Intravascular drug release kinetics dictate arterial drug deposition, retention, and distribution

Abstract

Millions of patients worldwide have received drug-eluting stents to reduce their risk for in-stent restenosis. The efficacy and toxicity of these local therapeutics depend upon arterial drug deposition, distribution, and retention. To examine how administered dose and drug release kinetics control arterial drug uptake, a model was created using principles of computational fluid dynamics and transient drug diffusion-convection. The modeling predictions for drug elution were validated using empiric data from stented porcine coronary arteries. Inefficient, minimal arterial drug deposition was predicted when a bolus of drug was released and depleted within seconds. Month-long stent-based drug release efficiently delivered nearly continuous drug levels, but the slow rate of drug presentation limited arterial drug uptake. Uptake was only maximized when the rates of drug release and absorption matched, which occurred for hour-long drug release. Of the two possible means for increasing the amount of drug on the stent, modulation of drug concentration potently impacts the magnitude of arterial drug deposition, while changes in coating drug mass affect duration of release. We demonstrate the importance of drug release kinetics and administered drug dose in governing arterial drug uptake and suggest novel drug delivery strategies for controlling spatio-temporal arterial drug distribution.

Figure 1

Schematic representation of an implanted endovascular drug coated stent strut residing in the blood flow field and overlying the arterial wall. Ω_Tissue, Ω_Blood, Ω_Coat represent the tissue (shaded gray), lumen (shaded tan), and drug laden strut coating (shaded blue) regions. Blood flow occurs in the positive z axial direction.

Figure 2

Governing equations and boundary conditions describing the physics of fluid dynamics and transient drug transport. The arterial luminal radius (R) is 1.5 mm and the arterial wall thickness (W_tissue) is 1 mm. The velocity map in the radial and axial directions, v_r and v_z, were calculated based on the inlet parabolic profile with centerline velocity (V_c) of 46 cm/s. Tissue and blood drug concentrations, (C_t and C_b) were normalized to the strut drug concentration, C_c = 1. D_b, D_t, D_c are drug diffusion coefficients in blood, 10⁺⁵ um²/s, in the arterial wall, 1 um²/s, and in the coating, ranging from 10⁺⁵ - 10^-5 um²/s.

Figure 3

Experimental validation for computationally predicted fractional drug release from a stent. In vivo data were obtained from analysis of porcine implanted stent drug levels at designated time points of 1, 8, 14, 30, 60, and 90 days post-implantation. Computationally predictions of fractional drug release were obtained using coating drug diffusivity of 1.5×10^-5 um²/s.

Figure 4

Impact of varying drug release rate from the coated strut by changing drug diffusivity within the coating within a 10 log range. A. Average coating drug concentration vs. time, B. Average arterial drug deposition vs. time, C. Arterial drug concentration vs. longitudinal position along the arterial wall at a location <1 strut depth within the arterial wall at 110s and 1 day post-implantation. All data were acquired using a transient computational model with equivalent initial drug load conditions.

Figure 5

Impact of modulating release rate by (1) increasing coating drug diffusivity while maintaining constant coating drug load and (2) increasing applied drug concentration and coating drug load while maintaining constant coating drug diffusivity. A. Average coating drug concentration vs. time. B. Average arterial drug concentration vs. time.

Figure 6

Impact of altering release rate independently of initial drug load by simultaneous and opposite variations in relative coating thickness and coating drug concentration using a coating drug diffusivity of 10^-5 um²/s. A. Average coating drug concentration vs. time. B. Average arterial drug concentration vs. time.

Figure 7

Impact of altering release rate by changing initial drug load via increased coating thickness using coating drug diffusivity of 10^-5 um²/s. A. Average coating drug concentration vs. time for different coating thicknesses and distributions of coating around the strut, B. Drug released from the stent normalized by the initial drug load on the “x” coating thickness strut, C. Average arterial drug concentration vs. time. All initial coating drug concentrations were unity.

Figure 8

Impact of variations in coated strut size and coating drug load on drug release kinetics and arterial drug uptake using coating drug diffusivity of 10^-5 um²/s. A. Average coating drug concentration vs. time, B. Average arterial drug concentration vs. time for different strut sizes. All coating drug concentrations were initially unity. Brackets around legend entries indicate overlapping curves as designated by arrow.