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

Abstract

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.

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study

“…Simulated results are displayed in Figure 5 . Based on the simulation results, the recommended dosing regimen for pediatric HSCT recipients to achieve a therapeutic target AUC 0–12 within the range of 30–60 mg·h/L was the oral administration of MMF at a dose of 900 mg/m 2 twice daily [ 11 , 35 , 36 ].…”

Optimization of Voriconazole Dosing Regimens Against Aspergillus Species and Candida Species in Pediatric Patients After Hematopoietic Cell Transplantation: A Theoretical Study Based on Pharmacokinetic/Pharmacodynamic Analysis

“…However, such adjustment is not an adequate substitute for therapeutic drug monitoring (TDM) because other factors (ie, liver function, drug interactions, the site of infection, and comorbidities) can also influence VRC exposure. [36][37][38][39][40] Therefore, dose adjustments should be combined with TDM to reduce the risk of adverse reactions. Furthermore, risk-benefit analysis should be performed in combination with the patient's actual situation.…”

“…Our data indicated that dose adjustments should be based on CYP2C19 phenotype, body weight, and drug susceptibility testing. However, such adjustment is not an adequate substitute for therapeutic drug monitoring (TDM) because other factors (ie, liver function, drug interactions, the site of infection, and comorbidities) can also influence VRC exposure 36–40 . Therefore, dose adjustments should be combined with TDM to reduce the risk of adverse reactions.…”

Therapeutic drug monitoring (TDM) as intervention: A cross-sectional analysis of characteristics of 173 registered clinical trials

“…Various organizations have laid down guidelines for TDM. Vancomycin is a glycopeptide antibiotic with an activity against Gram-positive bacteria [ 13 ], comprising the methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin notoriously has a NTI [ 14 ].…”