Author + information
- David G. Rizik, MD,
- Louis Cannon, MD,
- Gregg W. Stone, MD∗ (, )
- Maureen Kennedy, MN,
- Karine Piard-Ruster, PhD,
- Peter Staehr, MD,
- Stephen G. Ellis, MD and
- Dean J. Kereiakes, MD
- ↵∗Columbia University Medical Center, Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022
The Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) is designed to reduce chronic adverse cardiovascular events that may occur from the permanent presence of a metallic stent and/or durable polymer. The systemic pharmacokinetic (PK) profile of BVS has not been described. ABSORB III PK is a prospective, open-label, nonrandomized substudy of the ABSORB III randomized trial (1), in which either 1 (n = 8) or 2 (n = 4) BVS were implanted in de novo coronary artery stenoses. Inclusion/exclusion criteria were the same as for ABSORB III (1), namely noncomplex lesions in patients with stable ischemic heart disease or stabilized acute coronary syndromes. All patients provided written informed consent for this substudy and were enrolled following successful BVS deployment at 2 U.S. sites between June 2, 2014, and September 17, 2014.
Detailed methods for the PK analysis are described elsewhere (1). Briefly, subjects had blood drawn at 16 time points between pre-procedure and 30 days (prior to implantation of the first BVS and at 10 min, 30 min, and 1, 2, 4, 6, 12, 24, 48, 72, 96, 120 [day 5], 168 [day 7], 336 [day 14], and 720 [day 30] h after last BVS deployment). Everolimus blood concentrations were measured, and noncompartmental analysis was performed to determine PK parameters (Cmax, tmax, t1/2, AUC24h, AUClast, and AUC0–∞). To explore dose proportionality of everolimus, a regression analysis on dose-normalized (to 1 μg) PK parameters for everolimus was performed. Blood concentration-time profiles and PK parameters of everolimus were compared with prior PK results obtained from the Xience V cobalt chromium everolimus-eluting stent (CoCr-EES) (Abbott Vascular) in the SPIRIT II and III (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects with de Novo Native Coronary Artery Lesions) trial substudies (2,3).
Twelve patients were enrolled, all of whom remained in the PK substudy through 30 days. The mean age was 60.1 years, and 91.7% of subjects were male. Risk factors included current tobacco use (25.0%), diabetes (33.3%), hypertension (100%), dyslipidemia (100%), and prior MI (18.2%). Stable or unstable angina was present in 75% and 25% of subjects, respectively. The target lesion was the left circumflex artery in 50% of patients, the left anterior descending artery in 42%, and the right coronary artery in 8%. One-third of lesions were moderately or severely calcified. Mean lesion length was 12.2 ± 4.4 mm, and mean pre-procedure reference vessel diameter was 2.73 ± 0.41 mm. Scaffold diameters ranged from 2.5 to 3.5 mm, and scaffold lengths ranged from 8 to 28 mm. The average total length of scaffold implanted at the lesion site was 24.5 ± 8.6 mm. The total dose of loaded everolimus ranged from 181 to 443 μg.
Individual tmax ranged from 0.17 to 2.37 h across all dose levels. Everolimus blood concentrations could be quantified for up to 168 h after implantation of the last BVS (Figure 1A). Individual Cmax values increased proportionally with dose, ranging from 1.085 to 4.460 ng/ml. Similarly, individual AUC24h (ranging from 12.09 to 44.22 ng·h/ml), AUClast (ranging from 25.37 to 104.60 ng·h/ml) and AUC0–∞ (ranging from 33.15 to 120.80 ng·h/ml) increased proportionally with dose. Terminal half-life ranged from 45.9 to 115.0 h, with no obvious trend with dose. Interindividual variability (% coefficient of variation) in everolimus exposure after BVS deployment ranged between 23.3% and 35.6% for dose-normalized Cmax, AUC24h, AUClast, and AUC0–∞.
Although short-lived, individual Cmax values (1.085 to 4.460 ng/ml) were slightly higher than the minimum systemic, chronically maintained therapeutic level of ≥3.0 ng/ml required for effective prevention of organ rejection (4). However, everolimus blood concentrations declined rapidly after reaching Cmax and were <3.0 ng/ml in all subjects by 4 h after the last scaffold deployment. In addition, Cmax levels obtained after Absorb BVS were well below mean steady-state Cmax (61 ng/ml) observed in patients with solid tumors treated with 10 mg/day of everolimus (5).
These results are consistent with 2 prior PK studies of everolimus elution from the metallic XIENCE V stent (2,3), which has the same drug dose density as BVS (100 μg/cm2) (Figure 1B). Examining the concentration-time PK results from the BVS scaffold and the CoCr-EES stent with a common load of 181 ug of everolimus, both devices demonstrated a rapid increase in systemic everolimus levels after stent/scaffold deployment, reaching maximal concentrations within 2.5 h, followed by a biexponential decline, with an initial rapid phase followed by a slower terminal phase; levels remained above the limit of detection (0.1 ng/ml) for up to 168 h after stent/scaffold deployment. Similar to CoCr-EES, an increase in total everolimus dose by BVS resulted in a proportional increase in Cmax and AUC (Figure 1A). Although the early peak everolimus concentrations with BVS appear slightly higher than with CoCr-EES, inferences should not be drawn from small differences as the studies with the 2 devices were done at different times in different patients.
In conclusion, the systemic PK characteristics of everolimus after BVS deployment are predictable with dose-proportional behavior. Local coronary arterial delivery results in limited systemic exposure, suggesting a low risk of systemic toxicity. The PK profile of systemic everolimus exposure from BVS is similar to that from the metallic CoCr-EES.
Please note: Abbott Vascular provided funding for this work. Dr. Rizik has received honoraria and grant support from Abbott Vascular. Dr. Cannon has served as a consultant for and received honoraria from Abbott Vascular. Dr. Stone is a consultant to Reva Corporation; and is the uncompensated study chairman of the ABSORB III and IV trials. Drs. Kennedy, Piard-Ruster, and Staehr are employees of Abbott Vascular. Dr. Ellis has received honoraria and travel expenses from Abbott Vascular. Dr. Kereiakes has received honoraria from Boston Scientific and Abbott Vascular; and has served as a consultant for Abbott Vascular, Boston Scientific, and Svelte Medical Systems, Inc. The authors gratefully thank Emil Samara for his assistance with interpretation of the PK results.
- 2015 American College of Cardiology Foundation