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 dosefinding trials.

Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis

“…Interestingly, it should be kept in mind that this is not related to distribution. In relation to this explanation is the fact that drug disappearance from a physiological liquid such as cerebrospinal fluid due to turnover could also contribute to AUC ratios less than unity (3,27). Yet, one should keep in mind that such situations should be the exception, since, according to basic pharmacokinetic concepts, peripheral ECF tissue AUC-to-blood AUC ratios should be equal to unity, as a general rule (29).…”

Daptomycin Is Highly Efficacious against Penicillin-Resistant and Penicillin- and Quinolone-Resistant Pneumococci in Experimental Meningitis

“…CL bulk is the clearance by CSF bulk flow, or active efflux (20). CL metab , the clearance by drug metabolism in the CSF, is assumed to be negligible (20). P csf equals the penetration of daptomycin into the CSF (expressed as a percentage) and equals the ratio of CSF-to-plasma area under the concentration time curve (AUC), expressed as the ratio AUC csf /AUC plasma .…”

“…CL out is the total clearance from the CSF compartment to the central compartment in milliliters per minute. CL bulk is the clearance by CSF bulk flow, or active efflux (20). CL metab , the clearance by drug metabolism in the CSF, is assumed to be negligible (20).…”

“…A zero-order input (bolus injection), first-order elimination, expanded three-compartment model is used to describe the time course of serum and CSF drug concentrations. The three-compartment model consists of a central compartment (serum), which is linked to a peripheral compartment and the CSF compartment (7,20). Influx and efflux clearances in the CSF compartment are modeled as CL in ϭ CL diff , CL out ϭ CL diff ϩ CL bulk ϩ CL metab , and P csf ϭ CL in /CL out , where CL in is the total clearance from the central compartment to the CSF compartment in milliliters per minute, assumed to be equal to CL diff , the passive transcellular diffusion clearance (i.e., active influx clearance is absent).…”

Activities of Ertapenem, a New Long-Acting Carbapenem, against Penicillin-Sensitive or -Resistant Pneumococci in Experimental Meningitis

“…A zero-order input (bolus injection), firstorder elimination, and expanded three-compartment model is used to describe the time course of serum and CSF drug concentrations. The three-compartment model consists of a central compartment (serum), which is linked to a peripheral compartment, and the CSF compartment (5,18). Influx and efflux clearance in the CSF compartment are modeled as CL in ϭ CL diff , CL out ϭ CL diff ϩ CL bulk ϩ CL metab , and P csf ϭ CL in /CL out , where CL in is the total clearance from the central compartment to the CSF compartment (in milliliters/minute) and is assumed to be equal to CL diff , the passive transcellular diffusion clearance (i.e., the active influx clearance is absent).…”