized Nanoparticles for the Quantification of Epirubicin in Biological Matrices

by Natalia Treder, Natalia Szuszczewicz, Anna Roszkowska, Ilona Olędzka, Tomasz Bączek, Ewa Bień, Małgorzata Anna Krawczyk and Alina Plenis

Pharmaceutics 2023, 15(4), 1227; https://doi.org/10.3390/pharmaceutics15041227 - 12 Apr 2023

Cited by 1 | Viewed by 1343

Abstract

Due to epirubicin’s (EPI) narrow therapeutic index and risk of cardiotoxicity, it is critical to monitor concentrations of this drug when being used to treat cancer patients. In this study, a simple and fast magnetic solid-phase microextraction (MSPME) protocol for the determination of [...] Read more.

Due to epirubicin’s (EPI) narrow therapeutic index and risk of cardiotoxicity, it is critical to monitor concentrations of this drug when being used to treat cancer patients. In this study, a simple and fast magnetic solid-phase microextraction (MSPME) protocol for the determination of EPI in plasma and urine samples is developed and tested. Experiments were performed using prepared Fe₃O₄-based nanoparticles coated with silica and a double-chain surfactant—namely, didodecyldimethylammonium bromide (DDAB)—as a magnetic sorbent. All the prepared samples were analyzed via liquid chromatography coupled with fluorescence detection (LC-FL). The validation parameters indicated good linearity in the range of 0.001–1 µg/mL with a correlation coefficient > 0.9996 for plasma samples, and in the range of 0.001–10 µg/mL with a correlation coefficient > 0.9997 for urine samples. The limit of detection (LOD) and limit of quantification (LOQ) for both matrices were estimated at 0.0005 µg/mL and 0.001 µg/mL, respectively. The analyte recovery after sample pretreatment was 80 ± 5% for the plasma samples and 90 ± 3% for the urine samples. The developed method’s applicability for monitoring EPI concentrations was evaluated by employing it to analyze real plasma and urine samples collected from a pediatric cancer patient. The obtained results confirmed the proposed MSPME-based method’s usefulness, and enabled the determination of the EPI concentration–time profile in the studied patient. The miniaturization of the sampling procedure, along with the significant reduction in pre-treatment steps, make the proposed protocol a promising alternative to routine approaches to monitoring EPI levels in clinical laboratories. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Graphical abstract

19 pages, 3068 KiB

Open AccessArticle

Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges

by Jens Borggaard Larsen, Elke Hoffmann-Lücke, Per Hersom Aaslo, Niklas Rye Jørgensen and Eva Greibe

Pharmaceutics 2023, 15(2), 673; https://doi.org/10.3390/pharmaceutics15020673 - 16 Feb 2023

Cited by 2 | Viewed by 1754

Abstract

Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference [...] Read more.

Therapeutic drug monitoring is a tool for optimising the pharmacological treatment of diseases where the therapeutic effect is difficult to measure or monitor. Therapeutic reference ranges and dose-effect relation are the main requirements for this drug titration tool. Defining and updating therapeutic reference ranges are difficult, and there is no standardised method for the calculation and clinical qualification of these. The study presents a basic model for validating and selecting routine laboratory data. The programmed algorithm was applied on data sets of antidepressants and antipsychotics from three public hospitals in Denmark. Therapeutic analytical ranges were compared with the published therapeutic reference ranges by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) and in additional literature. For most of the drugs, the calculated therapeutic analytical ranges showed good concordance between the laboratories and to published therapeutic reference ranges. The exceptions were flupentixol, haloperidol, paroxetine, perphenazine, and venlafaxine + o-desmethyl-venlafaxine (total plasma concentration), where the range was considerably higher for the laboratory data, while the calculated range of desipramine, sertraline, ziprasidone, and zuclopenthixol was considerably lower. In most cases, we identified additional literature supporting our data, highlighting the need of a critical re-examination of current therapeutic reference ranges in Denmark. An automated approach can aid in the evaluation of current and future therapeutic reference ranges by providing additional information based on big data from multiple laboratories. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Figure 1

18 pages, 2674 KiB

Open AccessArticle

A Volumetric Absorptive Microsampling UPLC-MS/MS Method for Simultaneous Quantification of Tacrolimus, Mycophenolic Acid and Creatinine in Whole Blood of Renal Transplant Recipients

by Xueqiao Wang, Xinhua Dai, Shiqi Wan, Yu Fan, Lijuan Wu, Huan Xu, Lin Yan, Xingxin Gong, Yamei Li, Yao Luo, Yangjuan Bai and Yi Li

Pharmaceutics 2022, 14(12), 2547; https://doi.org/10.3390/pharmaceutics14122547 - 22 Nov 2022

Cited by 5 | Viewed by 1339

Abstract

(1) Background: Continuous monitoring of tacrolimus (TAC), mycophenolic acid (MPA), and creatinine (Cre) after renal transplantation is vitally important. In this study, we developed a new method based on volumetric absorptive microsampling (VAMS) combined with Ultra Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) to [...] Read more.

(1) Background: Continuous monitoring of tacrolimus (TAC), mycophenolic acid (MPA), and creatinine (Cre) after renal transplantation is vitally important. In this study, we developed a new method based on volumetric absorptive microsampling (VAMS) combined with Ultra Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) to simultaneously quantify three analytes including TAC, MPA, and Cre in whole blood. (2) Methods: The VAMS-based UPLC-MS/MS assay used a shared extraction and a single injection to simultaneously quantify the included TAC, MPA, and Cre. Development and validation were carried out following the Food and Drug Administration and European Medicines Agency guidelines for the validation of bioanalytical methods. Moreover, clinical validation for the three analytes was performed in both dried blood spot (DBS) and VAMS. Furthermore, a willingness survey was conducted using the system usability scale (SUS) for renal transplant recipients. (3) Results: The assay was successfully validated for all analytes. No interference, carryover, or matrix effects were observed, and extraction recoveries and process efficiencies were >90.00%. Analysis was unaffected by hematocrit (0.20~0.60, L/L) and anticoagulants (EDTA-2K). Dried VAMS samples were stable for 7 days at ambient temperature and stable for at least 1 month at −20 °C. During clinical validation, the measured TAC, corrected MPA, and Cre concentrations of VAMS samples met the analytical standards (95.00%, 88.57%, and 92.50%). When more stringent clinical acceptance criteria were set, the results obtained by VAMS (90.00%, 71.43%, and 85.00%) better than DBS (77.50%, 62.86%, and 70.00%). Compared with DBS, the survey found that renal transplant recipients are more inclined to use VAMS. (4) Conclusions: A robust extraction and UPLC-MS/MS analysis method in VAMS tips was developed and fully validated for the simultaneous quantification of TAC, MPA, and Cre concentrations. This method provides analytical support for the one-sample remote monitoring of both immunosuppressive drug concentrations and renal function in allo-renal recipients. Based on the good consistency between this method and the routine detection of venous blood samples and higher patient satisfaction than DBS, we believe that VAMS sampling can be a better alternative to venous whole-blood sampling. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Figure 1

14 pages, 2086 KiB

Open AccessArticle

Factors Associated with Aspirin Resistance in Hong Kong Chinese Patients with Stable Coronary Heart Disease Using the Multiplate^® Analyzer and Serum Thromboxane B₂

by Weiwei Zeng, Tanya T. W. Chu, Elaine Y. K. Chow, Miao Hu, Benny S. P. Fok, Juliana C. N. Chan, Bryan P. Y. Yan and Brian Tomlinson

Pharmaceutics 2022, 14(10), 2099; https://doi.org/10.3390/pharmaceutics14102099 - 01 Oct 2022

Viewed by 1397

Abstract

Introduction: Aspirin resistance may be associated with various conditions. We measured serum thromboxane B₂ (TXB₂) and platelet function using the Multiplate^® Analyzer with arachidonic acid (ASPI) in patients on long term aspirin therapy to identify aspirin resistance and associated [...] Read more.

Introduction: Aspirin resistance may be associated with various conditions. We measured serum thromboxane B₂ (TXB₂) and platelet function using the Multiplate^® Analyzer with arachidonic acid (ASPI) in patients on long term aspirin therapy to identify aspirin resistance and associated factors. Materials and Methods: Chinese patients with stable coronary heart disease had samples for serum TXB₂ and ASPI measurement taken before and 1 h after taking a morning dose of 80 mg aspirin. Results: In 266 patients with mean age 66.6 ± 10.7 years, 17% were female and 55% were current or previous smokers. TXB₂ and ASPI measurements were significantly higher before the dose than at 1 h post dose, with 46% of subjects having high ASPI values (AUC > 300 AU*min) pre dose compared with 27% at 1 h post dose. TXB₂ and ASPI measures of platelet aggregation showed weak correlations, which were only significant before the dose (r = 0.219, p = 0.001). Increased ASPI measurements were associated with white blood cell (WBC) count, haematocrit, platelet count and heart rate at 24 h post dose but only with WBC count, smoking history and heart rate at 1 h post dose. Diabetes was not associated with reduced platelet response to aspirin. The WBC count associated with aspirin resistance was over 6.55 × 10⁹/L by receiver operating characteristic analysis. Conclusions: The antiplatelet response to aspirin was reduced in a large proportion of patients. Patients with higher WBC count within the normal range appear to be at increased risk of aspirin resistance. Higher or more frequent doses of aspirin may be needed in many patients. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Figure 1

Review

Jump to: Research

15 pages, 281 KiB

Open AccessReview

Model-Informed Precision Dosing Software Tools for Dosage Regimen Individualization: A Scoping Review

by Paula Del Valle-Moreno, Paloma Suarez-Casillas, Marta Mejías-Trueba, Pablo Ciudad-Gutiérrez, Ana Belén Guisado-Gil, María Victoria Gil-Navarro and Laura Herrera-Hidalgo

Pharmaceutics 2023, 15(7), 1859; https://doi.org/10.3390/pharmaceutics15071859 - 01 Jul 2023

Cited by 5 | Viewed by 2191

Abstract

Background: Pharmacokinetic nomograms, equations, and software are considered the main tools available for Therapeutic Drug Monitoring (TDM). Model-informed precision dosing (MIPD) is an advanced discipline of TDM that allows dose individualization, and requires a software for knowledge integration and statistical calculations. Due to [...] Read more.

Background: Pharmacokinetic nomograms, equations, and software are considered the main tools available for Therapeutic Drug Monitoring (TDM). Model-informed precision dosing (MIPD) is an advanced discipline of TDM that allows dose individualization, and requires a software for knowledge integration and statistical calculations. Due to its precision and extensive applicability, the use of these software is widespread in clinical practice. However, the currently available evidence on these tools remains scarce. Objectives: To review and summarize the available evidence on MIPD software tools to facilitate its identification, evaluation, and selection by users. Methods: An electronic literature search was conducted in MEDLINE, EMBASE, OpenAIRE, and BASE before July 2022. The PRISMA-ScR was applied. The main inclusion criteria were studies focused on developing software for use in clinical practice, research, or modelling. Results: Twenty-eight software were classified as MIPD software. Ten are currently unavailable. The remaining 18 software were described in depth. It is noteworthy that all MIPD software used Bayesian statistical methods to estimate drug exposure and all provided a population model by default, except NONMEN. Conclusions: Pharmacokinetic software have become relevant tools for TDM. MIPD software have been compared, facilitating its selection for use in clinical practice. However, it would be interesting to standardize the quality and validate the software tools. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

62 pages, 2237 KiB

Open AccessReview

Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?

by Aura Rusu, Alexandra-Cristina Munteanu, Eliza-Mihaela Arbănași and Valentina Uivarosi

Pharmaceutics 2023, 15(3), 804; https://doi.org/10.3390/pharmaceutics15030804 - 01 Mar 2023

Cited by 15 | Viewed by 6294

Abstract

Antibacterial fluoroquinolones (FQs) are frequently used in treating infections. However, the value of FQs is debatable due to their association with severe adverse effects (AEs). The Food and Drug Administration (FDA) issued safety warnings concerning their side-effects in 2008, followed by the European [...] Read more.

Antibacterial fluoroquinolones (FQs) are frequently used in treating infections. However, the value of FQs is debatable due to their association with severe adverse effects (AEs). The Food and Drug Administration (FDA) issued safety warnings concerning their side-effects in 2008, followed by the European Medicine Agency (EMA) and regulatory authorities from other countries. Severe AEs associated with some FQs have been reported, leading to their withdrawal from the market. New systemic FQs have been recently approved. The FDA and EMA approved delafloxacin. Additionally, lascufloxacin, levonadifloxacin, nemonoxacin, sitafloxacin, and zabofloxacin were approved in their origin countries. The relevant AEs of FQs and their mechanisms of occurrence have been approached. New systemic FQs present potent antibacterial activity against many resistant bacteria (including resistance to FQs). Generally, in clinical studies, the new FQs were well-tolerated with mild or moderate AEs. All the new FQs approved in the origin countries require more clinical studies to meet FDA or EMA requirements. Post-marketing surveillance will confirm or infirm the known safety profile of these new antibacterial drugs. The main AEs of the FQs class were addressed, highlighting the existing data for the recently approved ones. In addition, the general management of AEs when they occur and the rational use and caution of modern FQs were outlined. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Therapeutic Drug Monitoring

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI