Do pharmacokinetics explain persistent restenosis inhibition by a single dose of paclitaxel?

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.

Slightly oversized paclitaxel-coated balloons (dose 3 or 9 μg/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 <10 ng/mL. In arteries of domestic pigs and minipigs treated with paclitaxel-coated balloons with premounted stents, 10%±5% or 21%±8% of dose, respectively, was initially detected and decreased to 3.5%±3.1% of dose (domestic pig) by Day 7. Within 6 months it fell with a half-life of 1.9 months to 0.40%±0.35%. After 3 months the concentration in the arterial wall was 17±11 μmol/L. Without a stent, drug transfer to the vessel wall was somewhat reduced and elimination faster. Immediately after treatment up to 26%±4% of dose was detected in the residual whole hearts. It dropped with a half-life of 45 days to 1.5%±0.6% of dose (0.3 μmol/L) within 6 months.

After a single local administration with coated balloons, paclitaxel stays in the vessel wall of pigs long enough to explain persistent inhibition of neointimal proliferation. The pharmacokinetics of paclitaxel does, however, not exclude other reasons for sustained efficacy such as early blocking of processes initiating excessive and prolonged neointimal proliferation.