Pulmonary artery chemoembolization in a sheep model: Evaluation of performance and safety of irinotecan eluting beads (DEB‐IRI)

Abstract

The purpose of this study was to evaluate and compare plasma pharmacokinetics, lung tissue concentration, and the potential toxicity of drug eluting beads loaded with irinotecan (DEB-IRI) in a sheep pulmonary artery chemoembolization (PACE) model. Sheep (n = 24) were embolized with DEB-IRI loaded with different doses (0, 20, 50, or 100 mg). Direct pulmonary artery (PA) injections of irinotecan were also performed at two doses (50 or 100 mg; n = 4 sheep). Irinotecan was quantified in plasma and lung tissue (liquid chromatography-fluorescence detection); pathological examination of lungs was performed 4 days or 4 weeks after PACE. Irinotecan was detected in the systemic circulation within a few minutes after PACE, for several hours in DEB-IRI 20 and DEB-IRI 50 groups, and for 24 hours for DEB-IRI 100. Both Cmax and AUC values increased significantly with dose (p = 0.0078 and p = 0.0008, respectively) after PACE. Cmax and AUC values were significantly reduced (by 80%, p = 0.0036, and by 50%, p = 0.0393, respectively) after PACE than after direct PA injection. Irinotecan was not detected in tissue 4 days after PACE. No sign of lung toxicity was observed, except a limited hemorrhagic angionecrosis seen 4 days after PACE with DEB-IRI 100. Inflammatory response on beads was moderate in all DEB-IRI groups. Compared to other routes of administration, DEB loaded with irinotecan at doses up to 100 mg was well tolerated. DEB loaded with 100 mg irinotecan seem a promising candidate for future PACE trials in patients.

Safety and Efficacy Compared between Irinotecan-Loaded Microspheres HepaSphere and DC Bead in a Model of VX2 Liver Metastases in the Rabbit

“…The different microspheres available have been tested in separate preclinical studies but have never been compared in a controlled trial (12)(13)(14)(15)(16). Three studies have evaluated the efficacy of IRI-loaded beads on a single and large VX2 tumor in the liver (14)(15)(16).…”

“…Several microspheres loadable with IRI are now proposed: DC Bead ® (DC; Biocompatibles UK Ltd, London, United Kingdom), HepaSphere™ (HS; BioSphere Medical, Roissy-en-France, France), and TANDEM ® (CeloNova BioSciences, Newnan, Georgia). Preclinical trials evaluated the properties of the three products individually but not comparatively (12)(13)(14)(15)(16). One in vitro study suggested slight differences in the physical characteristics or elution properties of the different brands of microspheres (17).…”

Evaluation of the Plasmatic and Parenchymal Elution Kinetics of Two Different Irinotecan-Loaded Drug-Eluting Embolics in a Pig Model

“…Irinotecan inhibits the DNA topoisomerase (13) and is a prodrug with the active metabolite SN-38 (14,15). Several experimental studies have investigated the pharmacokinetics of irinotecan after chemoembolization with DEBIRI (16)(17)(18)(19)(20). Plasma irinotecan levels were 70%-75% lower after embolization with drug-eluting embolic agents than after intra-arterial administration of irinotecan (19).…”

“…TANDEM microspheres are nonresorbable polymethacrylate hydrogel particles 75 mm Ϯ 15 in size coated with Polyzene-F. Previous studies (17,23) have shown that the release of irinotecan from DC Bead particles is faster than the release of doxorubicin, which was attributed to weaker ionic interactions between irinotecan and the embolic agents. With DEBIRI, irinotecan elution is controlled by an ion-exchange mechanism between the positively charged irinotecan hydrochloride salt and the sulfonate-containing hydrogel embolic agents (20).…”

Lung Metastatic Disease: Surgical Resection and Locoregional Chemotherapy

“…This study showed that embolisation was reversible without any early toxicity. Baylatry et al (174) showed in a sheep model that drug eluting beads loaded with irinotecan resulted in lower systemic exposure compared to direct injection of irinotecan into the pulmonary artery. In a rat model of adenocarcinoma lung metastases, chemo-embolisation was compared with ILuP and IV treatment with carboplatin (175).…”