Pharmacokinetics of Sirolimus-Eluting Stents Implanted in the Neonatal Arterial Duct

Abstract

S tent implantation is a recognized management option in maintaining arterial duct patency in newborns with ductdependent pulmonary blood flow, but with bare metal stents the reintervention rate (redilation or need for a surgical shunt) is 17% to 25% at 6 months. [1][2][3] The neointimal proliferative process associated both with spontaneous ductal closure and in reaction to stent implantation compromises luminal diameter. [3][4][5][6][7] In this regard, sirolimus, an immunosuppressive agent with anti-inflammatory and antiproliferative effects, has theoretical benefits. 8,9 Drug-eluting stent technology enables topical drug delivery with therapeutic drug concentrations locally within the blood vessel wall, despite substantially lower systemic blood levels.10 Sirolimus-eluting stents (SES) are effective and safe in adult coronary arteries.11 SES implanted in the porcine neonatal arterial duct have higher patency rates compared with bare-metal stents and also exhibit an antiproliferative action on arterial duct smooth muscle. 12 Pharmacokinetic studies of SES in adult pigs 10 and humans 13 have shown low peak serum drug levels occurring at 1 and between 3 and 4 hours, respectively, with minimal detectable levels by 3 and 7 days, respectively. SES implantation has been reported in children, but little is known regarding subsequent pharmacokinetics in the pediatric population. [14][15][16][17][18][19] The youngest patient previously reported was 3 months old at the time of SES implantation in the right ventricular outflow tract (peak ≈8 μg/L, undetectable between 12 and 37 days 15 ), and to our knowledge, there are no reports of neonatal use. Sirolimus experience in the pediatric population is predominantly in the form of oral immunosuppressive therapy in transplant recipients. Dosage is titrated by steady-state trough levels (target 5-15 μg/L). 20,21 In this study, we report the pharmacokinetics of sirolimus after single SES implantation in the neonatal arterial duct. Model-free point estimates were obtained by noncompartmental analysis, and in addition, a one-compartment Bayesian population pharmacokinetic model was used to provide point estimates with credible intervals, and this also allowed the prediction of pharmacokinetics if 2 stents had been implanted.Background-Sirolimus-eluting stents may have clinical advantages over bare-metal stents in the extremely proliferative environment of the neonatal arterial duct. However, sirolimus has immunosuppressive actions and little is known regarding sirolimus pharmacokinetics in the newborn. Methods and Results-This is a retrospective review of sirolimus pharmacokinetics in neonates who underwent sirolimuseluting stent implantation in the arterial duct for pulmonary blood flow augmentation. Pharmacokinetic parameters were obtained by noncompartmental analysis and by a Bayesian one-compartment nonlinear mixed model. Nine neonates received a single sirolimus-eluting stent with a total sirolimus dose of 245 μg (n=1), 194 μg (n=5), or 143 μg (n=3). Peak sirolimus concentra...

First use and limitations of Magmaris® bioresorbable stenting in a low birth weight infant with native aortic coarctation

“…Thus, Magmaris® implantation may provide acceptable short‐term results in infants with aortic coarctation, but does not seem to be a promising option as a mid‐term bridge‐to‐surgery. Second, sirolimus levels of 5 ng/mL, which may cause systemic immunosuppression, were achieved 48 hours after the implantation. Although in our patient no infectious complications were observed, the long‐term sequelae of immunosuppression by Magmaris® in smaller children and infants are unknown.…”

Comparison of drug eluting versus bare metal stents for pulmonary vein stenosis in childhood

“…In a study of DES implanted in newborns to maintain patency of the arterial duct, sirolimus levels were found to be in the immunosuppressive range, but without clinical side effects. 24 While we did not systematically measure drug levels in our cohort, levels obtained at serial intervals between 6-72 hr in two patients were found to be sub-therapeutic, and none of our patients suffered serious bacterial, viral or fungal infections. In adults with PVS following ablation for atrial fibrillation, DES have been used with success, 25 however this entity responds more favorably to standard balloon angioplasty and BMS placement as well, has a unique etiology and carries a better prognosis 26,27 than PVS in childhood.…”

“…Using an everolimus‐eluting stent and paclitaxel coated balloon in an infant with PVS, Muller et al found sub‐therapeutic levels of both drugs after 24 hr. In a study of DES implanted in newborns to maintain patency of the arterial duct, sirolimus levels were found to be in the immunosuppressive range, but without clinical side effects . While we did not systematically measure drug levels in our cohort, levels obtained at serial intervals between 6–72 hr in two patients were found to be sub‐therapeutic, and none of our patients suffered serious bacterial, viral or fungal infections.…”

Stenting of the ductus arteriosus for ductal-dependent pulmonary blood flow-current techniques and procedural considerations

“…20 Preliminary data on the use and pharmacokinetics in neonates using a single DES to stent the PDA have been reported. 22 These preliminary data suggest significantly lower clearance of sirolimus in neonates and peak sirolimus levels being 20 times higher than in older children and adults. Despite these findings, the authors did not note any adverse clinical outcomes due to the prolonged immunosuppressive sirolimus levels.…”

“…Drug eluting stents have been purported to result in less lumen loss than bare metal stents when deployed in the PDA in an animal model . Preliminary data on the use and pharmacokinetics in neonates using a single DES to stent the PDA have been reported . These preliminary data suggest significantly lower clearance of sirolimus in neonates and peak sirolimus levels being 20 times higher than in older children and adults.…”