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Therapeutic Drug Monitoring and Adverse Drug Reactions

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 29 June 2024 | Viewed by 10690

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Special Issue Editors

Dr. Engi Abd El Hady Algharably

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Guest Editor

Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Charitéplatz 1, 10117 Berlin, Germany
Interests: clinical pharmacokinetics; pharmacogenetics; risk assessment; pbpk modeling; hypertension

Prof. Dr. Ursula Gundert-Remy

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Guest Editor

Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Charitéplatz 1, 10117 Berlin, Germany
Interests: toxicokinetics; toxicity; pharmacokinetics; bioavailability; clinical pharmacokinetics pharmacokinetic modeling; pkpd modeling; pharmacovigilance; risk assessment; toxicology

Special Issue Information

Dear Colleagues,

Therapeutic drug monitoring (TDM) and the prevention of adverse drug reactions (ADRs) are of utmost importance in optimizing patient care and medication safety. To explore the latest advancements and insights in this field, Pharmaceuticals is pleased to announce a Special Issue on therapeutic drug monitoring and adverse drug reactions. This issue aims to provide a comprehensive platform for researchers, clinicians and pharmacologists to present their original research, reviews and case studies related to TDM and ADRs.

The Special Issue seeks contributions covering various topics, including novel methodologies and technologies for TDM, individualized dosing strategies, biomarkers for predicting drug response and ADRs, strategies to minimize ADRs and enhance medication safety, pharmacogenomics in TDM and the implementation of TDM in clinical practice.

By exploring these themes, the Special Issue aims to enhance our understanding of drug efficacy, toxicity and personalized treatment strategies. It also seeks to highlight the importance of TDM in optimizing drug therapy, minimizing ADRs and improving patient outcomes. Researchers and clinicians are encouraged to submit their high-quality manuscripts to contribute to the advancements in therapeutic drug monitoring and adverse drug reactions.

Dr. Engi Abd El Hady Algharably
Prof. Dr. Ursula Gundert-Remy
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. 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
adverse drug reactions
pharmacokinetics
personalized medicine
medication safety
biomarkers
pharmacogenomics
drug therapy optimization

Published Papers (9 papers)

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Research

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13 pages, 927 KiB

Open AccessArticle

Effects of CYP3A5 Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation

by Daniel N. Marco, Mònica Molina, Ana-María Guio, Judit Julian, Virginia Fortuna, Virginia-Lucila Fabregat-Zaragoza, María-Queralt Salas, Inés Monge-Escartín, Gisela Riu-Viladoms, Esther Carcelero, Joan Ramón Roma, Noemí Llobet, Jordi Arcarons, María Suárez-Lledó, Laura Rosiñol, Francesc Fernández-Avilés, Montserrat Rovira, Mercè Brunet and Carmen Martínez

Pharmaceuticals 2024, 17(5), 553; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17050553 - 25 Apr 2024

Viewed by 367

Abstract

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C₀/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C₀/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C₀ at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier. Full article

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

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16 pages, 2939 KiB

Open AccessArticle

An LC-MS/MS Method for Quantification of Lamotrigine and Its Main Metabolite in Dried Blood Spots

by Daniela Milosheska, Robert Roškar, Tomaž Vovk, Bogdan Lorber, Iztok Grabnar and Jurij Trontelj

Pharmaceuticals 2024, 17(4), 449; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17040449 - 30 Mar 2024

Viewed by 683

Abstract

Background: The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response. Results: The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients. Conclusions: The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination. Full article

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

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11 pages, 272 KiB

Open AccessArticle

Risk Factors for Respiratory Depression Associated with Tramadol Based on the Global Pharmacovigilance Database (VigiBase)

by Sunny Park, Geon-Ho Lee, Soyun Kim, Solee Kim, Yeju Kim and Soo-An Choi

Pharmaceuticals 2024, 17(2), 205; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17020205 - 5 Feb 2024

Viewed by 1190

Abstract

Tramadol, a weak μ-opioid receptor agonist, has been used worldwide for pain management. It is considered to have a favorable safety profile without serious adverse events; however, safety issues of respiratory depression were proposed by regulatory governments. We aimed to examine the risk and contributing factors associated with tramadol-related respiratory depression using a real-world database, VigiBase. Disproportionality analysis of tramadol and tramadol/paracetamol was performed using proportional reporting ratios, reporting odds ratios, and information components for all drugs and opioids. Factors related to respiratory depression, including sex, age, presence of abuse, death, and various concomitant medications, were evaluated. Among 140,721 tramadol reports, respiratory depression was reported in 1126 cases, 81.3% of which were deemed serious. Five adverse events were detected as signals of tramadol-related acute central respiratory depression (ACRD) in 882 reports. A higher proportion of ACRD cases in children and adolescents was observed than all adverse events cases of tramadol. Concomitant users of CYP2D6 inhibitors, opioids, benzodiazepines, and anti-depressant drugs showed a higher proportion in ACRD cases than non-ACRD cases. ACRD was related to drug abuse and death. This pharmacovigilance study, using VigiBase, confirmed a high risk of respiratory depression (a serious, potentially fatal adverse event) secondary to the use of tramadol, especially in pediatric patients, drug abusers, or during concomitant use of opioids, benzodiazepines, or antidepressants. Full article

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

14 pages, 1653 KiB

Open AccessArticle

Association between Prescribing and Intoxication Rates for Selected Psychotropic Drugs: A Longitudinal Observational Study

by Matej Dobravc Verbič, Iztok Grabnar and Miran Brvar

Pharmaceuticals 2024, 17(1), 143; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17010143 - 22 Jan 2024

Viewed by 977

Abstract

Psychotropic prescription drugs are commonly involved in intoxication events. The study’s aim was to determine a comparative risk for intoxication in relation to prescribing rates for individual drugs. This was a nationwide observational study in Slovenian adults between 2015 and 2021. Intoxication events with psychotropic drugs were collected from the National Register of intoxications. Dispensing data, expressed in defined daily doses, were provided by the Health Insurance Institute of Slovenia. Intoxication/prescribing ratio values were calculated. The correlation between trends in prescribing and intoxication rates was assessed using the Pearson correlation coefficient. In total, 2640 intoxication cases with psychotropic prescription drugs were registered. Anxiolytics and antipsychotics were the predominant groups. Midazolam, chlormethiazole, clonazepam, sulpiride, and quetiapine demonstrated the highest risk of intoxication, while all antidepressants had a risk several times lower. The best trend correlation was found for the prescribing period of 2 years before the intoxication events. An increase of 1,000,000 defined daily doses prescribed resulted in an increase of fifty intoxication events for antipsychotics, twenty events for antiepileptics, and five events for antidepressants. Intoxication/prescribing ratio calculation allowed for a quantitative comparison of the risk for intoxication in relation to the prescribing rates for psychotropic drugs, providing additional understanding of their toxicoepidemiology. Full article

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

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20 pages, 1232 KiB

Open AccessArticle

Drug-Induced Anaphylaxis: National Database Analysis

by Olga Butranova, Sergey Zyryanov, Anastasia Gorbacheva, Irina Asetskaya and Vitaly Polivanov

Pharmaceuticals 2024, 17(1), 90; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17010090 - 9 Jan 2024

Cited by 1 | Viewed by 1500

Abstract

(1) Background: National health system databases represent an important source of information about the epidemiology of adverse drug reactions including drug-induced allergy and anaphylaxis. Analysis of such databases may enhance the knowledge of healthcare professionals regarding the problem of drug-induced anaphylaxis. (2) Methods: A retrospective descriptive analysis was carried out of spontaneous reports (SRs) with data on drug-induced anaphylaxis (SRsAs) extracted from the Russian National Pharmacovigilance database (analyzed period 2 April 2019–21 June 2023). The percentage of SRsAs among SRs of drug-induced allergy (SRsDIAs) was calculated, as well as of pediatric, elderly, and fatal SrsAs. Drugs involved in anaphylaxis were assessed among total SRsAs, pediatric, and elderly SRsAs, and among fatal SRsAs. Demographic parameters of patients were assessed. (3) Results: SRsAs were reported in 8.3% of SRsDIAs (2304/27,727), the mean age of patients was 48.2 ± 15.8 years, and females accounted for 53.2% of cases. The main causative groups of drugs were antibacterials (ABs) for systemic use (44.6%), local anesthetics (20.0%), and cyclooxygenase (COX) inhibitors (10.1%). Fatal SRsAs were reported in 9.5% (218/2304) of cases, the mean age of patients was 48.0 ± 16.7 years, and females accounted for 56.4% of cases. Pediatric SRsAs accounted for 3.9% of pediatric SRsDIAs and 5.8% of all SRsAs, with a mean age of 11.8 ± 4.5 years, and females acccounted for 51.9% of cases. Elderly SRsAs accounted for 2% of elderly SRsDIAs and 2.8% of all SRsAs, and the mean age was 73.0 ± 5.3 years, and females accounted for 43.5% of cases. ABs caused 40% of SRsAs in the elderly, 42.9% in children, and 50% of fatal SRsAs. (4) Conclusions: Our study revealed a relatively high proportion of anaphylaxis among SRs of drug-induced allergy. ABs were the most prevalent causative agents, especially in fatal SRsAs. Full article

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

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16 pages, 2577 KiB

Open AccessArticle

Association of ABCB1 Polymorphisms with Efficacy and Adverse Drug Reactions of Valproic Acid in Children with Epilepsy

by Jiahao Zhu, Jieluan Lu, Yaodong He, Xianhuan Shen, Hanbing Xia, Wenzhou Li, Jianping Zhang and Xiaomei Fan

Pharmaceuticals 2023, 16(11), 1536; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16111536 - 30 Oct 2023

Viewed by 902

Abstract

Genetic polymorphisms in ATP-binding cassette subfamily B member 1 (ABCB1, also known as MDR1) have been reported to be possibly associated with the regulation of response to antiseizure medications. The aim of this study was to investigate the association of ABCB1 polymorphisms with the efficacy of and adverse drug reactions to valproic acid among Chinese children with epilepsy. A total of 170 children from southern China with epilepsy treated with valproic acid for more than one year were recruited, including 61 patients with persistent seizures and 109 patients who were seizure-free. Two single nucleotide polymorphisms of ABCB1, rs1128503 and rs3789243, were genotyped using the Sequenom MassArray system. The two single nucleotide polymorphisms of ABCB1 were found to be significantly associated with treatment outcomes of valproic acid in children with epilepsy. Carriers with the TT genotype of ABCB1 rs1128503 were more inclined to exhibit persistent seizures after treatment with valproic acid (p = 0.013). The CC genotype of rs3789243 was observed to be a potential protective factor for valproic acid-induced gastrointestinal adverse drug reactions (p = 0.018), but possibly increased the risk of valproic acid-induced cutaneous adverse drug reactions (p = 0.011). In contrast, the CT genotype of rs3789243 was associated with a lower risk of valproic acid-induced cutaneous adverse drug reactions (p = 0.011). Haplotype analysis showed that CC haplotype carriers tended to respond better to valproic acid treatment (p = 0.009). Additionally, no significant association was found between ABCB1 polymorphisms and serum concentrations of valproic acid. This study revealed that the polymorphisms and haplotypes of the ABCB1 gene might be associated with the treatment outcomes of valproic acid in Chinese children with epilepsy. Full article

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

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24 pages, 2823 KiB

Open AccessArticle

Comprehensive Study of Drug-Induced Pruritus Based on Adverse Drug Reaction Report Database

by Yuriko Nakao, Mizuho Asada and Yoshihiro Uesawa

Pharmaceuticals 2023, 16(10), 1500; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16101500 - 21 Oct 2023

Viewed by 1785

Abstract

Drug-induced pruritus triggers a desire to scratch, thereby diminishing one’s quality of life. Certain instances of this phenomenon follow complex mechanisms of action that diverge from histamine-mediated pathways, known contributors to pruritus. However, investigations into the relationship between drugs and pruritus are limited. In this study, data mining techniques were employed to comprehensively analyze the characteristics of drugs linked to pruritus, using the FDA’s Adverse Event Reporting System (FAERS) data. Reports linked to pruritus demonstrated noteworthy differences in gender, age, and weight when compared with non-pruritus cases. Among the leading candidates for drugs prompting pruritus were ophthalmic drugs, systemic antibacterials, contrast media, dermatological antifungals, and dermatological preparations. A principal component analysis showed that the second principal component served as an indicator for distinguishing between onsets at mucous membranes or the skin’s surface. Additionally, the third principal component functioned as an indicator for categorizing administration methods as either invasive or noninvasive. Furthermore, a hierarchical cluster analysis conducted on these obtained principal components revealed the potential for classifying drugs based on the site of pruritus onset and the method of drug administration. These findings contribute to the development of targeted prevention and treatment strategies for avoiding pruritus in clinical practice. Full article

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

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Review

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21 pages, 901 KiB

Open AccessReview

Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example

by Jens-Uwe Peter, Peter Dieudonné and Oliver Zolk

Pharmaceuticals 2024, 17(4), 473; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17040473 - 8 Apr 2024

Viewed by 942

Abstract

Midazolam, a short-acting benzodiazepine, is widely used to alleviate patient anxiety, enhance compliance, and aid in anesthesia. While its side effects are typically dose-dependent and manageable with vigilant perioperative monitoring, serious cardiorespiratory complications, including fatalities and permanent neurological impairment, have been documented. Prolonged exposure to benzodiazepines, such as midazolam, has been associated with neurological changes in infants. Despite attempts to employ therapeutic drug monitoring for optimal sedation dosing, its efficacy has been limited. Consequently, efforts are underway to identify alternative predictive markers to guide individualized dosing and mitigate adverse effects. Understanding these factors is crucial for determining midazolam’s suitability for future administration, particularly after a severe adverse reaction. This article aims to elucidate the factors influencing midazolam’s pharmacokinetics and pharmacodynamics, potentially leading to adverse events. Finally, a case study is presented to exemplify the complex investigation into the causative factors of midazolam-related adverse events. Full article

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

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72 pages, 1834 KiB

Open AccessReview

A Drug Safety Briefing (II) in Transplantation from Real-World Individual Pharmacotherapy Management to Prevent Patient and Graft from Polypharmacy Risks at the Very Earliest Stage

by Ursula Wolf

Pharmaceuticals 2024, 17(3), 294; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17030294 - 25 Feb 2024

Viewed by 1226

Abstract

For early and long-term patient and graft survival, drug therapy in solid organ and hematopoietic stem cell transplantation inevitably involves polypharmacy in patients with widely varying and even abruptly changing conditions. In this second part, relevant medication briefing is provided, in addition to the scores defined in the previously published first part on the design of the Individual Pharmacotherapy Management (IPM). The focus is on the growing spectrum of contemporary polypharmacy in transplant patients, including early and long-term follow-up medications. 1. Unlike the available drug–drug interaction (DDI) tables, for the first time, this methodological all-in-one device refers to the entire risks, including contraindications, special warnings, adverse drug reactions (ADRs), and DDIs. The selection of 65 common critical drugs results from 10 years of daily IPM with real-world evidence from more than 60,800 IPM inpatient and outpatient medication analyses. It includes immunosuppressants and typical critical antimicrobials, analgesics, antihypertensives, oral anticoagulants, antiarrhythmics, antilipids, antidepressants, antipsychotics, antipropulsives, antiemetics, propulsives, proton pump inhibitors (PPIs), sedatives, antineoplastics, and protein kinase inhibitors. As a guide for the attending physician, the drug-related risks are presented in an alphabetical overview based on the Summaries of Product Characteristics (SmPCs) and the literature. 2. Further briefing refers to own proven clinical measures to manage unavoidable drug-related high-risk situations. Drug-induced injuries to the vulnerable graft and the immunosuppressed comorbid patient require such standardized, intensive IPM and the comprehensive preventive briefing toolset to optimize the outcomes in the polypharmacy setting. Full article

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

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