Published on September 17, 2020 By: Dr. D.C Sharma, Dr. Tharun Tej,  Dr.S. Anoop, Dr. Murali B.V., Mr. S.K. Jahangir, Mr. Pavankumar, Dr.V. Sthevaan.  

WHAT IS A DRUG ELUTING STENT?

A drug-eluting stent, or DES, is a small, metal mesh coil placed in a blocked coronary artery. The metal is coated in medicine and helps reopen artery and keep it open. The drugs coated on latest generation stents act as anti-proliferative, immunosuppressive effects, and shows rapid absorption into the arterial wall at the site of vessel injury.

WHY PRECLINICAL PHARMACOKINETICS OF DRUG ELUTING STENTS IS REQUIRED?

Optimum concentration of drug on the stent improves immune responsiveness and prevents hyperplastic growth of smooth muscle in the re-stenotic state. Its success is therefore empirically associated with effective delivery of potent therapeutics to the target site at a therapeutic concentration, for a sufficient time, and in a biologically active form. The local delivery of the drug in the vascular wall with drug-eluting stents imparts large pharmacodynamic importance but whether the drug is released in the blood compartment of the circulatory physiology also imparts importance to know the concentration left over for local delivery.

A preclinical pharmacokinetic evaluation is very important to device corrections at the R & D level in the DES lab scale manufacturing process as well as its regulatory submissions as a prelude for the clinical trials.

CHALLENGES FOR THE CORRECT MODEL FOR THE PHARMACOKINETIC STUDIES

Swine model is so far considered a standard model for stent implantation studies for tissue pharmacokinetic, safety performance evaluation studies. Although it can also be used for the pharmacokinetic evaluation in the blood/plasma compartment but as the quantity that is released in to the blood is very low the bio-analytical quantifiable concentration detection levels become very low (<0.01ng/ml). This is mainly due to low drug concentration on the stent in relation to the systemic blood volume even when 3 stents are implanted to evaluate the concentration in the systemic circulation. Hence a lower species that is rabbit needs to be used for the pharmacokinetic evaluation for coronary DES implanted in peripheral arteries (incompatibility of coronary sizes and delivery device). Even though this model is not a correct simulation of the clinical use we adopted this preclinical model for evaluation of the blood/plasma concentration of the drug as one of the regulatory requirement as blood concentration of a drug governs the local pharmacokinetics within the arterial wall by drug-eluting stent.  

At MRIDA (Medical Research institute for devices assessment) a medical devices testing wing of Palamur Biosciences Private limited skilled veterinarians, cathlab technologists and study scientists were able to implant drug eluting stents in rabbit descending aorta and detect everolimus drug levels in blood compartment to calculate the pharmacokinetic parameters. 

The experiments were approved by the animal ethical committee at Palamur biosciences private limited Rabbit was instrumented under general anaesthesia and analgesia in the angiography cathlab. Surgical exposure of the left common carotid artery was performed to insert 5 F sheath for angiography and stent implantation. The same side was used to expose left external jugular vein to insert 5F sheath for serial blood collection. Right marginal ear vein was cannulated for fluid infusion.

Baseline angiography was performed to explore target region in the the peripheral vasculature (illiofemoral arteries) but the iliofemoral arteries were smaller to implant 3 mm x 20mm everolimus DES. (Figure 1). Descending aorta cranial to iliac bifurcation was selected as target site to place 3 coronary evrolimus DES after angiographic quantitative vessel analysis (Fig 2 & Fig 3). Blood samples were collected serially from the sheath inserted in jugular vein pre-implantation at 0 min (baseline) and post-implantation at 5, 10, 20, 30, 60, 120, 240 min and 24hr. maximum concentration (Cmax) was 1.48ng/ml achieved in 30min (Tmax) and there were no detectable levels at 24hrs. 

Based on this experiment it is feasible to detect everolimus drug concentration coated on the DES and implanted in rabbit aorta or arteries

Figure 1- Quantitative Figure 1- Quantitative vessel analysis of peripheral arteries of rabbit 

Figure 2- Quantitative vessel analysis of descending aorta of rabbit

Figure 3- Quantitative vessel analysis of descending aorta deployed with three stents