Pharmacometrics-based dose selection of levofloxacin as a treatment for postexposure inhalational anthrax in children

Abstract

Levofloxacin was recently (May 2008) approved by the U.S. Food and Drug Administration as a treatment for children following inhalational exposure to anthrax. Given that no clinical trials to assess the 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 of body weight levofloxacin and two studies of 47 healthy adults receiving 500 and 750 mg/kg levofloxacin were used for the pharmacometric analyses. Body weight was found to be a significant covariate for levofloxacin clearance and the volume of distribution. Consistently with developmental physiology, clearance also was found to be reduced in pediatric patients under 2 years of age due to immature renal function. Different dosing regimens were simulated to match adult exposure (area under the concentration-time curve from 0 to 24 h at steady state, maximum concentration of drug in serum at steady state, and minimum concentration of drug in serum at steady state) following the approved adult dose of 500 mg once a day. The recommended dose of 8 mg/kg twice a day 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 efficacy comparable to that of adults.

FIG. 1.

Standardized residual error for clearance model 1 (top) and model 2 (bottom) versus body weight (left) and age (right). The solid black line is a local smoothing line, and the solid black dots are the standardized residuals (raw residuals divided by the corresponding standard errors) for each individual.

FIG. 2.

Estimated renal function maturation curve versus age.

FIG. 3.

Predicted AUC_0-24,ss (left) and C_max,ss (right) following 15 mg/kg q.d. levofloxacin (not exceeding 500 mg) versus body weight.

FIG. 4.

Predicted C_max,ss versus body weight following 7.5 mg/kg b.i.d. levofloxacin (not exceeding 250 mg/dose) for all children (left) as well as 7.5 mg/kg b.i.d. levofloxacin (not exceeding 250 mg/dose) for children <50 kg and 500 mg q.d. for children ≥50 kg (right).