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Antimicrobial Agents and Chemotherapy, April 2007, p. 1246-1252, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.00685-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetic Model for Gatifloxacin in Pediatric Patients{triangledown}

Christopher M. Rubino,1* Edmund V. Capparelli,2 John S. Bradley,3 Jeffrey L. Blumer,4,5 Gregory L. Kearns,6 Michael Reed,4,7 Richard F. Jacobs,8 Brenda Cirincione,1 and Dennis M. Grasela9

Cognigen Corporation, Buffalo, New York,1 UCSD Pediatric ACTG Pharmacology Laboratory, San Diego, California,2 Division of Infectious Diseases, Children's Hospital, San Diego, California,3 Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children's Hospital, Cleveland, Ohio,4 Department of Pediatrics and Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio,5 Departments of Pediatrics and Pharmacology, University of Missouri—Kansas City, and Pediatric Pharmacology Research Unit, Children's Mercy Hospitals and Clinics, Kansas City, Missouri,6 Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio,7 Pediatric Infectious Disease, University of Arkansas for Medical Sciences, and Arkansas Children's Hospital, Little Rock, Arkansas,8 Department of Clinical Pharmacology/Experimental Medicine, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey9

Received 2 June 2006/ Returned for modification 31 October 2006/ Accepted 28 December 2006

The broad spectrum of antimicrobial activity, oral bioavailability, extensive tissue distribution, and once-daily intravenous or oral dosing of gatifloxacin, an expanded-spectrum 8-methoxy fluoroquinolone, make it a potentially useful agent for the treatment of pediatric infections. A population pharmacokinetic model was developed to describe the pharmacokinetics of gatifloxacin in children. Data for analysis were obtained from a single-dose safety/pharmacokinetic study utilizing intensive blood sampling in patients aged 6 months to 16 years. Each subject received a single oral dose of gatifloxacin as a suspension, at doses of 5, 10, or 15 mg/kg of body weight. A total of 845 samples were obtained from 82 patients. A one-compartment model with first-order absorption and elimination was the most appropriate to describe the gatifloxacin concentrations. Covariate analysis using forward selection and backward elimination found that apparent clearance was related to body surface area, and apparent volume of distribution was related to body weight. No effect of age on drug clearance could be identified once clearance was corrected for body surface area. Based on pharmacokinetic simulations, the 10-mg/kg (maximum, 400 mg) once-daily dose of gatifloxacin is expected to provide drug exposure similar to that in healthy adults. The population pharmacokinetic model described herein will be used for Bayesian analyses of sparse pharmacokinetic sampling in phase II/III clinical trials and for Monte Carlo simulation experiments. The success of this strategy provides a model for future pediatric drug development programs.

* Corresponding author. Present address: Institute for Clinical Pharmacodynamics, Ordway Research Institute, 1365 Washington Avenue, Suite 201, Albany, NY 12206-1072. Phone: (518) 429-2600. Fax: (518) 429-2601. E-mail: CRubino-ICPD{at}ordwayresearch.org

{triangledown} Published ahead of print on 12 January 2007.

Antimicrobial Agents and Chemotherapy, April 2007, p. 1246-1252, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.00685-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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