Voriconazole pharmacokinetics and pharmacodynamics in children.
BACKGROUND
Voriconazole pharmacokinetic and pharmacodynamic data are lacking in children.


METHODS
Records at the Childrens Hospital Los Angeles were reviewed for children with > or =1 serum voriconazole concentration measured from 1 May 2006 through 1 June 2007. Information on demographic characteristics, dosing histories, serum concentrations, toxicity and survival, and outcomes was obtained.


RESULTS
A total of 207 voriconazole measurements were obtained from 46 patients (age, 0.8-20.5 years). A 2-compartment Michaelis-Menten pharmacokinetic model fit the data best but explained only 80% of the observed variability. The crude mortality rate was 28%, and each trough serum voriconazole concentration <1000 ng/mL was associated with a 2.6-fold increased odds of death (95% confidence interval, 1.6-4.8; P=.002). Serum voriconazole concentrations were not associated with hepatotoxicity. Simulations predicted an intravenous dose of 7 mg/kg or an oral dose of 200 mg twice daily would achieve a trough >1000 ng/mL in most patients, but with a wide range of possible concentrations.


CONCLUSIONS
We found a pharmacodynamic association between a voriconazole trough >1000 ng/mL and survival and marked pharmacokinetic variability, particularly after enteral dosing, justifying the measurement of serum concentrations.
Neely
Michael
M
Division of Pediatric Infectious Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. mneely@usc.edu
Rushing
Teresa
T
Kovacs
Andrea
A
Jelliffe
Roger
R
Hoffman
Jill
J
D000293:Adolescent; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007223:Infant; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D009181:Mycoses / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D065819:Voriconazole; D055815:Young Adult
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole