Investigating the transurothelial delivery of therapeutic agents

• Main Author: Williams, Nicholas
• Published: Cardiff University 2015
• Subjects: Q Science (General)
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.655950

Intravesical drug delivery (IDD) offers a unique opportunity to target pathology of the lower urinary tract. High concentrations of drug can be delivered directly to the bladder with minimal systemic absorption. IDD has been used successfully to manage a range of conditions such as bladder cancer and overactive bladder and continues to be investigated for novel indications. Despite this the majority of IDD regimens remain empirically driven and as a result its potential largely unfulfilled. This thesis developed and validated an ex' vivo porcine model to investigate the transurothelial delivery and bladder wall distribution of drugs after topical application to the urothelium. Using the model, transurothelial permeability coefficients were determined and tissue layer specific bladder wall concentrations calculated for a range of clinically relevant drugs including ketorolac and oxybutynin. The results of these studies were used to inform on the viability of delivering these drugs intravesically in' vivo. Additionally a computer - based pharmacokinetic model of IDD was developed using STELLA® modelling software. The model was used to investigate the key variables associated with IDD and suggest novel techniques and dosing concepts to improve its efficacy. For the first time, the relative permeability of the upper and lower urinary tract was investigated for a single drug. Ex'vivo porcine ureteral urothelium was shown to be significantly more permeable to mitomycin C than that of the bladder. If translated into human, the more permeable urothelium may provide higher target tissue concentrations after local delivery and a significant opportunity to manage upper tract urothelial carcinoma conservatively. This project developed novel ex'vivo and in'silico methods to investigate IDD. These techniques can be used to rationally inform on the design of new, or optimisation of existing, IDD regimens.