Pharmacokinetic interpretation of data gathered during therapeutic drug monitoring.

Abstract We review some pharmacokinetic principles that can facilitate interpretation of data obtained during therapeutic drug monitoring: the one- and two-compartment models, volume of drug distribution, drug clearance, organ clearance, bioavailability, first-pass effect, chronic or repetitive dosing, and use of urine and saliva to measure drug clearance and drug binding to plasma proteins, respectively. We also describe use of saliva to estimate rapidly, conveniently, and noninvasively the concentration of the free, pharmacologically active form of the drug as well as the fraction of drug bound to plasma protein.

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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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Recent Advances in Therapeutic Drug Monitoring of Voriconazole, Mycophenolic Acid, and Vancomycin: A Literature Review of Pediatric Studies

Pharmaceutics ◽

10.3390/pharmaceutics13121991 ◽

2021 ◽

Vol 13 (12) ◽

pp. 1991

Author(s):

Matylda Resztak ◽

Joanna Sobiak ◽

Andrzej Czyrski

Keyword(s):

Therapeutic Drug Monitoring ◽

Mycophenolic Acid ◽

Drug Monitoring ◽

Pediatric Patients ◽

Fungal Infections ◽

Cord Blood Transplantation ◽

Active Form ◽

Therapeutic Drug ◽

Hematopoietic Stem ◽

Acute Kidney Disease

The review includes studies dated 2011–2021 presenting the newest information on voriconazole (VCZ), mycophenolic acid (MPA), and vancomycin (VAN) therapeutic drug monitoring (TDM) in children. The need of TDM in pediatric patients has been emphasized by providing the information on the differences in the drugs pharmacokinetics. TDM of VCZ should be mandatory for all pediatric patients with invasive fungal infections (IFIs). Wide inter- and intrapatient variability in VCZ pharmacokinetics cause achieving and maintaining therapeutic concentration during therapy challenging in this population. Demonstrated studies showed, in most cases, VCZ plasma concentrations to be subtherapeutic, despite the updated dosages recommendations. Only repeated TDM can predict drug exposure and individualizing dosing in antifungal therapy in children. In children treated with mycophenolate mofetil (MMF), similarly as in adult patients, the role of TDM for MMF active form, MPA, has not been well established and is undergoing continued debate. Studies on the MPA TDM have been carried out in children after renal transplantation, other organ transplantation such as heart, liver, or intestine, in children after hematopoietic stem cell transplantation or cord blood transplantation, and in children with lupus, nephrotic syndrome, Henoch-Schönlein purpura, and other autoimmune diseases. MPA TDM is based on the area under the concentration–time curve; however, the proposed values differ according to the treatment indication, and other approaches such as pharmacodynamic and pharmacogenetic biomarkers have been proposed. VAN is a bactericidal agent that requires TDM to prevent an acute kidney disease. The particular group of patients is the pediatric one. For this group, the general recommendations of the dosing may not be valid due to the change of the elimination rate and volume of distribution between the subjects. The other factor is the variability among patients that concerns the free fraction of the drug. It may be caused by both the patients’ population and sample preconditioning. Although VCZ, MMF, and VAN have been applied in pediatric patients for many years, there are still few issues to be solve regarding TDM of these drugs to ensure safe and effective treatment. Except for pharmacokinetic approach, pharmacodynamics and pharmacogenetics have been more often proposed for TDM.

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Evidence-based Implementation of Free Phenytoin Therapeutic Drug Monitoring

Clinical Chemistry ◽

10.1093/clinchem/46.8.1132 ◽

2000 ◽

Vol 46 (8) ◽

pp. 1132-1135 ◽

Cited By ~ 41

Author(s):

Martha Burt ◽

David C Anderson ◽

Julie Kloss ◽

Fred S Apple

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Medical Center ◽

Clinical Findings ◽

Therapeutic Monitoring ◽

Therapeutic Drug ◽

Clinical Indicator ◽

Interindividual Variations ◽

Data Points ◽

Pharmacologically Active

Abstract Background: The majority of laboratories measure total phenytoin concentration for therapeutic drug monitoring. However, there are substantial interindividual variations in free phenytoin concentrations, the pharmacologically active component. Methods: We describe the process and data used to implement monitoring of free phenytoin only in an urban medical center. Over a 6-week period, total and free phenytoin concentrations were measured, clinical charts reviewed, and indications for alterations in the percentage of free phenytoin fraction were determined. Results: Of the 189 phenytoin requests from 139 patients, 136 data points were analyzed. Free phenytoin concentrations were 6.8–35.3%, with 50% outside the expected range of 8–12%. Clinical indications likely responsible for variations were hypoalbuminemia, drug interactions, uremia, pregnancy, and age. Overall, 30% of patients demonstrated a discrepancy between therapeutic, subtherapeutic, or supratherapeutic concentrations between free and total phenytoin concentrations. The largest discordance (53%) occurred in the patient group with free phenytoin <8% or >12%. Conclusions: This study supports previous clinical findings that monitoring total phenytoin is not as reliable as free phenytoin as a clinical indicator for therapeutic and nontherapeutic concentrations. Thus, we recommend that therapeutic monitoring should use free phenytoin concentrations only.

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OP21 Positivity thresholds of total infliximab and adalimumab anti-drug antibody assay: The prevalence of clearing and transient anti-drug antibodies in a national therapeutic drug monitoring service

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.020 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S018-S019

Author(s):

R Nice ◽

N Chanchlani ◽

H Green ◽

C Bewshea ◽

N Kennedy ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Drug Clearance ◽

Therapeutic Drug ◽

Test Results ◽

Antibody Assays ◽

Single Positive ◽

Antibody Elisa ◽

Monitoring Service ◽

Antibody Levels

Abstract Background Anti-drug antibodies can affect biopharmaceutical pharmacokinetics by increasing or decreasing drug clearance. Drug-tolerant (total), unlike drug-sensitive (free), antibody assays permit antibodies to be measured in the presence of a drug. We sought to confirm the positivity threshold of our total anti-tumour necrosis factor (TNF) antibody ELISA assays in a sample of healthy volunteers and to use this threshold to report the prevalence of clearing and transient antibodies in patients treated with infliximab and adalimumab. Methods Serum was obtained from a random sample of 498 anti-TNF-naïve healthy adults recruited to the Exeter Ten Thousand study and tested for total anti-drug antibodies to infliximab and adalimumab. Using recommendations for confirmatory anti-drug antibody validation, we used bootstrapping to calculate the 80% one-sided lower confidence interval [CI] of the 99th centile to define assay thresholds. We used paired drug and anti-drug antibody levels derived from our national therapeutic drug monitoring service to report the distribution of clearing (antibody positive, drug negative) vs. non-clearing (antibody positive, drug positive) antibodies. In patients with at least two test results, antibodies were classified as transient (single positive test with subsequent negative test) or persistent (at least two positive tests). Results The 80% one-sided lower CI of the 99th centile titre for total anti-drug antibody to infliximab and adalimumab were 8.7 AU/ml and 5.9 AU/ml, respectively. Using the manufacturer’s recommended threshold of 10 AU/ml for both total anti-TNF antibody assays, in healthy individuals, the prevalence of positive antibodies to infliximab and adalimumab was 1% (5/498) and 0.2% (1/498), respectively. Using the manufacturer’s threshold, at the time of last testing, of 7447 and 4054 patients treated with infliximab and adalimumab; 20.9% (n = 1,554) and 8.0% (n = 326) had clearing antibodies and 26.5% (n = 1973) and 12.1% (n = 490) had non-clearing antibodies, respectively (Figure 1). Using our newly defined threshold in the same cohorts; 21.1% (n = 1573) and 8.4% (n = 339) had clearing antibodies and 28.0% (n = 2083) and 20.0% (n = 812) had non-clearing antibodies, to infliximab and adalimumab, respectively. Amongst patients with at least two tests, most developed persistent antibodies (Figure 2). Irrespective of anti-TNF drug, or threshold used, less than 10% patients developed transient antibodies. Conclusion We report lower positivity thresholds for the IDKmonitor® total anti-TNF antibody ELISA assays than the manufacturer, in particular, for adalimumab. Transient antibody formation is uncommon: most patients develop persistent anti-drug antibodies that lead to drug clearance.

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From therapeutic drug monitoring to total drug monitoring and drug-omics

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-0339 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Michael Vogeser

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Laboratory Medicine ◽

The Other ◽

Therapeutic Drug ◽

Total Drug ◽

The One ◽

The Right ◽

Realistic Goal

AbstractIn view of the role of pharmacotherapy in medicine, on the one hand, and the powerful technical possibilities that are now available on the other hand, therapeutic drug monitoring is a surprisingly neglected area of laboratory medicine. In this viewpoint article, an “omics approach” to pharmacovigilance and drug monitoring is proposed and discussed. A realistic goal for laboratory medicine in the 21st century should indeed be to enable clinicians to check whether the right drug is present in the right patient with an appropriate blood concentration for each compound.

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Diagnose und Monitoring bei chronisch-entzündlicher Darmerkrankung

Therapeutische Umschau ◽

10.1024/0040-5930/a001002 ◽

2018 ◽

Vol 75 (5) ◽

pp. 316-328

Author(s):

Christian Ansprenger ◽

Emanuel Burri

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Morbus Crohn ◽

Therapeutic Drug ◽

Körperliche Untersuchung

Zusammenfassung. Die Diagnose und auch die Überwachung von chronisch entzündlichen Darmerkrankungen ruht auf mehreren Säulen: Anamnese, körperliche Untersuchung, Laborwerte (im Blut und Stuhl), Endoskopie, Histologie und Bildgebung. Die Diagnose kann nicht anhand eines einzelnen Befundes gestellt werden. In den letzten Jahren hat sich das Therapieziel weg von klinischen Endpunkten hin zu endoskopischen und sogar histologischen Endpunkten entwickelt. Für einige dieser neuen Therapieziele existiert allerdings noch keine allgemein gültige Definition. Regelmässige Endoskopien werden von Patienten schlecht toleriert, weshalb Surrogat-Marker wie Calprotectin untersucht wurden und eine gute Korrelation mit der mukosalen Entzündungsaktivität nachgewiesen werden konnte. Entsprechend zeigte sich bei Morbus Crohn eine Algorithmus-basierte Therapiesteuerung – unter anderem basierend auf Calprotectin – einer konventionellen Therapiesteuerung überlegen. Die Überwachung der medikamentösen Therapie («Therapeutic Drug Monitoring» [TDM]) ist ein zweites Standbein des Monitoring von chronisch entzündlichen Darmerkrankungen. Mit zunehmendem Einsatz vor allem der Biologika-Therapien wurden sowohl reaktives TDM (in Patienten mit klinischem Rezidiv) als auch proaktives TDM (in Patienten in Remission / stabiler Erkrankung) untersucht und haben (teilweise) Eingang in aktuelle Richtlinien gefunden. Zukünftige Studien werden die vorgeschlagenen Therapieziele besser definieren und den Nutzen der medikamentösen Therapieüberwachung auf den Krankheitsverlauf weiter untersuchen müssen.

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