title: Population pharmacokinetic model for gatifloxacin in pediatric patients.
abstract: 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.
authors.affiliation: Cognigen Corporation, Buffalo, NY, USA. CRubino-ICPD@ordwayresearch.org
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rubino
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.forename: John S
authors.initials: JS
authors.lastname: Bradley
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Blumer
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kearns
authors.forename: Michael
authors.initials: M
authors.lastname: Reed
authors.forename: Richard F
authors.initials: RF
authors.lastname: Jacobs
authors.forename: Brenda
authors.initials: B
authors.lastname: Cirincione
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
mesh_terms: D000284:Administration, Oral; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D024841:Fluoroquinolones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077734:Gatifloxacin; D006801:Humans; D007223:Infant; D008954:Models, Biological; D015233:Models, Statistical; D009010:Monte Carlo Method
chemical_list: D024841:Fluoroquinolones; D000077734:Gatifloxacin