Do Pharmacokinetics Explain Persistent Restenosis Inhibition by a Single Dose of Paclitaxel?

Abstract

Background-The purpose of this study was to investigate the elimination of paclitaxel from the arterial wall after a single short administration with a coated balloon. Methods and Results-Slightly oversized paclitaxel-coated balloons (dose 3 or 9 g/mm 2 ) without or with premounted stents were inflated in nonatherosclerotic coronary arteries of either young domestic pigs or adult Goettingen minipigs. The paclitaxel content of plasma, arterial segments, and residual hearts (without treated arteries) was measured for up to 180 days using high-performance liquid chromatography/ultraviolet detection or mass spectrometry. Angiograms were evaluated for lumen narrowing. The paclitaxel concentration in plasma remained Ͻ10 ng/mL. In arteries of domestic pigs and minipigs treated with paclitaxel-coated balloons with premounted stents, 10%Ϯ5% or 21%Ϯ8% of dose, respectively, was initially detected and decreased to 3.5%Ϯ3.1% of dose (domestic pig) by Day 7. Within 6 months it fell with a half-life of 1.9 months to 0.40%Ϯ0.35%. After 3 months the concentration in the arterial wall was 17Ϯ11 mol/L. Without a stent, drug transfer to the vessel wall was somewhat reduced and elimination faster. Immediately after treatment up to 26%Ϯ4% of dose was detected in the residual whole hearts. It dropped with a half-life of 45 days to 1.5%Ϯ0.6% of dose (0.3 mol/L) within 6 months. Conclusions-After

Novel Sirolimus–Coated Balloon Catheter

“…45 Long persistence of the drug in the vessel wall has been proposed as the mechanism of action underlying the effectiveness of PCBs. 20 Drug deposits on the vessel surface driving diffusion into the arterial tissue may support intramural drug persistence in the early phase. 46 Long-term drug persistence in the vessel wall is facilitated by crystalline paclitaxel coatings.…”

“…4,[17][18][19] Persistence of paclitaxel in the vessel wall after a single local administration with a coated balloon has been proposed as one mechanism of action for PCB. 20 Irreversible binding to microtubules 21 and the detection of paclitaxel in solid tumors 1 week after a single intravenous administration in patients 22 give some indication of the peculiarity of its pharmacokinetics. Although paclitaxel is the only drug on clinically proven and US Food and Drug Administration approved balloon catheters, coronary interventions are dominated by limuseluting stents.…”

Biological effect on drug distribution and vascular healing via paclitaxel‐coated balloon technology in drug eluting stent restenosis swine model

“…All published pharmacokinetic data presented to date has been derived from computational models or experimental studies using normal vessels 11, 12, 13, 14. PCB showed a uniform drug distribution on a non‐stented vessel surface 15.…”

Drug-Coated Balloons for Restenosis Prophylaxis

“…Existing data do not rule out either explanation. Paclitaxel released from a coated balloon persists in the vessel wall for weeks to months [35]. On the other hand, it is known that cell proliferation is fastest during the first week after vessel wall injury [67].…”

“…In the case of delivery by injection [18,19,33], short perfusion [34], or a coated balloon [28,33], the desired dose is administered at once. Uptake must be immediate and loss to the general circulation slow in order to maintain the effective local concentration for long enough [35].…”