ABSORB III substudy: Systemic everolimus pharmacokinetics after BVS predictable by dose proportion

SAN FRANCISCO — The findings from a substudy of ABSORB III showed that the pharmacokinetic characteristics of everolimus after treatment with bioresorbable vascular scaffold are predictable with dose-proportional behavior, according to data presented at the annual TCT Scientific Symposium.

David G. Rizik, MD, of the Scottsdale-Lincoln Health Network in Scottsdale, Arizona, and colleagues conducted the prospective, open-label, nonrandomized investigation in 12 patients (mean age, 60.1 years; 91.7% men) with either one bioresorbable vascular scaffold (BVS; n = 8; Absorb, Abbott Vascular) or two BVS (n = 4) implanted in de novo coronary artery stenosis.

Patient risk factors were current tobacco use (25%), diabetes (33.3%), hypertension (100%), dyslipidemia (100%) and previous MI (18.2%). Stable or unstable angina existed in 75% of patients with one BVS and 25% of patients with two BVS.

Target lesions were located mostly in the left circumflex artery (50%), followed by the left anterior descending artery (42%) and the right coronary artery (8%). Mean lesion length was 12.2 ± 4.4 mm, and moderate or severe calcification existed in one-third of lesions.

Reference vessel diameter was 2.73 ± 0.41 mm before the procedure. BVS diameters ranged from 2.5 mm to 3.5 mm and lengths ranged from 8 mm to 28 mm; the average total length implanted at the lesion site was 24.5 ± 8.6 mm. Total dose of everolimus ranged from 181 μg to 443 μg.

The researchers drew blood at 16 time points, including before initial BVS implantation and at specified intervals after the last BVS. The team assessed everolimus blood concentrations and conducted an analysis to calculate pharmacokinetic parameters (C_max, t_max, t_1/2, AUC_24h, AUC_last, and AUC_0-∞). They then performed a regression analysis on dose-normalized (to 1 μg) parameters for everolimus to examine dose proportionality.

The investigators compared blood concentration-time profiles and pharmacokinetic parameters of everolimus against previous results from the cobalt-chromium everolimus-eluting stent (Xience V, Abbott Vascular) gathered from substudies of the SPIRIT II and III trial.

Across all doses, individual t_max ranged from 0.17 to 2.37 hours. Individual C_max values increased along with dose (range, 1.085-4.46 ng/mL). Dose-proportional increases were also observed for individual AUC_24h (range, 12.09-44.22 ng.h/mL), AUC_last (range, 25.37-104.6 ng.h/mL) and AUC_0-∞ (range, 33.15-120.8 ng.h/mL).

Individual C_max values (range, 1.085-4.460 ng/mL) were slightly higher than the minimum systemic therapeutic level (≥ 3 ng/mL) needed to prevent organ rejection; blood concentrations quickly diminished after reaching C_max and were less than 3 ng/mL in all patients at 4 hours after last BVS deployment.

Further, C_max levels after BVS were below the mean steady C_max(61 ng/mL) seen in patients with solid tumors who received everolimus 10 mg/day.

At a common everolimus load of 181 µg, both BVS and cobalt-chromium everolimus-eluting stent showed a rapid rise in systemic everolimus levels after treatment. The highest concentrations were observed within 2.5 hours; this was followed by a decline involving an initial rapid phase then a slower terminal phase.

Increases in total everolimus dose resulted in proportional increases in C_max and AUC with BVS, as seen with cobalt-chromium everolimus-eluting stent, according to the researchers.

“The pharmacokinetics of the Absorb scaffold, showing similar everolimus elution and tissue concentration as the Xience metallic drug-eluting stent, suggest it will have similar efficacy as Xience,” said Gregg W. Stone, MD, an investigator on the substudy and an Editorial Board member for Cardiology Today’s Intervention. – by Allegra Tiver

References:

Rizik DG, et al. Poster 513. ABSORB III PK: Pharmacokinetics of everolimus eluted from the Absorb bioresorbable vascular scaffold. Presented at: TCT Scientific Symposium; Oct. 11-15, 2015; San Francisco.

Rizik DG, et al. J Am Coll Cardiol. 2015;doi:10.1016/j.jacc.2015.09.030.

Disclosure: Rizik reports either he or his spouse/partner have had financial interests with Abbott Vascular, Boston Scientific or TriReme Medical.