Modeling of transfer kinetics at the serum-cerebrospinal fluid barrier in rabbits with experimental meningitis: application to grepafloxacin

Abstract

The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CL(diff)) and active efflux clearance (CL(active)) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CL(diff), and efflux clearance is the sum of CL(diff), CL(active), and bulk flow clearance (CL(bulk)). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CL(bulk) of 0.01 ml/min, CL(active) was estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.

FIG. 1.

(A) Population kinetic three-compartment model. S, central compartment (serum); P, peripheral compartment; C, CSF compartment; Q, intercompartmental clearance between the central and peripheral compartments; CL, total clearance; CL_in, total CSF influx clearance; CL_out, total CSF efflux clearance. (B) Transfer kinetic processes at the serum-CSF barrier. CL_diff, clearance by passive transcellular diffusion; CL_active, clearance by active efflux; CL_bulk, clearance by CSF bulk flow.

FIG. 2.

Goodness-of-fit plots of the three-compartment pharmacokinetic model for grepafloxacin. (Upper panels) Measured concentrations in serum versus predictions for the population (PRED) and predictions for individuals (IPRED). (Lower panels) Measured concentrations in CSF versus predictions for the population and predictions for individuals. Each fine solid line in the left panels represents one animal. Fine dashed lines, lines of identity; heavy dashed lines, smoothed curves for the measured concentrations versus the predictions for the population and predictions for individuals, as illustrated in the corresponding plot.

FIG. 3.

Passive transcellular diffusion clearance (CL_diff) for different intravenous grepafloxacin dose regimens (15 mg/kg once, 30 mg/kg once, and 50 mg/kg twice). Boxes delimit the interquartile range R (third quartile to first quartile); whiskers indicate 1.5R.

FIG. 4.

Percentage of fraction of CSF grepafloxacin concentrations greater than 0.06 mg/liter versus time as a function of dose for 400 simulated rabbits. Solid lines, profiles when the indicated dose is given; shaded areas around solid lines, 90% certainty intervals for the curves (see text); dotted line, 90% probability of having a CSF grepafloxacin concentration greater than the MIC.

FIG. 5.

Percentage of AUC_CSF/MIC ratios higher than 50, 100, or 150 at different doses for 400 simulated rabbits. Solid lines, profiles when the indicated dose is given; shaded areas around solid lines, 90% certainty intervals for the curves (see text); dotted line, 90% probability of having the ratio greater than 50, 100, or 150.