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

Abstract

Prostatitis has remained a pathological entity that is difficult to treat. Part of the difficulty revolves about the putative offending pathogens. For acute prostatitis, members of the Enterobacteriaceae, particularly Escherichia coli, play a central role, while intracellular pathogens such as Chlamydia are more frequently seen in chronic prostatitis. Consequently, a drug needs to be able to penetrate to this specialized site in both the acute and chronic infection forms of the disease and also have potent activity against the most common causative pathogens, both intracellular and extracellular. Levofloxacin has such an activity profile. We wished to document its ability to penetrate to the site of infection. Patients undergoing prostatectomies were administered 500 mg of levofloxacin orally every 24 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. Prostate biopsy times were determined by randomizing subjects into one of four groups, based on the interval after the i.v. dose. All plasma and prostate drug concentrations were comodeled by a population modeling program, BigNPEM, implemented on the Cray T3E Supercomputer housed at the Supercomputer Center at the University of California at San Diego. Penetration was determined as the ratio of the area under the concentration-time curve (AUC) of levofloxacin in the prostate to the plasma levofloxacin AUC. When calculated from the mean population parameters, this penetration ratio was 2.96. We also performed a 1,000-subject Monte Carlo simulation from the mean parameter vector 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 penetration ratio in excess of 1.0. Levofloxacin adequately penetrates a noninflamed prostate and should be evaluated for the therapy of prostatitis.

FIG. 1

Concentrations of levofloxacin in the prostate as determined by high-performance liquid chromatography. Times are after the end of the actual administration of the intravenous infusion are shown. ●, concentration of drug in prostate.

FIG. 2

(A) Simulation from the mean parameter vector of the plasma and prostate concentration-time profiles of levofloxacin. (B) Simulation from the mean parameter vector of the plasma and prostate amount-time curves of levofloxacin. Dotted line, drug concentration in prostate; solid line, drug concentration in plasma.

FIG. 3

(A) Mean concentration-time curve in plasma and the 95% confidence interval derived from a Monte Carlo simulation. ●, drug concentration in plasma. (B) Mean concentration-time curve in the prostate and the 95% confidence interval derived from a Monte Carlo simulation. ●, drug concentration in prostate.

FIG. 4

(A) Histogram of a 1,000-subject Monte Carlo simulation of the AUC_prostate/AUC_plasma of levofloxacin. (B) As in panel A, but with only the range of the ratio of 0 to 2 displayed.