title: 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.
authors.affiliation: UPRES EA 2706 Department, Paris Sud-XI University, Châtenay-Malabry, France. minhtam.baylatry@sat.aphp.fr
authors.forename: Minh-Tâm
authors.initials: MT
authors.lastname: Baylatry
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelage
authors.forename: Michel
authors.initials: M
authors.lastname: Wassef
authors.forename: Homayra
authors.initials: H
authors.lastname: Ghegediban
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Joly
authors.forename: Andrew
authors.initials: A
authors.lastname: Lewis
authors.forename: Pascal
authors.initials: P
authors.lastname: Lacombe
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Alex
authors.initials: A
authors.lastname: Laurent
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016461:Chemoembolization, Therapeutic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D064420:Drug-Related Side Effects and Adverse Reactions; D000077146:Irinotecan; D008863:Microspheres; D010599:Pharmacokinetics; D011651:Pulmonary Artery / Q000187:drug effects*; D012756:Sheep; D014018:Tissue Distribution; D059004:Topoisomerase I Inhibitors
chemical_list: D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin