Introduction:

Gemcitabine has been used for many years as an intravesical instillation to treat non-muscle invasive bladder cancer (NMIBC). However, due to its short half-life (<3h), each instillation contains a high dose of gemcitabine to ensure adequate tissue penetration, which increases the risk of toxicity. TAR-200 is a novel intravesical (IVes) targeted releasing system designed to provide local continuous/sustained release of gemcitabine within the bladder and with potentially deep-tissue penetration. The objective of this preclinical study was to evaluate the penetration of gemcitabine (dFdC) and its active metabolites, diphosphate and triphosphate of dFdC (dFdCDP, dFdCTP), in bladder tissues up to 96h after TAR-200 administration or intravesical instillation.

Methods:

Bladder tissue concentrations of gemcitabine and its active metabolites (dFdCDP, dFdCTP) were measured in 5 minipigs following gemcitabine administration either by intravesical or TAR-200 instillation. Three animals received a 2-hour (h) bolus intravesical instillation of 2g free base-equivalent (FBE) of gemcitabine hydrochloride dissolved in saline (40 mg/mL), after which tissue samples were collected from one animal at 2h, a second animal at 24h (day 1) and a third animal at 96h (day 4). The TAR-200 delivery system, containing 225mg FBE, was placed into the bladder of two animals, where it remained until tissue collection at 48h (day 2) and 96h (day 4), respectively. At necropsy, samples of dome, left and right lateral wall, and trigone were collected and the urothelium with underlying lamina propria were separated from the muscle layer of the urinary bladder. The results were reported as the mean of the four tissue samples collected.

Results:

Following intravesical delivery of gemcitabine (2h), total bladder tissue concentrations of the active phosphorylated metabolites of gemcitabine (dFdCDP, dFdCTP) were high and were detected in all layers of the bladder (lamina propria/urothelium and muscle) but were virtually undetectable in tissues samples after 24h and 96h (estimated half-life <3h, Figure 1A). When gemcitabine was delivered with the TAR-200 system, active metabolites (dFdCDP, dFdCTP) could be detected in all layers of the bladder tissue over the investigated indwelling period up to 96h (Figure 1B).

'

Conclusion:

Following administration of gemcitabine using the TAR-200 delivery system, measurable levels of active phosphorylated metabolites were detected in all layers of the bladder tissues including the urothelium/lamina propria and the muscle at 48h and 96h. Comparatively, tissue exposure to gemcitabine delivered through a bolus instillation over a 2h indwelling period is limited by its short half-life (<3h) with little evidence of gemcitabine active metabolites in bladder tissue by 24h. The results of this study demonstrate that sustained local delivery of gemcitabine to the bladder through the TAR-200 system can deliver active metabolites to all layers of the bladder at least 4 days following TAR 200 placement.

Funding: The study was sponsored by Jansen Research and Development