Prostatic tissue distribution of gepotidacin in patients undergoing prostatectomy: an ex-vivo microdialysis and pharmacokinetic modelling study

Abstract Objectives The objective of the study was to explore the distribution of gepotidacin into prostate tissue by ex-vivo microdialysis (MD) following a single oral dose of gepotidacin. Methods We developed and validated an ex-vivo MD technique to quantify unbound gepotidacin concentrations in the interstitial fluid of human prostate tissue following a single oral dose of 1500 mg. Adult male patients scheduled for radical prostatectomy received gepotidacin at different time-points prior to surgery. MD probes were inserted into prostate tissue immediately after surgical removal for sampling of tissue concentrations. Plasma samples were collected in parallel. Population pharmacokinetic (popPK) modelling was used to analyze the concentration data. Results Thirty participants were recruited, of whom 24 had at least one prostate MD sample with concentrations above the limit of quantification. A popPK model was successfully developed which described plasma and prostate gepotidacin concentration well. The model-predicted geometric mean of unbound area under the concentration–time curve from zero to infinity was 15500 h*ng/mL (GCV: 15.7%) in both prostate and plasma (prostate penetration ratio=1). The model-predicted geometric mean of the unbound peak concentration (Cmax) of 1340 ng/mL (GCV: 38.7%) was reached after 4.25 hours (range: 3.25, 12.2h) in prostate tissue. The model predicted-geometric mean of unbound plasma Cmax of 2090 (GCV 48.2%) ng/mL was reached after 1.75 hours (range: 0.75, 8.25h). Model-estimated median total apparent plasma clearance (CL/F) and terminal apparent volume of distribution (Vz/F) were 65.0 L/h (GCV 15.7%) and 1310 L (GCV 11.2%), respectively. Conclusions Ex-vivo MD proved feasible for quantifying gepotidacin in human prostate tissue, interstitial fluid showing exposures comparable to plasma. However, defining PK/PD targets against relevant pathogens for bacterial prostatitis remains essential for predicting drug efficacy for treatment of this disease.