Prediction of brain delivery of ofloxacin, a new quinolone, in the human from animal data.

We attempted to predict the delivery of ofloxacin (OFLX), a new quinolone antibacterial agent (NQ), into cerebrospinal fluid (CSF) in the human based on the physiological properties and pharmacokinetic parameters of NQs in various animals. Physiological properties for evaluation of drug delivery into CSF such as volume and the bulk flow rate of CSF and weight of choroid plexus, were compared among the rat, rabbit, cat, dog, and human. Statistically significant correlations with power values of 0.82-0.89 in the linear regression were observed on log-log plots between brain weight and those properties of each species. Delivery of OFLX into CSF from blood was analyzed by "diffusion and flow model" with unidirectional efflux process from CSF to blood. The blood-CSF diffusion clearance and the efflux clearance of OFLX in the human were extrapolated from animal data based on the allometric correlations between brain weight and these parameters in the rat, rabbit, and dog. The apparent volume of distribution and the total body clearance of NQs in the human could also be predicted from animal data based on the classical Adolph-Dedrick approach. To simulate the CSF concentration-time profile of OFLX in the human by using these predicted parameters, it was necessary to consider both the lumbar CSF compartment and the ventricular CSF compartment. Both plasma and CSF concentration-time profiles of OFLX predicted from only animal experimental data were in good agreement with those observed clinically.