Site-Specific Intracoronary Delivery of Octreotide in Humans: A Pharmacokinetic Study to Determine Dose-Efficacy in Restenosis Prevention

Somatostatin analogues have been shown to inhibit smooth muscle cell proliferation after local administration in vivo in animal models and in vitro using human coronary smooth muscle cell cultures. However, the optimal dosage for attaining effective site-specific administration remains undefined. This study was performed to determine the required theoretical dose of the somatostatin analogue, octreotide, to be delivered site specifically, for prevention of restenosis after coronary angioplasty in humans using a previously described methodology to determine regional pharmacokinetics of site-specific intracoronary administrated compounds. In 7 patients, 111In-octreotide, a γ-labeled somatostatin analogue, was infused post angioplasty at the site of dilatation via a coil-balloon and quantified using a radio-isotopic technique. Efficiency of delivery ranged from 0.1% to 2.7% of the total infused dose of 0.18 μg, corresponding to a mean peak delivered amount of 1.8 ± 1.9 ng. Total locally bioavailable 111In-octreotide reached 2.28 ± 2.15 ng h. Based on current in vitro bioavailability and peak concentration data to inhibit proliferation and thymidine incorporation in human coronary smooth muscle cells, a 4000× higher averaged dose (∼700 μg) should be infused site specifically to obtain a biologic efficacy in 50% of the treated patients (ED50). Quantification of regional pharmacokinetics enables the determination of a theoretical site-specific dose for achieving appropriate bioavailablility above the therapeutic threshold concentration for smooth muscle cell inhibition. This approach is proposed for the determination of the appropriate site-specific coronary infusion dose for the inhibition of restenosis after balloon angioplasty.