Modelling and evaluation of interventions to support overactive bladder issues in spinal cord injury subjects

This thesis uses mathematical modelling to improve understanding and address the challenges associated with a neurogenic bladder in patients with spinal cord injuries (SCIs), focusing on an overactive bladder (OAB) and detrusor sphincter dyssynergia (DSD). OAB refers to the occurrence of unwanted and uncontrolled contractions during the bladder’s filling stage, while DSD involves simultaneous contractions of the detrusor and urethral sphincters [1]. Traditionally, OAB symptoms have been treated with anticholinergic drugs, particularly oxybutynin (OXY). However, due to the typical occurrence of adverse effects, a novel drug called mirabegron (MBG) has been developed with the aim of minimising these unwanted effects [2]. Botulinum toxin type A (BoNT/A) injections are also administered as a second-line treatment, every 6 to 9 months, depending on the reappearance of involuntary contractions [3]. Furthermore, clean intermittent catheterisation is typically performed for DSD every 4 to 6 hours [4], [5]. This thesis represents the initial phase of a larger project that aims to develop a “smart” catheter to assist SCI patients with OAB and DSD symptoms. The primary objective of this device is to estimate unwanted bladder contractions associated with OAB, facilitating patient monitoring by the clinician. The thesis specifically focuses on characterising the associated fluid dynamics and the development of structurally identifiable pharmacometrics models for the three different treatments (BoNT/A, OXY and MBG) targeting OAB, using the limited literature data available in these areas. In this thesis population pharmacokinetic (PK) models have been developed for OXY and MBG using mean human data from the literature. Covariate assessment methods have been employed to explore their potential influence on the PK, aiming to identify factors contributing to observed variability in plasma versus time profiles of OXY and MBG. BoNT/A has been characterised through a preliminary target-mediated drug disposition (TMDD) kinetic/pharmacodynamic (K-PD) model, based on limited contractility versus time data. This model is the first study that attempts to mathematically characterise the long-term effects of BoNT/A on the detrusor of SCI patients. The duration of the effects of BoNT/A is medically significant, considering the limited knowledge available on its long-term application, and the timing of re-treatment is of significant importance to SCI sufferers. Thus, once fully validated, this model could potentially determine the appropriate timing for rescheduling of BoNT/A treatment for each individual patient, based on minimal and appropriate effect versus time data. Additionally, a comprehensive investigation into the differences between males and females regarding estimation of urodynamic variables at the outlet of intermittent catheters has been conducted employing mathematical modelling methodologies and in vitro experimental techniques to support model validation. The thesis examines current data limitations in these fields, outlines subsequent steps in the longer-term project and establishes methodological foundations for PK/PD model development across the current drug treatments, to account for contractility effects in the detrusor of SCI patients. The findings from this study contribute to potential improvements in strategies and provide a basis for future research in this field