Immunosuppressant quantification in intravenous microdialysate – towards novel quasi-continuous therapeutic drug monitoring in transplanted patients

AbstractObjectivesTherapeutic drug monitoring (TDM) plays a crucial role in personalized medicine. It helps clinicians to tailor drug dosage for optimized therapy through understanding the underlying complex pharmacokinetics and pharmacodynamics. Conventional, non-continuous TDM fails to provide real-time information, which is particularly important for the initial phase of immunosuppressant therapy, e.g., with cyclosporine (CsA) and mycophenolic acid (MPA).MethodsWe analyzed the time course over 8 h of total and free of immunosuppressive drug (CsA and MPA) concentrations measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 16 kidney transplant patients. Besides repeated blood sampling, intravenous microdialysis was used for continuous sampling. Free drug concentrations were determined from ultracentrifuged EDTA-plasma (UC) and compared with the drug concentrations in the respective microdialysate (µD). µDs were additionally analyzed for free CsA using a novel immunosensor chip integrated into a fluorescence detection platform. The potential of microdialysis coupled with an optical immunosensor for the TDM of immunosuppressants was assessed.ResultsUsing LC-MS/MS, the free concentrations of CsA (fCsA) and MPA (fMPA) were detectable and the time courses of total and free CsA comparable. fCsA and fMPA and area-under-the-curves (AUCs) in µDs correlated well with those determined in UCs (r≥0.79 and r≥0.88, respectively). Moreover, fCsA in µDs measured with the immunosensor correlated clearly with those determined by LC-MS/MS (r=0.82).ConclusionsThe new microdialysis-supported immunosensor allows real-time analysis of immunosuppressants and tailor-made dosing according to the AUC concept. It readily lends itself to future applications as minimally invasive and continuous near-patient TDM.

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An Aptamer-Based Biosensor for the Azole Class of Antifungal Drugs

mSphere ◽

10.1128/msphere.00274-17 ◽

2017 ◽

Vol 2 (4) ◽

Cited By ~ 7

Author(s):

Gregory R. Wiedman ◽

Yanan Zhao ◽

Arkady Mustaev ◽

Jinglei Ping ◽

Ramya Vishnubhotla ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Field Effect ◽

Field Effect Transistor ◽

Drug Dosage ◽

Antifungal Drugs ◽

Therapeutic Drug ◽

Drug Concentrations ◽

Graphene Field Effect Transistor ◽

Effect Transistor

ABSTRACT We have developed the first aptamer directed toward the azole class of antifungal drugs and a functional biosensor for these drugs. This aptamer has a unique secondary structure that allows it to bind to highly hydrophobic drugs. The aptamer works as a capture component of a graphene field effect transistor device. These devices can provide a quick and easy assay for determining drug concentrations. These will be useful for therapeutic drug monitoring of azole antifungal drugs, which is necessary to deal with the complex drug dosage profiles. This technical report describes the development of an aptamer for sensing azole antifungal drugs during therapeutic drug monitoring. Modified synthetic evolution of ligands through exponential enrichment (SELEX) was used to discover a DNA aptamer recognizing azole class antifungal drugs. This aptamer undergoes a secondary structural change upon binding to its target molecule, as shown through fluorescence anisotropy-based binding measurements. Experiments using circular dichroism spectroscopy revealed a unique G-quadruplex structure that was essential and specific for binding to the azole antifungal target. Aptamer-functionalized graphene field effect transistor (GFET) devices were created and used to measure the strength of binding of azole antifungals to this surface. In total, this aptamer and the supporting sensing platform provide a valuable tool for therapeutic drug monitoring of patients with invasive fungal infections. IMPORTANCE We have developed the first aptamer directed toward the azole class of antifungal drugs and a functional biosensor for these drugs. This aptamer has a unique secondary structure that allows it to bind to highly hydrophobic drugs. The aptamer works as a capture component of a graphene field effect transistor device. These devices can provide a quick and easy assay for determining drug concentrations. These will be useful for therapeutic drug monitoring of azole antifungal drugs, which is necessary to deal with the complex drug dosage profiles.

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Rapid point-of-care anti-infliximab antibodies detection in clinical practice: comparison with ELISA and potential for improving therapeutic drug monitoring in IBD patients

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284821999902 ◽

2021 ◽

Vol 14 ◽

pp. 175628482199990

Author(s):

Sonia Facchin ◽

Andrea Buda ◽

Romilda Cardin ◽

Nada Agbariah ◽

Fabiana Zingone ◽

...

Keyword(s):

Clinical Practice ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Point Of Care ◽

Drug Clearance ◽

Elisa Test ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Drug ◽

Drug Concentrations ◽

Inflammatory Bowel

Anti-drug antibodies can interfere with the activity of anti-tumor necrosis factor (TNF) agents by increasing drug clearance via direct neutralization. The presence of anti-drug antibodies is clinically relevant when trough drug concentrations are undetectable or sub-therapeutic. However, traditional immunoassay is not easily and rapidly accessible, making the translation of the results into treatment adjustment difficult. The availability of a point-of-care (POC) test for therapeutic drug monitoring (TDM) might represent an important step forward for improving the management of inflammatory bowel disease (IBD) patients in clinical practice. In this pilot study, we compared the results obtained with POC tests with those obtained by enzyme-linked immunosorbent assay (ELISA) in a group of IBD patients treated with Infliximab (IFX). We showed that POC test can reliably detect presence of antibody-to-IFX with 100% of specificity and 76% sensitivity, in strong agreement with the ELISA test ( k-coefficient = 0.84).

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Real-Time Therapeutic Drug Monitoring-Based Pharmacokinetic/Pharmacodynamic Optimization of Complex Antimicrobial Therapy in a Critically Ill Morbidly Obese Patient. Grand Round/A Case Study

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000740 ◽

2020 ◽

Vol 42 (3) ◽

pp. 349-352

Author(s):

Pier Giorgio Cojutti ◽

Alessia Carnelutti ◽

Silvia Mattelig ◽

Assunta Sartor ◽

Federico Pea

Keyword(s):

Therapeutic Drug Monitoring ◽

Obese Patient ◽

Real Time ◽

Antimicrobial Therapy ◽

Drug Monitoring ◽

Grand Round ◽

Therapeutic Drug ◽

Morbidly Obese ◽

Morbidly Obese Patient

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Pharmacokinetic Properties of New Antiepileptic Drugs

Journal of Pharmacy Practice ◽

10.1177/0897190005282733 ◽

2005 ◽

Vol 18 (6) ◽

pp. 444-460 ◽

Cited By ~ 8

Author(s):

Michele Y. Splinter

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Interactions ◽

Antiepileptic Drugs ◽

Drug Monitoring ◽

The United States ◽

Therapeutic Drug ◽

Kinetic Properties ◽

New Antiepileptic Drugs ◽

Drug Concentrations ◽

Pharmacokinetic Properties

Eight new antiepileptic drugs (AEDs) have been approved for use within the United States within the past decade. They are felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide. These afford clinicians with more options to increase efficacy and tolerability in the treatment of patients with epilepsy. Pharmacokinetic properties and drug interactions with other AEDs and other medications taken for comorbidities are individually discussed for each of these new agents. Drug concentrations are not routinely monitored for these newer agents, and there have been few studies designed to investigate their concentration-effect relationships. For most of these medications, the concentrations observed in responders and nonresponders overlap considerably and levels associated with efficacy are often associated with adverse events, complicating the definition of target ranges. Also, epilepsy manifests itself sporadically causing difficulty in clinically monitoring efficacy of medications. Therapeutic drug monitoring provides for the individualization of treatment for these agents, which is important because they demonstrate significant variability in inter- and intraindividual pharmaco-kinetic properties. Therapeutic drug monitoring also allows for identification of noncompliance, drug interactions, and toxicity. Current knowledge of the relationships between efficacy, toxicity, and drug concentrations is discussed.

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N22 Nurse led therapeutic drug monitoring (TDM) of Infliximab in IBD

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.1005 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S667-S668

Author(s):

S Gleeson ◽

K Sugrue ◽

M Buckley ◽

J McCarthy

Keyword(s):

Therapeutic Drug Monitoring ◽

Trough Concentration ◽

Drug Monitoring ◽

Response Assessment ◽

Symptom Improvement ◽

Therapeutic Drug ◽

Serum Samples ◽

Drug Concentrations ◽

Biologic Response ◽

Trough Levels

Abstract Background Therapeutic drug monitoring (TDM) is the clinical practice of measuring serum drug concentrations to guide clinical decision making. Achieving therapeutic drug concentrations has been associated with clinical, endoscopic and histological outcomes in IBD. The use of TDM offers a more personalised treatment approach and is associated with sustained clinical remission. Proactive TDM was introduced to the Mercy University Hospital in 2014 for all patients on biologics. Methods One hundred patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement. Results Thirty-five per cent of patients had sub therapeutic trough levels at week 12. They subsequently received 3 increased doses of 10mgs/kg and levels were rechecked. Of these 90% achieved therapeutic levels after the dose escalation. 65% of patients had therapeutic levels at week 12. There was a correlation between therapeutic trough levels and patient reported improvement of clinical symptoms in 85% of respondents. Conclusion TDM in our unit facilitates appropriate dose 100 patients receiving biologic infusion (Infliximab) were evaluated post induction (week 12) for therapeutic drug trough concentration and for clinical response. Serum samples were taken from all IBD patients at week 12. Biologic response assessment forms were complete for all patients to assess symptom improvement.

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Therapeutic drug monitoring in special populations

Clinical Chemistry ◽

10.1093/clinchem/44.2.415 ◽

1998 ◽

Vol 44 (2) ◽

pp. 415-419 ◽

Cited By ~ 20

Author(s):

Philip D Walson

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Diagnostic Testing ◽

Drug Effects ◽

Special Populations ◽

Therapeutic Drug ◽

Drug Reactions ◽

Drug Concentrations ◽

Dosing Regimens ◽

Multiple Drugs

Abstract Therapeutic drug monitoring (TDM) is commonly used to maintain “therapeutic” drug concentrations. Even in compliant patients, with “average” drug kinetics, TDM is useful to identify the causes of unwanted or unexpected responses, prevent unnecessary diagnostic testing, improve clinical outcomes, and even save lives. TDM has greatest promise in certain special populations who are: (a) prone to under- or overrespond to usual dosing regimens, (b) least able to tolerate, recognize, or communicate drug effects, or who are (c) intentionally or accidentally misdosed. TDM is especially useful in patients at the extremes of age, in adolescents, and in patients who are either taking multiple drugs or expressing unusual pharmacokinetics as a result of physiological, environmental, or genetic causes. Less-well-appreciated uses of TDM include prevention of dangerousunderdosing of patients, investigation of adverse drug reactions, and identification of serious medication errors, even for a number of drugs that are not traditionally monitored. TDM can be useful for some drugs in any patient and for most drugs in some special populations.

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The role of therapeutic drug monitoring in individualised drug dosage and exposure measurement in tuberculosis and HIV co-infection

European Respiratory Journal ◽

10.1183/09031936.00157914 ◽

2015 ◽

Vol 45 (2) ◽

pp. 571-574 ◽

Cited By ~ 4

Author(s):

Susanna Esposito ◽

Luigi R. Codecasa ◽

Rosella Centis

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Drug Dosage ◽

Therapeutic Drug ◽

Exposure Measurement

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The significance of a new parameter – plasma protein binding – in therapeutic drug monitoring and its application to carbamazepine in epileptic patients

RSC Advances ◽

10.1039/c7ra02991h ◽

2017 ◽

Vol 7 (45) ◽

pp. 28048-28055 ◽

Cited By ~ 1

Author(s):

Jing-lin Gao ◽

Xin-yu Wang ◽

Jing An ◽

Chao-hui Du ◽

Meng-jiao Li ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Protein Binding ◽

Plasma Protein Binding ◽

Plasma Protein ◽

Drug Monitoring ◽

Drug Dosage ◽

Therapeutic Drug ◽

Dosage Regimens ◽

Epileptic Patients

The primary cause of the variability of Cf in pharmacology is the change in plasma protein binding (PPB), thus PPB monitoring should be applied to a better individualization of drug dosage regimens in clinical patients.

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Therapeutic Drug Monitoring of Piperacillin-Tazobactam Using Spent Dialysate Effluent in Patients Receiving Continuous Venovenous Hemodialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00548-10 ◽

2010 ◽

Vol 55 (2) ◽

pp. 557-560 ◽

Cited By ~ 25

Author(s):

Michael J. Connor ◽

Charbel Salem ◽

Seth R. Bauer ◽

Christina L. Hofmann ◽

Joseph Groszek ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Kidney Injury ◽

Therapeutic Drug ◽

Plasma Drug ◽

Drug Dosing ◽

Drug Levels ◽

Drug Concentrations ◽

Continuous Venovenous Hemodialysis ◽

Dosing Strategies

ABSTRACTSepsis and multisystem organ failure are common diagnoses affecting nearly three-quarters of a million Americans annually. Infection is the leading cause of death in acute kidney injury, and the majority of critically ill patients who receive continuous dialysis also receive antibiotics. Dialysis equipment and prescriptions have gradually changed over time, raising concern that current drug dosing recommendations in the literature may result in underdosing of antibiotics. Our research group directed its attention toward antibiotic dosing strategies in patients with acute renal failure (ARF), and we sought data confirming that patients receiving continuous dialysis and antibiotics actually were achieving therapeutic plasma drug levels during treatment. In the course of those investigations, we explored “fast-track” strategies to estimate plasma drug concentrations. As most antimicrobial antibiotics are small molecules and should pass freely through modern high-flux hemodialyzer filters, we hypothesized that continuous renal replacement therapy (CRRT) effluent could be used as the medium for drug concentration measurement by reverse-phase high-pressure liquid chromatography (HPLC). Here we present the first data demonstrating this approach for piperacillin-tazobactam. Paired blood and dialysate trough-peak-trough samples were drawn from 19 patients receiving piperacillin-tazobactam and continuous venovenous hemodialysis (CVVHD). Total, free, and dialysate drug concentrations were measured by HPLC. Dialysate drug levels predicted plasma free drug levels well (r2= 0.91 and 0.92 for piperacillin and tazobactam, respectively) in all patients. These data suggest a strategy for therapeutic drug monitoring that minimizes blood loss from phlebotomy and simplifies analytic procedures.

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