Vandetanib-eluting Radiopaque Beads: In vivo Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization

Abstract

PURPOSE: To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine.MATERIALS AND METHODS: In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads.RESULTS: The peak plasma levels of VTB (Cmax) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the in vitro IC50 for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue changes suggested a more effective embolization with VERB compared to the beads without drug.CONCLUSIONS: Hepatic intra-arterial administration of VERB results in a low systemic exposure and enables sustained delivery of VTB to target tissues following embolization. Changes in the liver tissue are consistent with an effective embolization and this study has demonstrated that VERB100 is well tolerated with no obvious systemic toxicity.

Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

“…Cells exposed to vandetanib for an extended 72 h time frame may die before the drug is removed, meaning the cells begin dying from autophagic exhaustion at some point between the conclusions of the short exposure and long exposure time frames, relative to drug dose. This may suggest local treatment with vandetanib, which has the advantage of prolonged high local dose avoiding systemic toxicity [ 39 , 40 , 41 ], may have a greater benefit than systemic treatment by increasing radiosensitivity and autophagy.…”

VEROnA Protocol: A Pilot, Open-Label, Single-Arm, Phase 0, Window-of-Opportunity Study of Vandetanib-Eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies

“…It is anticipated that the tissue concentrations of vandetanib and its major metabolite will be significantly higher in liver tumors following administration of TACE beads than following oral administration. One would speculate that the systemic concentrations of the drug should be lower following local delivery to the liver compared with oral administration, resulting in a more tolerable side effect profile, as observed in a pharmacokinetic study of BTG-002814 in a porcine model of hepatic artery embolization [27]. In this preclinical study, healthy swine were treated with intra-arterial vandetanib-eluting radiopaque beads, and tissue samples were taken from both embolized and nonembolized liver sections for determination of vandetanib and metabolite levels at necropsy (30 and 90 days).…”

“…As such, the study is not powered for any statistical hypotheses. On the basis of preclinical trials, a target size of 6 patients with each primary diagnosis is deemed sufficient to assess safety and drug concentrations in plasma and resected specimens following treatment [27]. All patients who receive treatment with BTG-002814 in the study will be included in the analysis population.…”

Handling and performance characteristics of a new small caliber radiopaque embolic microsphere

“…Pharmacokinetic (PK) analyses for both Dox and Iri delivered from LUMI40‐90 were conducted as described in detail previously (Denys et al, 2017) using the swine hepatic artery embolization model described in the previous section. Plasma samples were taken at selected time points over a 24 hr period and analyzed for drug levels using HPLC‐MS.…”

“…These were reviewed for LUMI40-90 visibility, location, area/volume of liver embolized, off-target embolization in adjacent organs, and other imaging findings, which may be related to hepatic embolization and associated ischemia. 2.9 | Pharmacokinetic evaluation and drug tissue effects in a swine hepatic arterial model Pharmacokinetic (PK) analyses for both Dox and Iri delivered from LUMI40-90 were conducted as described in detail previously (Denys et al, 2017) using the swine hepatic artery embolization model described in the previous section. Plasma samples were taken at selected time points over a 24 hr period and analyzed for drug levels using HPLC-MS.…”