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

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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Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02025-12 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1888-1894 ◽

Cited By ~ 28

Author(s):

William W. Hope ◽

Michael VanGuilder ◽

J. Peter Donnelly ◽

Nicole M. A. Blijlevens ◽

Roger J. M. Brüggemann ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Fungal Infections ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Cell Transplant ◽

Multiple Model ◽

Pharmacokinetic Variability ◽

Hematopoietic Stem ◽

Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

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1733. Voriconazole Prophylaxis Following Allogeneic Hematopoietic Stem Cell Transplant: How Much Is Enough, Are Low Voriconazole Levels Associated With Opportunistic Infections, and What Are the Reasons for Discontinuation?

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1596 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S635-S635

Author(s):

Giorgos Hadjivassiliou ◽

Claire Rummage ◽

Craig Hoesley ◽

Matthew L Brown

Keyword(s):

Stem Cell ◽

Therapeutic Drug Monitoring ◽

Hematopoietic Stem Cell ◽

Drug Monitoring ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Therapeutic Drug ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Subtherapeutic Level

Abstract Background Patients who undergo allogeneic hematopoietic stem cell transplantation (alloHSCT) are at increased risk for invasive fungal infections with associated high morbidity and mortality that necessitates the use of prophylactic antifungals. Voriconazole is commonly used for prophylaxis, but there are no recommendations for therapeutic drug monitoring. The purpose of this study was to characterize voriconazole therapeutic drug monitoring and associated outcomes in this patient population. Methods AlloHSCT patients receiving voriconazole prophylaxis at the University of Alabama at Birmingham Hospital between March 2015 and March 2018 were included in the analysis. Serum voriconazole levels (SVL) were evaluated to determine what percentage of patients achieved prophylactic or therapeutic concentrations. Incidence of invasive fungal infections (IFI) and voriconazole discontinuation was also assessed. Results Voriconazole prophylaxis was used in 151 of 162 alloHSCT patients, and 120 patients (79%) had SVL drawn correctly (≥4 days after initiation of course). We found that 35 (29%) patients achieved a subtherapeutic level (<0.5 μg/mL), 17 (14%) prophylactic level (0.5 to 1 μg/mL), 68 (57%) therapeutic level (1 to 5.5 μg/mL), and no patients achieved a supratherapeutic level (level ≥5.5 μg/mL). Voriconazole prophylaxis was discontinued early in 60 of 151 patients. Most common etiologies for discontinuation included liver function test abnormalities (44%) and encephalopathy (21%). The average SVL was 1.2 μg/mL in those requiring discontinuation. Four patients (3%) developed an IFI while receiving prophylactic voriconazole, of which only 1 had subtherapeutic level. Conclusion Even though approximately one-third of patients achieved a subtherapeutic SVL, there was no correlation with breakthrough IFI. There was also no linear correlation between SVL and risk of adverse effects requiring discontinuation. Our observational data do not support a need for therapeutic drug monitoring in alloHSCT patients receiving prophylactic voriconazole. Disclosures All authors: No reported disclosures.

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A UHPLC–MS/MS Method for Therapeutic Drug Monitoring of Aciclovir and Ganciclovir in Plasma and Dried Plasma Spots

Biomedicines ◽

10.3390/biomedicines9101379 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1379

Author(s):

Federica Pigliasco ◽

Alessia Cafaro ◽

Raffaele Simeoli ◽

Sebastiano Barco ◽

Alberto Magnasco ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Pediatric Patients ◽

Matrix Effects ◽

Statistical Tests ◽

Therapeutic Drug ◽

Solid Organ ◽

Bioanalytical Method Validation ◽

Hematopoietic Stem

The role of therapeutic drug monitoring (TDM) of valaciclovir (VA)/aciclovir (A) and valganciclovir/ganciclovir (VG/G) in critically ill patients is still a matter of debate. More data on the dose–concentration relationship might therefore be useful, especially in pediatrics where clinical practice is not adequately supported by robust PK studies. We developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) micro-method to simultaneously quantify A and G from plasma and dried plasma spots (DPS). The method was based on rapid organic extraction from DPS and separation on a reversed-phase C-18 UHPLC column after addition of deuterated internal standards. Accurate analyte quantification using SRM detection was then obtained using a Thermo Fisher Quantiva triple-quadrupole MS coupled to an Ultimate 3000 UHPLC. It was validated following international (EMA) guidelines for bioanalytical method validation and was tested on samples from pediatric patients treated with A, VG, or G for cytomegalovirus infection following solid organ or hematopoietic stem cell transplantation. Concentrations obtained from plasma and DPS were compared using Passing–Bablok and Bland–Altman statistical tests. The assay was linear over wide concentration ranges (0.01–20 mg/L) in both plasma and DPS for A and G, suitable for the expected therapeutic ranges for both Cmin and Cmax, accurate, and reproducible in the absence of matrix effects. The results obtained from plasma and DPS were comparable. Using an LC-MS/MS method allowed us to obtain a very specific, sensitive, and rapid quantification of these antiviral drugs starting from very low volumes (50 μL) of plasma samples and DPS. The stability of analytes for at least 30 days allows for cost-effective shipment and storage at room temperature. Our method is suitable for TDM and could be helpful for improving knowledge on PK/PD targets of antivirals in critically ill pediatric patients.

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Pharmacokinetic and Metabolic Investigations of Mycophenolic Acid in Pediatric Patients After Renal Transplantation: Implications for Therapeutic Drug Monitoring

Therapeutic Drug Monitoring ◽

10.1097/00007691-200002000-00004 ◽

2000 ◽

Vol 22 (1) ◽

pp. 20-26 ◽

Cited By ~ 135

Author(s):

Michael Oellerich ◽

Maria Shipkova ◽

Ekkehard Schütz ◽

Eberhard Wieland ◽

Lute Weber ◽

...

Keyword(s):

Renal Transplantation ◽

Therapeutic Drug Monitoring ◽

Mycophenolic Acid ◽

Drug Monitoring ◽

Pediatric Patients ◽

Therapeutic Drug

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Pharmacokinetic and Metabolic Investigations of Mycophenolic Acid in Pediatric Patients After Renal Transplantation: Implications for Therapeutic Drug Monitoring

Therapeutic Drug Monitoring ◽

10.1097/00007691-200008000-00024 ◽

2000 ◽

Vol 22 (4) ◽

pp. 500

Author(s):

&NA;

Keyword(s):

Renal Transplantation ◽

Therapeutic Drug Monitoring ◽

Mycophenolic Acid ◽

Drug Monitoring ◽

Pediatric Patients ◽

Therapeutic Drug

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Experience of a Strategy Including CYP2C19 Preemptive Genotyping Followed by Therapeutic Drug Monitoring of Voriconazole in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.717932 ◽

2021 ◽

Vol 12 ◽

Author(s):

Irene García-García ◽

Irene Dapía ◽

Jaime Montserrat ◽

Lucía Martinez de Soto ◽

David Bueno ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Initial Dose ◽

Pediatric Patients ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Hematopoietic Stem ◽

Cyp2c19 Gene ◽

Ultrarapid Metabolizers ◽

Combined Strategy

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1–5.5 μg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).

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THERAPEUTIC DRUG MONITORING OF VANCOMYCIN IN PEDIATRIC PATIENTS WITH EXTRACORPOREAL MEMBRANE OXYGENATION SUPPORT (ECMO)

10.26226/morressier.58fa1764d462b80290b509c1 ◽

2017 ◽

Author(s):

Giannina Izquierdo

Keyword(s):

Therapeutic Drug Monitoring ◽

Extracorporeal Membrane Oxygenation ◽

Drug Monitoring ◽

Pediatric Patients ◽

Therapeutic Drug ◽

Membrane Oxygenation

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A Novel, Rapid, and Low-Volume Assay for Therapeutic Drug Monitoring of Posaconazole and Other Long-Chain Azole-Class Antifungal Drugs

mSphere ◽

10.1128/msphere.00623-18 ◽

2018 ◽

Vol 3 (6) ◽

Cited By ~ 2

Author(s):

Gregory R. Wiedman ◽

Yanan Zhao ◽

David S. Perlin

Keyword(s):

Liquid Chromatography ◽

Therapeutic Drug Monitoring ◽

Human Serum ◽

Drug Monitoring ◽

Fungal Infections ◽

Antifungal Drugs ◽

Therapeutic Drug ◽

Serum Samples ◽

Human Serum Samples ◽

Long Chain

ABSTRACT Clinicians need a better way to accurately monitor the concentration of antimicrobials in patient samples. In this report, we describe a novel, low-sample-volume method to monitor the azole-class antifungal drug posaconazole, as well as certain other long-chain azole-class antifungal drugs in human serum samples. Posaconazole represents an important target for therapeutic drug monitoring (TDM) due to its widespread use in treating invasive fungal infections and well-recognized variability of pharmacokinetics. The current “gold standard” requires trough and peak monitoring through high-pressure liquid chromatography (HPLC) or liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Other methods include bioassays that use highly susceptible strains of fungi in culture plates or 96-well formats to monitor concentrations. Currently, no method exists that is both highly accurate in detecting free drug concentrations and is also rapid. Herein, we describe a new method using reduced graphene oxide (rGO) and a fluorescently labeled aptamer, which can accurately assess clinically relevant concentrations of posaconazole and other long-chain azole-class drugs in little more than 1 h in a total volume of 100 µl. IMPORTANCE This work describes an effective assay for TDM of long-chain azole-class antifungal drugs that can be used in diluted human serum samples. This assay will provide a quick, cost-effective method for monitoring concentrations of drugs such as posaconazole that exhibit well-documented pharmacokinetic variability. Our rGO-aptamer assay has the potential to improve health care for those struggling to treat fungal infections in rural or resource-limited setting.

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