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Pharmaceuticals
Special Issues
Therapeutic Drug Monitoring and Drug-Drug Interactions
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Therapeutic Drug Monitoring and Drug-Drug Interactions

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

Deadline for manuscript submissions: closed (1 September 2021) | Viewed by 21340

Special Issue Editors

Prof. Dr. Christoph Hiemke

E-Mail Website
Guest Editor
1. Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany
2. Department of Pharmacy University of Mainz, Mainz, Germany
Interests: therapeutic drug monitoring; drug–drug interactions; psychopharmacology; behavioral pharmacology; drug transport; drug analysis
Prof. Dr. Martina Hahn

E-Mail Website
Co-Guest Editor
Department of Psychiatry, Psychosomatic Medicine and Psyschotherapy of the University Hospital Frankfurt -Goethe University, Heinrich-Hofmann-Str. 10, 60528 Frankfurt, Germany
Interests: therapeutic drug monitoring; drug-drug and drug-food interactions; psychoeducation; drug therapy safety; pharmacogenetics; clinical pharmacy

Special Issue Information

Dear Colleagues,

Among the multiple indications to use therapeutic drug monitoring (TDM)—that is, the measurement and interpretation of drug concentrations in blood—to optimize pharmacotherapy, Drug-drug interactions are among the first-line indications. Drug-drug interactions, especially pharmacokinetic interactions, affect drug safety and efficacy. They may lead to intoxications due to the inhibition of a drug’s clearance and increased drug concentrations in blood or to a loss of action due to the induction of drug-metabolizing enzymes that accelerate the clearance of a drug and decrease its concentration in blood. On the other hand, a drug like cobicistat is pharmacologically inactive but due to inhibition of the cytochrome P450 iso-enzyme CYP3A4 it is an essential pharmacoenhancer that enables the use of the antiviral drugs emtricitabin and tenofoviralafen. Both are preferred substrates of CYP3A4. Effective drug concentrations in blood are only attained in the presence of a CYP3A4 inhibitor like cobicistat. Drug interactions complicate the widely established polypharmacotherapy. TDM is a tool to enhance its efficiency and safety. This Special Issue is intended to highlight the differential importance and benefit of TDM for the widespread use of polypharmacotherapy in psychiatry, epileptology, HIV therapy, or immunotherapy. You are invited to provide insight into the current state of knowledge on the use of TDM for safe polypharmacy in the different fields of pharmacotherapy.

Prof. Dr. Christoph Hiemke
Prof. Dr. Martina Hahn
Guest Editor

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

  • Drug-drug interaction
  • Therapeutic drug monitoring
  • Psychoactive drugs
  • Immunosuppressant drugs
  • Antiepileptic drugs
  • Anti-HIV drugs

Published Papers (5 papers)

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Research

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12 pages, 757 KiB  
Communication
Levetiracetam Therapeutic Drug Monitoring in a Large Cohort of Korean Epileptic Patients
by Changhee Ha, Hyun-Seung Lee, Eun Yeon Joo, Young-Min Shon, Seung Bong Hong, Dae-Won Seo and Soo-Youn Lee
Pharmaceuticals 2021, 14(8), 826; https://doi.org/10.3390/ph14080826 - 23 Aug 2021
Cited by 8 | Viewed by 3416
Abstract
Levetiracetam is a new antiepileptic drug (AED) used for treating and preventing partial or generalized seizures. The usefulness of levetiracetam therapeutic drug monitoring (TDM) is related to inter- or intra-individual pharmacokinetic variability, drug interactions, and patient noncompliance. We aimed to investigate the levetiracetam [...] Read more.
Levetiracetam is a new antiepileptic drug (AED) used for treating and preventing partial or generalized seizures. The usefulness of levetiracetam therapeutic drug monitoring (TDM) is related to inter- or intra-individual pharmacokinetic variability, drug interactions, and patient noncompliance. We aimed to investigate the levetiracetam TDM status in Korean epilepsy patients. Serum trough levetiracetam concentrations were measured using liquid chromatography–tandem mass spectrometry in 710 samples from 550 patients. The median (range) daily and weight-adjusted levetiracetam doses were 1500 (20–5000) mg and 25.5 (3.03–133.0) mg/kg, respectively. Patients on levetiracetam monotherapy constituted only 19.5% of the population, while 30.1% were on co-medication with valproate and 56.0% with enzyme-inducing AEDs (EIAEDs). Observed levetiracetam concentrations were widely distributed, ranging 0.8–95 mg/L, with a median of 17.3 mg/L. Levetiracetam concentrations were therapeutic, supra-therapeutic, and sub-therapeutic in 58.5% (n = 393), 11.6% (n = 78), and 29.9% (n = 201) of samples, respectively. There was a strong correlation between weight-adjusted levetiracetam dosage and concentrations (ρ = 0.6896, p < 0.0001). In this large-scale clinical study, a large inter-individual difference in levetiracetam pharmacokinetics was observed, and levetiracetam concentrations were influenced by EIAEDs. For individual dose adjustments and monitoring compliance, routine levetiracetam TDM is needed in epilepsy patients. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)
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10 pages, 774 KiB  
Article
Therapeutic Drug Monitoring of Busulfan in Patients Undergoing Hematopoietic Cell Transplantation: A Pilot Single-Center Study in Taiwan
by Rong-Long Chen, Li-Hua Fang, Xin-Yi Yang, Mohsin El Amrani, Esther Veronique Uijtendaal, Yen-Fu Chen and Wei-Chi Ku
Pharmaceuticals 2021, 14(7), 613; https://doi.org/10.3390/ph14070613 - 26 Jun 2021
Cited by 6 | Viewed by 2720
Abstract
Busulfan has been used as a conditioning regimen in allogeneic hematopoietic cell stem transplantation (HSCT). Owing to a large inter-individual variation in pharmacokinetics, therapeutic drug monitoring (TDM)-guided busulfan dosing is necessary to reduce graft failure and relapse rate. As there exists no TDM [...] Read more.
Busulfan has been used as a conditioning regimen in allogeneic hematopoietic cell stem transplantation (HSCT). Owing to a large inter-individual variation in pharmacokinetics, therapeutic drug monitoring (TDM)-guided busulfan dosing is necessary to reduce graft failure and relapse rate. As there exists no TDM of busulfan administration for HCT in Taiwan, we conducted a pilot study to assess the TDM-dosing of busulfan in the Taiwanese population; Seven patients with HCT from The Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, received conditioning regimens consisting of intravenous busulfan and other chemotherapies. After the initial busulfan dose, blood samples were collected for busulfan TDM at 5 min, 1 h, 2 h, and 3 h. Busulfan was extracted and detected by performing stable-isotope dilution LC–MS/MS. Plasma busulfan concentration was quantified and used for dose adjustment. Potential adverse effects of busulfan, such as mucositis and hepatic veno-occlusive disease (VOD), were also evaluated; The LC–MS/MS method was validated with an analyte recovery of 88–99%, within-run and between-run precision of <15%, and linearity ranging from 10 to 10,000 ng/mL. Using TDM-guided busulfan dosing, dose adjustment was necessary and performed in six out of seven patients (86%) with successful engraftments in all patients (100%). Mild mucositis was observed, and VOD was diagnosed in only one patient; This single-center study in Taiwan demonstrated the importance of busulfan TDM in increasing the success rate of HCT transplantation. It is also necessary to further investigate the optimal busulfan target value in the Taiwanese population in the future. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)
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Review

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32 pages, 375 KiB  
Review
Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics
by Nicole Moschny, Gudrun Hefner, Renate Grohmann, Gabriel Eckermann, Hannah B Maier, Johanna Seifert, Johannes Heck, Flverly Francis, Stefan Bleich, Sermin Toto and Catharina Meissner
Pharmaceuticals 2021, 14(6), 514; https://doi.org/10.3390/ph14060514 - 27 May 2021
Cited by 20 | Viewed by 5062
Abstract
Both inflammation and smoking can influence a drug’s pharmacokinetic properties, i.e., its liberation, absorption, distribution, metabolism, and elimination. Depending on, e.g., pharmacogenetics, these changes may alter treatment response or cause serious adverse drug reactions and are thus of clinical relevance. Antipsychotic drugs, used [...] Read more.
Both inflammation and smoking can influence a drug’s pharmacokinetic properties, i.e., its liberation, absorption, distribution, metabolism, and elimination. Depending on, e.g., pharmacogenetics, these changes may alter treatment response or cause serious adverse drug reactions and are thus of clinical relevance. Antipsychotic drugs, used in the treatment of psychosis and schizophrenia, should be closely monitored due to multiple factors (e.g., the narrow therapeutic window of certain psychotropic drugs, the chronicity of most mental illnesses, and the common occurrence of polypharmacotherapy in psychiatry). Therapeutic drug monitoring (TDM) aids with drug titration by enabling the quantification of patients’ drug levels. Recommendations on the use of TDM during treatment with psychotropic drugs are presented in the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology; however, data on antipsychotic drug levels during inflammation or after changes in smoking behavior—both clinically relevant in psychiatry—that can aid clinical decision making are sparse. The following narrative review provides an overview of relevant literature regarding TDM in psychiatry, particularly in the context of second- and third-generation antipsychotic drugs, inflammation, and smoking behavior. It aims to spread awareness regarding TDM (most pronouncedly of clozapine and olanzapine) as a tool to optimize drug safety and provide patient-tailored treatment. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)
15 pages, 2029 KiB  
Review
The Influence of Pharmacogenetics on the Clinical Relevance of Pharmacokinetic Drug–Drug Interactions: Drug–Gene, Drug–Gene–Gene and Drug–Drug–Gene Interactions
by Martina Hahn and Sibylle C. Roll
Pharmaceuticals 2021, 14(5), 487; https://doi.org/10.3390/ph14050487 - 20 May 2021
Cited by 25 | Viewed by 5358
Abstract
Drug interactions are a well-known cause of adverse drug events, and drug interaction databases can help the clinician to recognize and avoid such interactions and their adverse events. However, not every interaction leads to an adverse drug event. This is because the clinical [...] Read more.
Drug interactions are a well-known cause of adverse drug events, and drug interaction databases can help the clinician to recognize and avoid such interactions and their adverse events. However, not every interaction leads to an adverse drug event. This is because the clinical relevance of drug–drug interactions also depends on the genetic profile of the patient. If inhibitors or inducers of drug metabolising enzymes (e.g., CYP and UGT) are added to the drug therapy, phenoconcversion can occur. This leads to a genetic phenotype that mismatches the observable phenotype. Drug–drug–gene and drug–gene–gene interactions influence the toxicity and/or ineffectivness of the drug therapy. To date, there have been limited published studies on the impact of genetic variations on drug–drug interactions. This review discusses the current evidence of drug–drug–gene interactions, as well as drug–gene–gene interactions. Phenoconversion is explained, the and methods to calculate the phenotypes are described. Clinical recommendations are given regarding the integratation of the PGx results in the assessment of the relevance of drug interactions in the future. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)
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Other

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14 pages, 2980 KiB  
Perspective
A 5-Year Study of Lithium and Valproic Acid Drug Monitoring in Patients with Bipolar Disorders in an Italian Clinical Center
by Marco Carli, Eleonora Risaliti, Mena Francomano, Shivakumar Kolachalam, Biancamaria Longoni, Guido Bocci, Roberto Maggio and Marco Scarselli
Pharmaceuticals 2022, 15(1), 105; https://doi.org/10.3390/ph15010105 - 17 Jan 2022
Cited by 5 | Viewed by 3245
Abstract
Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this [...] Read more.
Therapeutic drug monitoring (TDM) is an effective tool used to improve the pharmacological treatment in clinical practice, especially to detect subtherapeutic drug plasma concentration (Cp) in order to consider a change of dosage during treatment and reach its putative therapeutic range. In this study, we report the Cp values of lithium and valproic acid (VPA), alone and in combination, mostly in bipolar patients admitted to an Italian clinical center of the University of Pisa during the years 2016–2020, which include 12,294 samples of VPA, 7449 of lithium and 1118 of both in combination. Lithium and VPA are the most utilized drugs in treating bipolar disorders, and their TDM is strongly recommended by recent guidelines. In relation to lithium Cp monitoring, several studies have underlined that 0.5–0.8 mmol/L is the optimal range for chronic treatment, and below 0.4 mmol/L, it is unlikely to produce a clinical response. For VPA, the therapeutic range is 50–100 μg/mL and a linear correlation between Cp and clinical efficacy has been proposed, where below 50 μg/mL, the clinical efficacy of VPA has not been proven thus far. Toxic levels of both drugs were rarely found in our study, while a high percentage of patients, about one-third, had sub-therapeutic Cp during their treatments. In addition, in several cases of patients receiving multiple blood sampling, the initial subtherapeutic Cp changed only partially without reaching its therapeutic window. In relation to age, we found a higher percentage of lithium and VPA Cp values in range in the adolescents than in the adults and elderly groups. No differences were reported when analyzing the distribution of Cp values in males and females. In conclusion, this present study suggests that TDM is widely used by many specialists, but there is still a window of improvement for optimizing pharmacological treatments in clinical practice. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Drug-Drug Interactions)
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