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

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

Cancers ◽

10.3390/cancers13246281 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6281

Author(s):

Anna Mc Laughlin ◽

Eduard Schmulenson ◽

Olga Teplytska ◽

Sebastian Zimmermann ◽

Patrick Opitz ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Anticancer Drugs ◽

Drug Monitoring ◽

Drug Exposure ◽

Plasma Concentrations ◽

Blood Sampling ◽

Therapeutic Drug ◽

Study Phase ◽

Blood Samples ◽

Drug Concentrations

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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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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Chronopharmacology in Therapeutic Drug Monitoring—Dependencies between the Rhythmics of Pharmacokinetic Processes and Drug Concentration in Blood

Pharmaceutics ◽

10.3390/pharmaceutics13111915 ◽

2021 ◽

Vol 13 (11) ◽

pp. 1915

Author(s):

Lukasz Dobrek

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Age Groups ◽

Therapeutic Drug ◽

Physiological Conditions ◽

Drug Concentrations ◽

Increased Risk ◽

Drugs In Blood ◽

Treatment Individualization ◽

The Given

The objective of the optimization of pharmacotherapy compliant with the basic rules of clinical pharmacology is its maximum individualization, ensuring paramount effectiveness and security of the patient’s therapy. Thus, multiple factors that are decisive in terms of uniqueness of treatment of the given patient must be taken into consideration, including, but not limited to, the patient’s age, sex, concomitant diseases, special physiological conditions (e.g., pregnancy, lactation, extreme age groups), polypharmacotherapy and polypragmasia (particularly related to increased risk of drug interactions), and patient’s phenotypic response to the administered drug with possible genotyping. Conducting therapy while monitoring the concentration of certain drugs in blood (Therapeutic Drug Monitoring; TDM procedure) is also one of the factors enabling treatment individualization. Furthermore, another material, and yet still a marginalized pharmacotherapeutic factor, is chronopharmacology, which indirectly determines the values of drug concentrations evaluated in the TDM procedure. This paper is a brief overview of chronopharmacology, especially chronopharmacokinetics, and its connection with the clinical interpretation of the meaning of the drug concentrations determined in the TDM procedure.

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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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Determination of Imatinib Plasma Levels by High Performance Liquid Chromatography (HPLC): Evaluation of Pharmacokinetic Variability and Haematological Consequences.

Blood ◽

10.1182/blood.v108.11.1375.1375 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1375-1375 ◽

Cited By ~ 4

Author(s):

Stephanie Haiat ◽

Xavier Decleves ◽

Benedicte Mittaine ◽

Ollivier Legrand ◽

Stephanie Francart ◽

...

Keyword(s):

Plasma Concentration ◽

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Plasma Concentrations ◽

Cytogenetic Response ◽

Therapeutic Drug ◽

Large Variability ◽

Complete Cytogenetic Response ◽

Daily Dose ◽

Trough Levels

Abstract Imatinib exerts a potent and selective inhibition of tyrosine kinase Bcr-Abl. It is currently used for treatment of chronic myeloid leukaemia (CML) and acute leukaemia (AL). Pharmacokinetic data indicate large variability especially in plasma exposure with many factors which could be involved (absorption, metabolism, drug-drug interactions). Compliance must also be taken in count. The aim of this study was to determine the variability of imatinib plasma concentrations in a « natural clinical setting» (outpatients on long-term treatment for CML or AL). Secondary objective was to perform a pilot assessment of the relationship between imatinib plasma concentration and clinical outcomes. Analysis was performed by HPLC. Sample treatment (500 μL of patient plasma) consisted of a liquid-solid extraction. Imatinib and internal standard (CGP 53716) were eluted on a Lichrosorb® RP8 column with methanol-THF-sodium acetate buffer 0.1M pH 5. Detection was performed with UV spectrophotometer (262 nm). The limit of quantification was set at 200 ng/mL. Within-day and inter-day precisions were lower than 15%. Blood samples were collected at steady-state (trough and peak values, ie before and 3h after drug administration) in outpatients treated for CML or AL with one imatinib daily dose, at clinical visits. Clinical evolution was considered as successful when following responses were obtained: complete haematological response within 3 months, or major cytogenetic response within 6 months, or complete cytogenetic response within 12 months, or major molecular response within 18 months in the CML group, and complete cytogenetic response after induction in the AL group. 68 imatinib measurements were obtained from 24 patients (13 CML and 11 AL). Mean age was 49 years (range 21–74) and weight was 73 kg (49–100). In patients receiving imatinib 400mg daily dose, trough and peak concentrations were respectively 1.60 ±1.28 (0.5–5.1) μg/mL (n=19), and 3.51 ±3.04 (1.0–11.1) μg/mL (n=9). In patients treated with a daily dose 600mg, trough and peak concentrations were respectively 2.62 ±2.10 (0.8–6.5) μg/mL (n=22), and 5.85 ±4.15 (1.2–15.1) μg/mL (n=18). Variability of trough concentrations of imatinib were 80% in both groups (400 and 600mg). 18 patients were evaluable. 15 efficient responses were obtained and all these patients showed imatinib trough levels above 0.5 μg/mL (target plasma concentration required to induce death of leukaemic cells). 3 patients with failure showed nevertheless imatinib trough levels of 1.5, 1.8 and 4.5 μg/mL. 3 patients showed accumulation of imatinib (trough levels higher than 5.0 μg/mL) due to hepatic impairment but without side effects. The method of analysis is very simple, sensitive and specific. Our results confirm the large variability of imatinib plasma concentrations and are consistent with previous results. These preliminary results showed a « safe » imatinib exposure which leads to therapeutic concentrations (higher than 0.5 μg/mL). Therapeutic drug monitoring seems to be not systematicaly necessary but could be reserved to specific cases of poor compliance, major risks of interaction or cases of failure or resistance. Studies of correlation with a larger cohort of patients is necessary to clarify the role of imatinib therapeutic drug monitoring for improving its use.

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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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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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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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