title: 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.
  
  
  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.
authors.affiliation: Department of Radiology, Charité, Humboldt University Berlin, Berlin, Germany. ulrich.speck@charite.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Speck
authors.forename: Bodo
authors.initials: B
authors.lastname: Cremers
authors.forename: Bettina
authors.initials: B
authors.lastname: Kelsch
authors.forename: Melanie
authors.initials: M
authors.lastname: Biedermann
authors.forename: Yvonne P
authors.initials: YP
authors.lastname: Clever
authors.forename: Silvio
authors.initials: S
authors.lastname: Schaffner
authors.forename: Dirk
authors.initials: D
authors.lastname: Mahnkopf
authors.forename: Uli
authors.initials: U
authors.lastname: Hanisch
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Bruno
authors.initials: B
authors.lastname: Scheller
mesh_terms: D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects / Q000295:instrumentation*; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D057785:Catheters; D002851:Chromatography, High Pressure Liquid; D020099:Coated Materials, Biocompatible; D017023:Coronary Angiography; D023903:Coronary Restenosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006207:Half-Life; D013058:Mass Spectrometry; D009206:Myocardium / Q000378:metabolism; D058426:Neointima; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013056:Spectrophotometry, Ultraviolet; D015607:Stents; D034421:Sus scrofa; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution
chemical_list: D002317:Cardiovascular Agents; D020099:Coated Materials, Biocompatible; D017239:Paclitaxel