Role of Therapeutic Drug Monitoring: Pediatric Patients

therapeutic drug monitoring

The use of voriconazole in pediatric patients has been described in several case reports and observational studies. In one study, treatment success (as determined by clinical, radiographic, and mycological evidence) was 45% among 58 children (ranging in age from 9 months to 15 years) with aspergillosis, candidiasis, or scedosporiosis. Cesaro and others conducted 2 small observational studies in pediatric patients with invasive fungal infections. In the first of these studies, 7 of the 8 patients had a response to voriconazole given as rescue or maintenance therapy. In the second study, 5 of 7 patients with invasive aspergillosis had a response to treatment with voriconazole. Kolve and others studied 37 immuno- compromised pediatric patients with invasive fungal infections and found that 86% of the patients with probable or proven infections and 100% of those with possible infections had a response to treatment and their condition remained stable. In a case series involving patients with cystic fibrosis and recurrent allergic bronchopulmonary aspergillosis, Hilliard and others reported a response to voriconazole therapy.

DRUG ASSAY

The second question in the algorithm for determining the appropriateness of TDM is whether the drug can be readily measured in the desired biological matrix.
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Data on drug concentrations can be used to guide clinical decision-making only if they are reliable. An ideal analytic assay is highly sensitive, specific, precise, accurate, rapid, and afford­able. Several analytic methods have been developed to quantify voriconazole concentration in human plasma or serum (Table 1). Most of these assays use high-performance liquid chromatography (HPLC) methods either with ultraviolet (UV) detection or coupled with mass spectrophotometry. Other methods such as microbiological assays have also been investigated.

Table 1. Analytic Methods for Voriconazole in Plasma or Serum

Study

LLOQ and Max

Sample

Interday

Intraday

Accuracy (%)

(Hg/mL)

Volume (mL)

Bioassay



Pascual et al.


0.2, 6



0.5


2.2-6.1


5.0-10.3


89.0-99.2



Perea et al.


0.25, 20


0.01


< 13



< 3


98.7-101.3


HPLC-UV



Chhun et al.


0.2, 10


0.1


3.73-10.1


3.48-10.4


90.5-101.5



Gage and Stopher


0.05, 10



0.5


0.75-4.7


2.6-13


97.0-105.0



Khoschsorur et al.


0.1, 8


1.0


2.1-6.6


2.6-9.3


95.7-104.3



Langman et al.


0.1, 20



0.5


2.5-7.7


4.4-6.8



NR



Pehourcq et al.


0.2, 7


0.01


4.0-5.8


4.0-6.6


92.5-98.6



Pennick et al.


0.2, 10



0.5


7.8-16


1.5-15.7


82.6-113.1



Pascual et al.


0.125, 25



0.5


4.3-6.3


3.9-6.6


89.8-100.7



Perea et al.


0.2, 10



0.5



< 4


< 2.5


99.2-100.8



Shihabi


0.4, 10



0.05



NR



NR


74.5-93.4



Stopher and Gage


0.005, 3



0.7


5.0-5.9


0.8-8.4


93.2-100.0



Wenk et al.


0.1, 10


0.25


1.58-6.06


0.34-3.8


99.5-106.0


HPLC-TMS



Egle et al.



0.05, 5



0.005


7.1-16.57


3.65-6.81


97.1-118.6



Keevil et al.


0.1, 20


0.01


4.8-17.0


3.6-10.0


82.0-105.0



Vogeser et al.



0.078, 5


0.1



NR


1.0-0.7


94.0-107.0

Some of the HPLC methods developed for quantifying voriconazole in plasma are limited by long turn-around time, complex procedures, and/or narrow quantification range that does not adequately reflect concentrations of voriconazole in the clinical setting. Although no therapeutic range has been decisively established, target concentrations reported in the literature have ranged from less than 0.5 to greater than 10 g/mL. A quantification range between 0.25 and 15 mg/L, as suggested by Pascual and others, appears reasonable. silagra tablets

Various methods combining HPLC with tandem mass spectrometry (TMS) have also been evaluated for measuring concentrations of voriconazole in plasma. These methods have the advantages of small sample volume requirements, high sensitivity, and short turn-around time. However, they are, in general, expensive and not readily available at some institutions.

Bioassays are an attractive option because they are relatively low in cost. However, they have the disadvantages of low sensitivity, long turn-around time, and potential cross-reactivity of the inactive metabolite in the bioassay. In one HPLC— TMS validation study, the dynamic range of the bioassay was inadequate and interassay reproducibility was lacking.

Two studies provided stability data, suggesting that plasma samples obtained for quantification of voriconazole are stable, with minimal change in concentration after 2 or 3 freeze-thaw cycles and storage at -25°C for up to 14 months. Stability was also good (i.e., percent coefficient of variation [CV] less than 6.6%, accuracy 91.2%) when samples were stored at room temperature for 24 h in daylight or in the dark.
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It appears that HPLC-UV may be the most acceptable analytic method for measuring voriconazole. Nevertheless, high costs and the requirement for specialized equipment mean that the assay is not readily accessible to many health care institutions.

Category: Drugs

Tags: antifungal, invasive fungal infection, pharmacokinetics, therapeutic drug monitoring, voriconazole

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