A population pharmacokinetic analysis of the penetration of the prostate by levofloxacin

Prostatitis has remained a pathological entity that is difficult to treat. Part of the difficultJ revolves about the putative offending pathogens. For acute prostatitis, members of the Enterobacteriaccae, particularly Escheri chia coli, play a central role, while intracellular pathogens such as Chlam ydia are more frequently seen In chronic prostatitis. Consequently, a drug needs to be able to penetrate to this specialized site in both the acute an d chronic infection forms of the disease and also have potent activity agai nst the most common causative pathogens, both intracellular and extracellul ar. Levofloxacin has such an activity profile. We wished to document its ab ility to penetrate to the site of infection. Patients undergoing prostatect omies were administered 500 mg of levofloxacin orally every 23 h for 2 days prior to surgery, and then on the day of surgery, 500 mg was administered as an hour-long, constant-rate intravenous (i.v.) infusion. A set of blood samples was obtained as guided by stochastic optimal design theory, Prostat e biopsy times were determined by randomizing subjects into one of four gro ups, based on the interval after the i.v. dose. All plasma and prostate dru g concentrations were comodeled by a population modeling program, BigNPEM, implemented on the Gray T3E Supercomputer housed at the Supercomputer Cente r at the University of California at San Diego, Penetration was determined as the ratio of the area under the concentration-time curve (AUC) of levofl oxacin in the prostate to the plasma levofloxacin AUG. When calculated from the mean population parameters, this penetration ratio was 2.96. We also p erformed a 1,000-subject Monte Carlo simulation from the mean parameter vec tor and covariance matrix. The mean penetration ratio here was 4.14 with a 95% confidence interval of 0.20 to 19.6. Over 70% of the population had a p enetration ratio in excess of 1.0. Levofloxacin adequately penetrates a non inflamed prostate and should be evaluated for the therapy of prostatitis.