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Antimicrobial Agents and Chemotherapy, March 2009, p. 935-944, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00751-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetic Analysis of Voriconazole Plasma Concentration Data from Pediatric Studies{triangledown}

Mats O. Karlsson,1* Irja Lutsar,2,{dagger} and Peter A. Milligan2

Uppsala University, Uppsala, Sweden,1 Pfizer Central Research, Sandwich, United Kingdom2

Received 9 June 2008/ Returned for modification 26 August 2008/ Accepted 3 December 2008

Voriconazole is a potent triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to <12 years of age, incorporating a range of single or multiple intravenous (i.v.) and/or oral (p.o.) doses. An appropriate pharmacokinetic model for this patient population was created using the nonlinear mixed-effect modeling approach. The final model described voriconazole elimination by a Michaelis-Menten process and distribution by a two-compartment model. It also incorporated a statistically significant (P < 0.001) influence of the CYP2C19 genotype and of the alanine aminotransferase level on clearance. The model was used in a number of deterministic simulations (based on various fixed, mg/kg of body weight, and individually adjusted doses) aimed at finding suitable i.v. and p.o. voriconazole dosing regimens for pediatric patients. As a result, 7 mg/kg twice a day (BID) i.v. or 200 mg BID p.o., irrespective of body weight, was recommended for this patient population. At these doses, the pediatric area-under-the-curve (AUC) distribution exhibited the least overall difference from the adult AUC distribution (at dose levels used in clinical practice). Loading doses or individual dosage adjustments according to baseline covariates are not considered necessary in administering voriconazole to children.

* Corresponding author. Mailing address: Department of Pharmaceutical Biosciences, Uppsala University, Box 591, S-751 24 Uppsala, Sweden. Phone: (46) 18 471-4105. Fax: (46) 18 471-4003. E-mail: Mats.Karlsson{at}farmbio.uu.se

{triangledown} Published ahead of print on 15 December 2008.

{dagger} Present address: University of Tartu, Tartu, Estonia.

Antimicrobial Agents and Chemotherapy, March 2009, p. 935-944, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00751-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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