Clin. Cardiol. Vol. 22 (Suppl. I), 1-10-1-16 (1999) Pharmacokinetics and Consistency of Pencardial Delivery Directed to Coronary Arteries: Direct Comparison with Endoluminal Delivery HANS-~TERSTOLL, M.D.,* KATHY CARLSON, B. A,,? LARRYK. KEEFER, PH.D.,$ JOSEPHA. HRABIE,PH.D.,§ KEITHL. MARCH,M.D., PH.D. FACC*II "Krannert Institute of Cardiology and tDepartmentof Radiology, Indiana University School of Medicine, Indianapolis, Indiana; $Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center; $Chemical Synthesis and Analysis Laboratory, SAIC Frederick, NCI-FCRDC, Frederick, Maryland; IIRichard L. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA Summary (median 0.27%). At 24 h, FID values ranged from O.OOO11 to 0.003 for P delivery (median 0.0013), and from 0.0002 to 1.4 Backgroundand hypothesis: Pharmacologic modulation of for EL delivery. The estimated T1/2 for bFGF redistribution the contents of the pericardial space has been shown to influ- from the vascular tissue was 22 h (P) and 7 h (EL), respective- ence the response of coronary arteries to balloon injury. Endo- ly, while the directly determined T1/2 values for NONO-albu- luminal (EL) local delivery of various drugs into coronaries min redistribution from the delivery region were 22.2 h (P) has been found to be limited by short residence time, as well as and 2.5 h (EL). by highly variable deposited agent concentration. We hypoth- Conclusions: These data show that pericardial fluid contents esized that compounds placed into the pericardial space (P) can access coronary arteries with intramural concentrations would penetrate into coronary tissue with greater consistency which typically vary by 10-15-fold, while EL delivery results than seen after EL delivery and provide for prolonged coro- in a remarkably wide intramural concentration range with up to nary exposure to agents. 33,000-fold variability. The apparent redistribution rate is more Methods and Results: '251-labeled basic fibroblast growth rapid following EL delivery, possibly due to sustained diffusive factor (bFGF), platelet-derived growth factor (PDGF), albu- tissue loading from the pericardial space. Pericardial delivery min, or 13'I-labeled diazeniumdiolated albumin (NONO-al- appears to offer substantial advantagesover EL administration bumin) were delivered as modelhherapeuticproteins into the with respect to residence time and reproducibility. porcine pericardial space (n = 15 pigs) or into coronaries using an EL delivery catheter (n = 48 arteries). In subjectsreceiving '251-labeledproteins, the delivery target or mid-regions of the Key words: pericardium, coronary disease, local drug deliv- left anterior descending (LAD) and left circumflex (LCx) ery, restenosis, angiogenesis arteries were harvested at 1 h or 24 h for gamma-counting and autoradiography, and fractional intramural delivery (FID) or retention measured as percent agent in 100 mg arteryiagent Introduction in infusate for both time points. In the animals receiving 1311- labeled NONO-albumin, serial gamma imaging was employ- Local drug delivery (LDD) within the cardiovascular sys- ed to evaluate the rate of redistribution in individual animals tem may offer a new therapeutic approach for focal vascular following either pericardial or endoluminal delivery. At 1 h, lesions by providing higher intramural concentrations and FID values ranged from O.OOO64 to 0.0052% for P delivery avoiding the side effects that accompany systemic administra- (median 0.0022%), and from 0.00021 to 6.7 for EL delivery tion.' In particular, the prevention of coronary restenosis fol- lowing catheter-based interventions appears to be a potential application for this approach. Another recent area of develop- ment in local delivery has involved attempts to facilitate collat- eral vessel development in ischemic tissues, both peripheral and coronary. The effectivenessof LDD for either of these ap- This study was supported in part by research grants from Chiron plications will ultimately depend on several factors including Corporation, Cordis, Inc., and Comedicus, Inc. the choice of the therapeutic agent, the mode of delivery, intra- Address for reprints: mural retention, and the effects of delivery on vascular struc- tural integrity. Keith L. March, M.D., Ph.D., FACC A number of local delivery catheters (LDCs) has been de- Krannert Institute of Cardiology Indiana University Medical Center signed and tested as means of endoluminal-based intramural I1 I1 W 10th Street delivery into coronary arteries. Comparative study of four de- Indianapolis, IN 46202-4800, USA vices employing pressure-driven convective transport of fluid H.-P. Stoll et al.: Pericardial versus endoluminal delivery to coronary arteries 1-1 1 to achieve deposition of therapeutic agent^^-^ has demonstrat- deliveries for acute (n = 24 arteries) or 24-h (n = 24 arteries) ed substantia~equivalence among these devices in the pattern evaluation (Group 1); two arteries were also harvested and and level of drug deposition achieved.6However, endoluminal studied in each of 12 animals receiving pericardial delivery deliveries by these are routinely characterized by several limi- for acute (n = 12 arteries) or 24-h (n = 12 arteries) evaluation tations: (1) inconsistency in delivery, (2) low absolute efficien- (Group 2); 1 animal was imaged serially after a single endolu- cy of localization, and (3) relatively rapid washout of agent minal delivery (Group 3); and 3 animals were imaged follow- from the target vessel.’ ing pericardial delivery (Group 4). All experiments and ani- The recent advent of catheter-based approaches to pericar- mal care conformed to National Institutes of Health and dial access has made possible the evaluation of agent delivery American Heart Association guidelines for the care and use directly into this space with the eventual goal of clinically use- of animals, and were approved by the Animal Care and Use ful therapies. We hypothesized that drug delivery into the peri- Committee of Indiana University. cardial sac would differ from endoluminal deliveries by (1) comparatively enhanced consistency,and (2) prolonged expo- Endoluminal Delivery Procedure sure of either coronary or myocardial tissues to drug as aresult ofa reservoir function of the pericardium. In all, 25 domestic swine (20-23 kg in weight) were pre- This study was designed to provide a direct comparison of medicated with 375 mg oral aspirin on the day prior to the endoluminal with intrapericardial delivery for selected agents study. Animals were sedated with a combination of ketamine which could be evaluated following delivery by these ap- (20 mg/kg), acepromazine (1.1 mg), and atropine (0.6 mg/kg) proaches. For endoluminal deliveries we employed a micro- by intramuscular injection. The animals were given pentobar- porous infusion catheter (MIC; Cordis Corp., Miami, Ha., bital sodium (300 mg) intravenously and were then intubated. USA) consisting of a flow-restricting inner balloon with mul- They were ventilated mechanically with ifotlurane 2% and tiple 25 pm holes and an outer balloon membrane with 0.8 p oxygen 90% (2 I/min) using a respirator. The electrocardio- pores, which provides a “weeping” convective transport of the gram (ECG) and intra-arterial blood pressure were monitored infused drug during balloon inflation? For intrapericardialde- continuously throughout the procedure. Arterial access was liveries, we employed either a hollow, helical-tipped catheter made via surgical cutdown of a carotid artery or femoral artery, designed for controlled penetration through the myocardium and an 8F introducer sheath was placed. Each animal received during fluoroscopicvisualization! or a sheathed needle with a a single dose of heparin (5000 U) and bretylium tosylate (2.5 suction tip designed for grasping the pericardium and access- mgjkg). Under l-luoroscopic guidance, an 8F guiding catheter ing the pericardial space using a transthoracic approach while was positioned in the left coronary ostiuni. After the intracoro- avoiding myocardial puncture. nary administration of nitroglycerin ( 100 pg), coronary angi- The substances chosen for this study were proteins with an ography was performed in the anterior-posterioror 30” left an- anticipated potential for therapeutic effect following local de- tenor oblique (LAO) position. After review of the angiogram, livery, as well as additional model proteins. These included (1) a 3.0 mm diameter segment of each of two coronary arterie\ albumin diazeniumdiolate(NONO-albumin), a potentially an- [left anterior descending (LAD) and left circumflex (LCx)] tirestenotic agent; (2) basic fibroblast growth factor (bFGF), was selected so as to minimize side branches or tortuosity. In an agent currently under evaluation for its proangiogenic ef- each case, measurements were performed using spot AP films fects; and (3) albumin and (4) platelet-derived growth factor and digital calipers. Coronary overstretch balloon injury at (PDGF)-BB,two model proteins with minimal and substantial each selected site was performed by angioplasty lwice for 15 s, receptor-bindingaffinities, respectively. These were delivered each time using a noncompliant angioplasty balloon, 0.5 mm either using the endoluminal catheter, or by a pericardial deliv- in diameter larger than the luminal diameter. Following bal- ery catheter as described below, and the consistency as well as loon injury, a delivery balloon was selected to match the