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

Author:

Speck Ulrich1,Cremers Bodo1,Kelsch Bettina1,Biedermann Melanie1,Clever Yvonne P.1,Schaffner Silvio1,Mahnkopf Dirk1,Hanisch Uli1,Böhm Michael1,Scheller Bruno1

Affiliation:

1. From the Department of Radiology, Charité′, Humboldt University Berlin, Berlin, Germany (U.S., B.K., M.B.); Department of Internal Medicine III, University of Saarland, Homburg/Saar, Germany (B.C., Y.P.C., M.B., B.S.); Medtronic Invatec Technology Center, Frauenfeld, Switzerland (S.S.); IMTR GmbH, Institute of Medical Technology & Research, Rottmersleben, Germany (D.M.); and Anakat GmbH, Robert-Koch-Platz 4, Berlin, Germany (U.H.).

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 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. Conclusions— 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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