Analyzing the effects of instillation volume on intravesical delivery using biphasic solute transport in a deformable geometry

Abstract

Ailments of the bladder are often treated via intravesical delivery-direct application of therapeutic into the bladder through a catheter. This technique is employed hundreds of thousands of times every year, but protocol development has largely been limited to empirical determination. Furthermore, the numerical analyses of intravesical delivery performed to date have been restricted to static geometries and have not accounted for bladder deformation. This study uses a finite element analysis approach with biphasic solute transport to investigate several parameters pertinent to intravesical delivery including solute concentration, solute transport properties and instillation volume. The volume of instillation was found to have a substantial impact on the exposure of solute to the deeper muscle layers of the bladder, which are typically more difficult to reach. Indeed, increasing the instillation volume from 50-100 ml raised the muscle solute exposure as a percentage of overall bladder exposure from 60-70% with higher levels achieved for larger instillation volumes. Similar increases were not seen for changes in solute concentration or solute transport properties. These results indicate the role that instillation volume may play in targeting particular layers of the bladder during an intravesical delivery.

Keywords: FEBio; bladder cancer; cystitis; intravesical delivery.

Fig. 1.

The bladder and factors influencing intravesical delivery.

Fig. 2.

Bladder geometry and mesh used for analysis. The bladder was assumed to be sphere and reduced to 1/8 of a sphere via symmetry. Three layers were included with identical mechanical properties and varying transport properties as indicated. The baseline conditions for umbrella permeability and solubility are shown. P = Permeability; Sol = Solubility.

Fig. 3.

(a) Bladder deformation at the beginning, after instillation and at the end of a 60-min intravesical treatment with of 50 ml (top) and 100 ml (bottom). The distribution of displacement reflects the thinning bladder wall. The bladder volume over time is shown in (b) for a range of . The wall thickness (c) is a function of and continued urine production over time. Volume of instillation; Volume of urine produced during treatment; Final volume at the end of treatment.

Fig. 4.

Solute concentration and exposure throughout the bladder in the baseline condition ( ml, pg/ml, , 2.94E-5 and D = 60 min). The concentration time course is shown in the lumen (a), umbrella cells (b), urothelium (c) and halfway through the muscle layer (d) with respect to time. The concentration profile (e) across the geometry after 60 min of instillation shows minimal solute penetration beyond 2.5 mm of depth. The cumulative exposure (f) across the bladder geometry demonstrates a lack of exposure at deeper layers. Bladder depth refers to the distance from the lumen in the nondeformed geometry. Volume of instillation; Solute concentration in instillation; Umbrella solubility; Umbrella permeability; D= Duration of instillation.

Fig. 5.

Effects of the umbrella layer solubility (a), umbrella layer permeability (b) and both increasing (c) and decreasing (d) starting drug concentration on cumulative exposure across the bladder. Bladder depth refers to the distance from the lumen in the nondeformed geometry. C instilled solute concentration; U Umbrella solubility; U Umbrella permeability.

Fig. 6.

Impact of volume of instillation on cumulative solute exposure throughout the bladder wall both as absolute values (a, c) and relative (b, d) to the baseline condition (V ml, C pg/ml, U, UE-5 and D = 60 min). In the upper graphs (a, b) the instillation concentration was changed with respect to instillation volume to keep the dose constant (constant C). In the lower graphs (c, d), the concentration was kept constant regardless of instillation volume, thus prescribing a changing dose. Bladder depth refers to the distance from the lumen in the nondeformed geometry. V Volume of instillation; CSolute concentration; U Umbrella solubility; U Umbrella permeability; D = Duration of instillation.

Fig. 7.

Instillation volume impacts the amount of time needed to reach the same final cumulative solute exposure at a given depth as in the baseline condition (V ml, C pg/ml, U, UE-5 and D = 60 min). Maintaining a constant dose (a) primarily impacted deeper layers (>1mm from the lumen), while (b) a constant C (or changing dose) sped the exposure to all layers. Bladder depth refers to the distance from the lumen in the nondeformed geometry. V Volume of instillation C Solute concentration; U Umbrella solubility; U Umbrella permeability; D = Duration of instillation.

Fig. 8.

Instillation volume impacts delivery to deeper bladder layers more efficiently than other parameters. The total tissue exposure (a) is a volumetric measure of cumulative exposure for the urothelium (<235 m) and the muscle layer (> 235 m). The percentage of total tissue exposure due to exposure within the muscle layer is shown in (b). Base conditions are the following: V ml; C pg/ml; U; UE-5; D = 60 min; V Volume of instillation with a constant dose; V Volume of instillation with a constant concentration; C Instillation solute concentration; U Umbrella solubility; U Umbrella permeability; D = Duration of instillation.