The pharmacokinetics of Biolimus A9 after elution from the BioMatrix II stent in patients with coronary artery disease: the Stealth PK Study.

OBJECTIVES: This prospective, open-label multicenter study was conducted to assess the pharmacokinetics of Biolimus A9 after elution from BioMatrix II coronary stents. Recent clinical trials have demonstrated the efficacy and safety of Biolimus A9 eluted from different stent platforms. To date, the pharmacokinetics of Biolimus A9 in patients following the deployment of BioMatrix II stents has not yet been studied METHODS: BioMatrix II stents were implanted into 27 patients with coronary artery disease. The primary endpoints of the study were the systemic concentrations of Biolimus A9 after 28 days and 6 months as measured using a sensitive validated liquid chromatography-tandem mass spectrometry assay. RESULTS: The highest measured blood concentration at any time point was 394 pg/mL. At 28 days and 6 months following stent placement, 51.8 and 100% of patients, respectively, had Biolimus A9 concentrations <10 pg/mL. After 9 months, 100% of the patients were free of major cardiac adverse events (MACE). There was no Biolimus A9 toxicity, no cardiac or non-cardiac deaths, no myocardial infarctions, nor target vessel or target lesion revascularizations during the 9 months of follow-up. No case of acute, subacute, or late stent thrombosis was detected. CONCLUSIONS: Compared to other drug-eluting stents, such as Cypher, BioMatrix II results in relatively low systemic exposure, which may be explained by the ablominal coating of the Biomatrix II stent in combination with Biolimus A9's high lipophilicity.

Randomized, double-blind, placebo-controlled, single intravenous dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics of the novel coronary smooth muscle cell proliferation inhibitor Biolimus A9 in healthy individuals.

Biolimus A9 (BA9) is a novel proliferation inhibitor of coronary smooth muscle cells that has been specifically designed for coating drug-eluting stents. The goals of this study were to identify the highest safe intravenous dose of BA9, to evaluate the dose-dependent pharmacokinetics of BA9 after intravenous administration in humans, and to characterize early clinical symptoms of BA9 toxicity in healthy subjects. This phase 1 trial in healthy subjects was designed as a double-blind, placebo-controlled, randomized, ascending single-dose study. After screening and randomization, 28 volunteers received either placebo (n = 7) or BA9 (n = 21) in a double-blinded fashion. Doses from 0.0075 mg/kg were escalated to 0.25 mg/kg in 4 cohorts. BA9 concentrations were measured using liquid chromatography-tandem mass spectrometry. BA9 doses up to 0.075 mg/kg were well tolerated. Only the highest BA9 dose of 0.25 mg/kg produced reversible drug-related adverse events. The most frequent adverse events were headache, nausea, and mouth ulcers, most likely due to immunosuppression. Exposure to BA9 did not result in electrocardiographic or clinical laboratory changes. BA9 had a terminal half-life of 90.0 ± 40.0 hours (all n = 21, mean ± standard deviation), an apparent clearance from blood of 0.96 ± 1.07 L/kg/h, and a volume of distribution of 96.5 ± 72.6 L/kg.

Development and validation of a semi-automated assay for the highly sensitive quantification of Biolimus A9 in human whole blood using high-performance liquid chromatography-tandem mass spectrometry.

Drug-eluting stents are sustained-release intra-coronary devices that are usually coated with a few hundred micrograms of drug. Measuring the drugs that are released over weeks in order to assess human pharmacokinetics is a challenge that requires assays with high sensitivity. We developed and validated a semi-automated LC-MS/MS assay for the quantification of Biolimus A9, a proliferation signal inhibitor that was specifically developed for coating on drug-eluting stents in human EDTA blood. The only manual step was the addition of a zinc sulfate/methanol protein precipitation solution which included the internal standard. Samples were injected into the HPLC and extracted online. The assay had the following performance characteristics: range of reliable response 0.01-100 ng/mL (r(2)>0.99), inter-day accuracy (0.033 ng/mL): 111.7%, and inter-day precision: 8.6%. There was no ion suppression, matrix interferences or carry-over. Extracted samples were stable in the autosampler at +4 degrees C for at least 24 h and could undergo three freeze-thaw cycles. The assay, with a lower limit of detection of 333 fg/mL and a lower limit of quantitation of 10 pg/mL, was sufficiently sensitive and robust for quantifying Biolimus A9 in clinical trials after i.v. injection and after stent implantation.

Polymer replicas of photonic porous silicon for sensing and drug delivery applications.

Elaborate one-dimensional photonic crystals are constructed from a variety of organic and biopolymers, which can be dissolved or melted, by templating the solution-cast or injection-molded materials in porous silicon or porous silicon dioxide multilayer (rugate dielectric mirror) structures. After the removal of the template by chemical dissolution, the polymer castings replicate the photonic features and the nanostructure of the master. We demonstrate that these castings can be used as vapor sensors, as deformable and tunable optical filters, and as self-reporting, bioresorbable materials.