"Stenosis limited release from drug coated balloons and local delivery to peripheral porcine arteries." Rami Tzafriri, Peter Markham, Benny Muraj, Jay Budrewicz, Anna-Maria Spognardi

Aims: The influence of lesion complexity on drug release and tissue delivery by drug coated balloons (DCB) cannot be studied clinically and has not been systematically studied in animal models. The reported in vivo porcine study aimed to quantify the influence of angiographic lesion parameters on the acute drug delivery performance of a commercial DCB in the setting of naïve and instent restenosis lesions (ISRL) in superficial femoral arteries (SFAs).

Methods and Results: All animal experiments were performed at CBSET, Inc. (AAALAC accredited) and adhered to the Guide for the Care and Use of Laboratory Animals under an Institutional Animal Care and Use Committee-approved protocol. At Day-30, bilateral ISRL were created in 8 SFAs of juvenile Yorkshire pigs via 30% overstretch of noncompliant balloons (POBA) followed by implantation of two consecutive 40 mm long nitinol stents at 100% overlap. By Day 0, 2 of the ISRL were totally occluded, so that only 6 of the ISRL could be treated. ISRL were predilated with POBA, resulting in minimum lumen diameters (MLDs) ranging from 1.7 to 2.7 mm (respectively, 92-78-% stenosis). The 6 postdilated ISRL and 8 naïve SFA from a second cohort of juvenile Yorkshire pigs were treated with a commercial 4.0x60 mm DCB (1542 μg paclitaxel/DCB) under angiographic guidance. In both SFA groups, DCBs were inflated for 60 seconds, at a balloon:artery ratio of 1.17:1 for the ISRL and 1.03:1 for the naïve SFA. Used DCBs were removed post-treatment and stored for paclitaxel quantification by liquid chromatography mass spectrometry (LC/MS-MS) along with 3 unused DCBs. Animals were euthanized 15-30 minutes after the second bilateral DCB treatment. SFA segments centered along the treatment sites (~60-70 mm long) were collected and processed for quantification of paclitaxel tissue deposition by LC/MS-MS. Paclitaxel release from DCB and tissue deposition in the naïve and ISRL groups were compared statistically using the Welch’s t-test. Treatment DCB released 5.2% (80 μg) more paclitaxel in naïve SFA vs ISRL (P=0.0067, 79.8 vs 74.6%). This resulted in 98 μg greater paclitaxel deposition in naïve SFA compared to ISRL (111.2 vs 13.1 μg, P=0.0018), illustrating a concordance between paclitaxel release and deposition trends. Moreover, in the ISRL group, the amounts of released paclitaxel and tissue deposited paclitaxel both trended monotonically higher with increasing MLD values (e.g. increasing stenosis levels), consistent with reduced contact dependent coating transfer when DCB diameter substantially exceeds the MLD.

Conclusions: This demonstration of significantly lower drug deposition in porcine ISRL compared to naïve arteries is consistent with hindered drug release from DCB owing to constricted balloon distention at low MLD. Thus, MLD emerges as an independent predictor of acute drug delivery performance by DCB in the pig, providing a relevant model for the study of vessel preparation effects on drug delivery.