Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs.

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Real-life isoniazid and rifampicin plasma concentrations in children: a tool for therapeutic drug monitoring of tuberculosis

BMC Infectious Diseases ◽

10.1186/s12879-021-06764-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chiara Tersigni ◽

Giulia Boiardi ◽

Lorenzo Tofani ◽

Elisabetta Venturini ◽

Carlotta Montagnani ◽

...

Keyword(s):

Plasma Concentration ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Venous Blood ◽

Plasma Concentrations ◽

Age Groups ◽

Real Life ◽

Therapeutic Drug ◽

Blood Samples ◽

Drug Concentrations

Abstract Background Low plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages. Methods Children with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method. Results In all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (≤ 2 years, 2–12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range. Conclusions Based on our findings, monitoring patients’ drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.

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Plasma vs whole blood for therapeutic drug monitoring of patients receiving FK 506 for immunosuppression

Clinical Chemistry ◽

10.1093/clinchem/40.12.2247 ◽

1994 ◽

Vol 40 (12) ◽

pp. 2247-2253 ◽

Cited By ~ 45

Author(s):

M Winkler ◽

B Ringe ◽

J Baumann ◽

M Loss ◽

K Wonigeit ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Enzyme Immunoassay ◽

Drug Monitoring ◽

Whole Blood ◽

Plasma Concentrations ◽

Therapeutic Monitoring ◽

Therapeutic Drug ◽

Fk 506 ◽

Blood Samples ◽

The Matrix

Abstract By retrospective analysis of 13,000 blood samples obtained from 248 patients receiving FK 506 therapy, we compared the suitability of plasma with that of whole blood as the matrix for therapeutic drug monitoring of FK 506. The plasma concentrations did not correlate with the concentrations in whole blood (r = 0.56). In contrast to plasma samples (analyzed by enzyme immunoassay), FK 506 was detectable in all whole-blood samples (analyzed by enzyme immunoassay/microparticle enzyme immunoassay). The inter- and intraindividual variations of FK 506 measurements were greater in plasma than in whole blood. Moreover, plasma concentrations correlated only poorly with clinical events. There was a tendency to greater plasma concentrations being measured during episodes of toxicity, but no clear difference was evident between stable course and rejection. In whole-blood specimens, a correlation between reduced or increased FK 506 concentrations and rejection or toxicity, respectively, was observed. The discriminatory power of whole-blood values was greater for the differentiation between toxicity and stable course than between rejection and stable course. We therefore recommend whole blood rather than plasma as the matrix for therapeutic monitoring of FK 506 concentrations.

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Combining Therapeutic Drug Monitoring with Biosimilars, a Strategy to Improve the Efficacy of Biologicals for Treating Inflammatory Bowel Diseases at an Affordable Cost

Digestive Diseases ◽

10.1159/000449085 ◽

2017 ◽

Vol 35 (1-2) ◽

pp. 61-68 ◽

Cited By ~ 14

Author(s):

Ann Gils

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Drug Exposure ◽

Drug Efficacy ◽

European Medicines Agency ◽

Therapeutic Drug ◽

Treatment Switching ◽

Loss Of Response ◽

Drug Concentrations ◽

Bowel Diseases

Background: Biologicals provide a tight disease control but not all patients respond favourably to treatment. Some patients do not respond at all (primary non-responders), while other patients respond initially but show loss of response over time (secondary non-responders). Drug concentrations in the serum of patients can be monitored and correlated with biological, clinical or endoscopic response. Therapeutic thresholds have been defined for infliximab and adalimumab. The European Medicines Agency has approved 3 biosimilars of infliximab and new biosimilars are waiting approval. Key Messages: Distinguishing primary non-responders from patients with insufficient drug exposure during induction through drug serum concentration determination will improve drug efficacy. Current algorithms to guide treatment of patients with secondary loss of response take into account that patients with high titers of anti-drug antibodies (ADA) do not respond to dose intensification and that patients with therapeutic drug concentrations cannot be switched to biologicals within class. For patients in clinical remission, the cost of biological treatment can be decreased by dose tapering patients with supra-therapeutic concentrations and/or by switching patients with adequate drug concentrations and no formation of ADA to biosimilar, whereas efficacy can be increased by dose-intensifying patients with low or transient ADA and by switching patients with persistent ADA to biologicals within or out-off class. Conclusions: As an objective tool, therapeutic drug monitoring can identify patients who are eligible for dose tapering, intensification of treatment, cessation of treatment, switching within- or out-of-class and switching to biosimilar.

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Therapeutic Drug Monitoring of Venlafaxine and Impact of Age, Gender, BMI, and Diagnosis

European Pharmaceutical Journal ◽

10.2478/afpuc-2020-0005 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

M. Krivosova ◽

M. Kertys ◽

M. Grendar ◽

I. Ondrejka ◽

I. Hrtanek ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Active Metabolite ◽

Common Mental Disorder ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Active Moiety ◽

Drug Concentrations ◽

First Choice ◽

Significant Difference

AbstractDepression is a common mental disorder affecting more than 264 million people in the world and 5.1% of the Slovak population. Although various antidepressant approaches have been used; still, about 40% of patients do not respond to a first-choice drug administration and one third of patients do not achieve total remission. Therapeutic drug monitoring (TDM) is a method used for quantification and interpreting the drug concentrations in plasma in order to optimize the pharmacotherapy. The aim of this study was to measure the plasma concentrations of venlafaxine, the fourth most prescribed antidepressant in Slovakia, as well as its active metabolite and interpret them with the relevant patients’ characteristics.The study was of retrospective nature and 28 adult patients in total were included. The concentrations of venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) in plasma were quantified using the validated UHPLC-MS/MS method. The effects of potential influencing factors were evaluated by a multivariate linear regression model.Only 39% of patients reached the venlafaxine active moiety concentrations within the recommended therapeutic range. Plasma concentrations were dependent on age, gender, and duration of the therapy. Venlafaxine metabolism expressed as a metabolite-to-parent concentrations ratio was influenced by a combination of age, gender, and body mass index (BMI). We did not observe any significant difference in plasma concentrations between the patients with a single and recurrent diagnosis of depression. Combining variables made an additive effect on plasma concentrations, for example, active moiety plasma concentrations were higher in older women. In contrast, drug metabolism was higher in older men and men with lower BMI. TDM of venlafaxine is recommended in clinical practice, especially in the elderly when beginning the pharmacotherapy.

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Monographs on drugs which are frequently analyzed in therapeutic drug monitoring/Arzneimittel-Monographien für Medikamente, die regelmäßig im Rahmen des Therapeutic Drug Monitorings analysiert werden

LaboratoriumsMedizin ◽

10.1515/labmed-2011-0013 ◽

2012 ◽

Vol 36 (2) ◽

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Clinical Chemistry ◽

Parent Drug ◽

Life Time ◽

Antiretroviral Drugs ◽

Blood Sampling ◽

Therapeutic Drug ◽

Drug Concentrations ◽

The Stability

AbstractIn addition to the monographs which have been published in the past 7 years by the working group “Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) [1–6], new monographs have been written. The data presented in these monographs provide an overview of the information which is important for the request and interpretation of the results. Therefore, laboratory health professionals and the receivers of the reports are the targeted readers. In this series, antiretroviral drugs are presented for which drug concentrations are regularly determined (protease inhibitors, non-nucleoside reverse transcriptase inhibitors). To date, no clear evidence has been established that therapeutic drug monitoring of these drugs increases the success of the antiretroviral therapy. Nevertheless, many cases have demonstrated that the therapy can be guided with much more confidence and with good success if the drug concentrations are determined, especially if the patient has a combination therapy with many pharmacokinetically interfering compounds. First, information is given about pharmacology and pharmacokinetics of these drugs, such as protein binding, metabolic pathways with specific enzymes involved, elimination half-life time, elimination route(s) of the parent drug, as well as therapeutic and toxic concentrations. Moreover, indications for therapeutic drug monitoring are listed with important preanalytical information (time point of blood sampling and time to steady state since beginning or after change of posology). Furthermore, the stability of the drug and its metabolite(s) after blood sampling are described. For readers with a specific interest, references to important publications are given. The number of monographs will be further enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for the better handling of therapeutic drug monitoring and we are looking forward to receiving comments from the readers.

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Abstract 11598: Is Therapeutic Drug Monitoring of Direct Anticoagulants Really Unnecessary?

Circulation ◽

10.1161/circ.132.suppl_3.11598 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Bernadette Baldin ◽

Marion Warembourg ◽

Guillaume Bardy ◽

Loïc Startari ◽

Fanny Rocher ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Medical Center ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Drug Concentrations ◽

Increased Risk ◽

Direct Anticoagulants

Introduction: no routine monitoring is deemed necessary with direct oral anticoagulants dabigatran (D) and rivaroxaban(R). Yet, their misuse may lead to inefficacy or increased risk of bleeding. Hypothesis: due to the prevalence of elderly patients in our medical center, the pharmacology department was asked to measure R and D plasma concentrations. Therefore we aimed not only to check their prescription adequacy but also to evaluate whether bleeding or thrombosis adverse events were associated with drug concentrations clearly outside of their expected “normal” range. Methods: Patients receiving R or D for either AFib, deep venous thrombosis or its prevention were included and had blood samples drawn for drug measurements, by HPLC-tandem mass spectrometry. Adequacy of the patient prescription was checked by pharmacists according D & R respective SmPCs. A robust and conservative method was applied to evaluate anticoagulant concentrations : D & R concentrations were blindly deemed “normal” when within the [IC] 95 limits (peak and trough, relative to the dose) observed in the respective RE-LY and Rocket-AF pivotal studies, as compared to “out of range” when outside of these limits. Results: 287 consecutive patients from our center had their concentration of R (n=219 : 76%) or D (n = 68 : 24%) measured. The inadequacy of the prescriptions was 31.4% alltogether. Seventy patients presented with bleeding (n = 48, 17%) or thrombosis (n = 22, 8%), that either led to their admission in emergency, or occurred in the hospital wards. Bleedings and thrombosis were significantly associated with out-of-range concentrations (p<0.01). Patients with hemorrhages had higher concentrations (R: 194 VS 83 μg.l -1 and D: 128 VS 80 μg.l -1 ) whereas thrombosis were associated with lower ones (R: 75 VS 106 μg.l -1 D: 29 VS 93 μg.l -1 ). HAS-BLED Score was 2.0 ± 0.9 for bleeding cases as compared to 1.5 ± 0.9 (p<0.01). Conclusions: therapeutic drug monitoring of direct oral anticoagulants might not be superfluous, at least for R & D, especially in patients with a higher score HAS-BLED.

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Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00177-10 ◽

2010 ◽

Vol 54 (11) ◽

pp. 4605-4610 ◽

Cited By ~ 108

Author(s):

Federico Pea ◽

Mario Furlanut ◽

Piergiorgio Cojutti ◽

Francesco Cristini ◽

Eleonora Zamparini ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

High Performance ◽

Drug Exposure ◽

Plasma Concentrations ◽

Hplc Method ◽

Therapeutic Drug ◽

Time Curve ◽

Standard Dosage ◽

Wide Variability

ABSTRACT The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [C min] and peak [C max] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC24]). The final database included 280 C min and 223 C max measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously (n = 58) or orally (n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for C min, 14.70 mg/liter [10.57 to 19.64] for C max, and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC24). Linezolid C min was linearly correlated with estimated AUC24 (r 2 = 0.85). Optimal pharmacodynamic target attainment (defined as C min of ≥2 mg/liter and/or AUC24/MIC90 ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as C min of ≥10 mg/liter and/or AUC24 of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.

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Biosensor-enabled on-site therapeutic drug monitoring of antibiotics

10.21203/rs.3.rs-429808/v1 ◽

2021 ◽

Author(s):

Can Dincer ◽

Hatice Ceren Ates ◽

Hasti Mohsenin ◽

Christin Wenzel ◽

Regina Glatz ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Point Of Care ◽

Exhaled Breath Condensate ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Optimal Dosage ◽

Large Animal ◽

Exhaled Breath ◽

Drug Concentrations

Abstract Antimicrobial resistance is increasing with an alarming rate for which the prime suspect is the “one size-fits-all” dosage strategies of antibiotics. Personalized antibiotherapy framework appears as a viable option to counteract inadequate dosage, as it offers the application of the optimal dosage regimen for each individual. Such individualized scheme, however, needs frequent sampling to tailor the blood antibiotic concentration to respond unique pharmacokinetic/pharmacodynamic (PK/PD) of the patient. Herein, there are two alternative paths for feasible therapeutic drug monitoring (TDM); transforming our understanding to utilize blood based sampling within the scope of point-of-care (POC), or focusing on non-invasive samples. Here, we present a versatile biosensor along with an antibody-free assay that can be utilized in both paths for on-site TDM. The developed platform is evaluated in a large animal study (pigs exposed with overdose, normal dose, and underdose of ß lactams), in which antibiotic concentrations are quantified in matrices including whole blood, plasma, urine, saliva, and exhaled breath condensate (EBC). Herein, the detection and the clearance of drug concentrations in EBC is demonstrated for the first time. Influence of the secretion mechanisms on measured drug concentrations is then quantified by comparing the plasma concentrations with those in EBC, saliva and urine. The potential of the developed platform for blood-based POC application is further illustrated by tracking ß lactam concentrations in untreated blood samples. Finally, multiplexing capabilities are explored successfully for multianalyte/sample analysis. Enabling a rapid, low-cost, sample-independent, and multiplexed on-site TDM, this system could pave the way for the personalized drug therapies and thus, shift the paradigm of “one size-fits-all” strategies.

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Impact on Antibiotic Resistance, Therapeutic Success, and Control of Side Effects in Therapeutic Drug Monitoring (TDM) of Daptomycin: A Scoping Review

Antibiotics ◽

10.3390/antibiotics10030263 ◽

2021 ◽

Vol 10 (3) ◽

pp. 263

Author(s):

Carolina Osorio ◽

Laura Garzón ◽

Diego Jaimes ◽

Edwin Silva ◽

Rosa-Helena Bustos

Keyword(s):

Side Effects ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Bacterial Resistance ◽

Plasma Concentrations ◽

Resistant Bacteria ◽

Therapeutic Drug ◽

Therapeutic Success ◽

Favorable Clinical Outcome ◽

And Control

Antimicrobial resistance (AR) is a problem that threatens the search for adequate safe and effective antibiotic therapy against multi-resistant bacteria like methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE) and Clostridium difficile, among others. Daptomycin is the treatment of choice for some infections caused by Gram-positive bacteria, indicated most of the time in patients with special clinical conditions where its high pharmacokinetic variability (PK) does not allow adequate plasma concentrations to be reached. The objective of this review is to describe the data available about the type of therapeutic drug monitoring (TDM) method used and described so far in hospitalized patients with daptomycin and to describe its impact on therapeutic success, suppression of bacterial resistance, and control of side effects. The need to create worldwide strategies for the appropriate use of antibiotics is clear, and one of these is the performance of therapeutic drug monitoring (TDM). TDM helps to achieve a dose adjustment and obtain a favorable clinical outcome for patients by measuring plasma concentrations of an administered drug, making a rational interpretation guided by a predefined concentration range, and, thus, adjusting dosages individually.

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Feasibility of Extrapolating Randomly Taken Plasma Samples to Trough Levels for Therapeutic Drug Monitoring Purposes of Small Molecule Kinase Inhibitors

Pharmaceuticals ◽

10.3390/ph14020119 ◽

2021 ◽

Vol 14 (2) ◽

pp. 119

Author(s):

Ruben A. G. van Eerden ◽

Esther Oomen-de Hoop ◽

Aad Noordam ◽

Ron H. J. Mathijssen ◽

Stijn L. W. Koolen

Keyword(s):

Therapeutic Drug Monitoring ◽

Small Molecule ◽

Trough Concentration ◽

Drug Monitoring ◽

Half Life ◽

Kinase Inhibitors ◽

Therapeutic Drug ◽

Blood Samples ◽

Elimination Half ◽

Trough Levels

Small molecule kinase inhibitors (SMKIs) are widely used in oncology. Therapeutic drug monitoring (TDM) for SMKIs could reduce underexposure or overexposure. However, logistical issues such as timing of blood withdrawals hamper its implementation into clinical practice. Extrapolating a random concentration to a trough concentration using the elimination half-life could be a simple and easy way to overcome this problem. In our study plasma concentrations observed during 24 h blood sampling were used for extrapolation to trough levels. The objective was to demonstrate that extrapolation of randomly taken blood samples will lead to equivalent estimated trough samples compared to measured Cmin values. In total 2241 blood samples were analyzed. The estimated Ctrough levels of afatinib and sunitinib fulfilled the equivalence criteria if the samples were drawn after Tmax. The calculated Ctrough levels of erlotinib, imatinib and sorafenib met the equivalence criteria if they were taken, respectively, 12 h, 3 h and 10 h after drug intake. For regorafenib extrapolation was not feasible. In conclusion, extrapolation of randomly taken drug concentrations to a trough concentration using the mean elimination half-life is feasible for multiple SMKIs. Therefore, this simple method could positively contribute to the implementation of TDM in oncology.

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