Abstract

Objective: Current pharmacological treatments for prostate diseases are limited by poor drug penetration into the prostate and systemic adverse effects. This study evaluated whether a novel vas-deferens injection device could improve targeted delivery of levofloxacin to the prostate. Methods: Healthy adult male Sprague–Dawley rats received a single dose of levofloxacin by either intravenous administration (IV) or trans-vas-deferens administration using a novel disposable device (VS). Plasma and prostate samples were collected from 0.5 to 24 h and analyzed by LC-MS/MS. Iodixanol micro-CT imaging was used to visualize the local delivery pathway. Pharmacokinetic evaluation included observed composite-profile Cmax/Tmax, AUC0-24, and fT. Time-dependent tissue selectivity was evaluated through partial AUC analyses, prostate-to-plasma exposure ratios, and pointwise concentration ratios. A bioequivalence-style framework was applied to compare relative exposure parameters using geometric mean ratios (GMRs) with the 80.00–125.00% reference interval. Exploratory PK/PD evaluation combined literature-derived free-drug fractions (fut_plasma = 0.55, fut_prostate = 0.080) to estimate fAUC/MIC against representative uropathogens, supplemented by Monte Carlo simulation (n = 5000) to estimate probability of target attainment (PTA) at an fAUC/MIC ≥ 30 threshold. Results: Imaging confirmed selective distribution within the reproductive tract after vas-deferens delivery. In plasma, VS substantially reduced systemic exposure compared with IV: Cmax was 4.74 μg/mL (VS) versus 10.72 μg/mL (IV), and AUC0-24 was 15.47 versus 28.59 μg·h/mL. In the prostate, VS maintained comparable or numerically higher exposure: Cmax was 61.96 μg/g (VS) versus 52.02 μg/g (IV), and AUC0-24 was 235.77 versus 208.77 μg·h/g. The tissue distribution factor fT was substantially elevated in VS (2.26; 95% CI: 1.58–3.19) compared with IV (1.06; 95% CI: 0.89–1.30). Bioequivalence-style analysis demonstrated that plasma GMRs for AUC0-24 and Cmax fell well below 80%, confirming reduced systemic burden, while prostate GMRs were maintained, and the prostate-to-plasma AUC ratio GMR was increased. Time-dependent partial AUC analyses revealed that VS significantly elevated the prostate-to-plasma exposure ratio. PK/PD evaluation showed that at 24 h, prostate fAUC/MIC against Enterobacteriaceae (MIC = 0.5 μg/mL) was 37.7 (VS) versus 33.4 (IV), with corresponding PTA values of 97% and 94%, while plasma fAUC/MIC remained substantially lower in the VS group. Conclusions: Trans-vas-deferens administration of levofloxacin via a novel injection device effectively reduced systemic drug exposure while maintaining or enhancing prostate tissue concentrations, thereby widening the therapeutic window and reducing systemic drug exposure.

IPC Classification

Keywords