Feasibility, safety and pharmacokinetic study of hepatic administration of drug-eluting beads loaded with irinotecan (DEBIRI) followed by intravenous administration of irinotecan in a porcine model

Abstract

Irinotecan eluting embolization beads (DEBIRI) are currently being evaluated in the clinic for the treatment of colorectal cancer metastases to the liver. The aim of this study was to determine the safety and pharmacokinetics associated with two cycles of hepatic embolization using DEBIRI followed by intravenous administration of irinotecan. Pigs were embolized with DEBIRI (100–300 μm, 100 mg dose, n = 6) and blood samples taken over 24 h to determine plasma levels of irinotecan and SN-38 metabolite and for haematology and biochemistry. At 24 h an IV infusion of 250 mg/m2 of irinotecan was administered and the plasma levels taken again. This cycle was repeated 3 weeks later. A single animal was subjected to a more aggressive regimen of embolization with 200 mg bead dose and IV of 350 mg/m2 for two cycles. Three animals were sacrificed at 6 weeks and the remaining four (n = 3 standard dose, n = 1 high dose) animals at 12 weeks and detailed histopathology performed. All animals tolerated the treatments well, with only minor changes in haematological and biochemical parameters. There was no overlap in drug plasma levels observed from the bead and IV treatments when given 24 h apart and no difference between the pharmacokinetic profiles of the two cycles separated by 3 weeks. Irinotecan plasma AUC values were similar in both the embolization and IV arms of the study. Cmax values obtained during the IV arms of the study are approximately double that of the embolization arms whilst Tmax times are shorter in the IV arms, supporting extended release of drug from the beads. Bioavailability for bead-based delivery was double that for IV administration, which was attributed to reduced clearance of the drug when delivered by this route. No additive toxicity was observed as a consequence of the combined treatments. The combination of irinotecan delivery via drug eluting bead and IV was well-tolerated with no significant clinical effects. Pharmacokinetic analyses suggest the bioavailability from bead-based delivery of drug is double that of IV infusion, attributable to reduced drug clearance for the former.

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

“…Accordingly, the C max was significantly higher for DC Bead M1. This fast initial elution of irinotecan has been previously described for DEBIRI (16). In a rabbit VX2 liver tumor model, Rao et al (18) observed the highest irinotecan plasma concentration after 10 minutes.…”

“…However, Lewis et al (16) applied a higher total dose (100 mg irinotecan) than used in the present study. Even with this higher dose of irinotecan, SN-38 levels were below the quantification level in many cases (16).…”

“…This is comparable to the findings of previous studies. In a porcine liver model, Lewis et al (16) reported very low SN-38 levels, which were approximately 1,000 times lower than the irinotecan levels. However, Lewis et al (16) applied a higher total dose (100 mg irinotecan) than used in the present study.…”

“…Lewis et al (16) observed only a minor elevation of serum aminotransferase levels after chemoembolization. In the present study, we did not find generally elevated aminotransferase levels or alkaline phosphatase values after embolization.…”

“…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).…”