AAC Accepts, published online ahead of print on 26 October 2009

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00667-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Pharmacometrics-Based Dose Selection of Levofloxacin as a Treatment for Post-Exposure Inhalational Anthrax in Children

Fang Li^*, Partha Nandy, Shuchean Chien, Gary J. Noel, and Christoffer W Tornoe

Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Advanced PK/PD Modeling and Simulation, Early Research and Development, Anti-infectives Research and Development, Johnson and Johnson Pharmaceutical Research and Development

^* To whom correspondence should be addressed. Email: fang.li{at}fda.hhs.gov.

Levofloxacin was recently (May 2008) approved by U.S. Food and Drug Administration as treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess efficacy of a chosen dose was conducted, the basis for the dose recommendation was based upon pharmacometric analyses. The objective of this paper is to describe the basis of the chosen pediatric dose recommended for the label. Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg levofloxacin and two studies in 47 healthy adults receiving 500 and 750 mg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and volume of distribution. Consistent with developmental physiology, clearance was also found to be reduced in pediatric patients below 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (AUC_0-24,ss, C_max,ss, and C_min,ss) following the approved adult dose of 500 mg q.d. The recommended dose of 8 mg/kg b.i.d. was found to match the exposure of the dose approved for adults in a manner that permitted confidence that this dose in children would achieve comparable efficacy to that of adults.