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Friday, February 8, 2019

Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization


Clinical question: What effect does the UGT1A1 phenotype have on plasma and tumor drug and metabolite concentrations and pharmacokinetics after hepatic chemoembolization with irinotecan-eluting beads (DEBIRI)?

Take-away point: Hepatic lobar DEBIRI results in similar exposure of target tumor and remote normal liver tissue to irinotecan and active metabolite regardless of UGT1A1 mutation status.

Reference: Levy EB, Peer C, Sissung TM, Venkatesan A, Pandalai P, Greten T, et al. Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization. J Vasc Interv Radiol. 2019 Jan;30(1):19–22.

Click here for abstract

Study design: Cohort study (prospective observational study)

Funding sources: Cooperative Research and Development agreement with BTG/Biocompatibles, the Intramural Research Program of the National Institutes of Health and the Center of Interventional Oncology, Grant ZID BC011242-10.

Setting: Single institution pilot study

Summary 


Chemoembolization with irinotecan-eluting beads (DEBIRI) as salvage therapy for colorectal hepatic metastases has shown improved progression-free survival (PFS) and overall survival (OS). However, the concentrations of irinotecan and active metabolites achieved within hepatic metastases after fixed-dose chemoembolization and the role of the UGT1A1 polymorphism on response and toxicity from DEBIRI are unknown.

The investigators performed a prospective study on five patients with inoperable hepatic metastases from 2011 to 2014. In the seven treatments performed, each patient received 2 ml of 100–300-μm DC Bead preloaded with 100 mg irinotecan through a microcatheter positioned in the proximal lobar and/or segmental artery. Demographic data collected included prior treatments, lesion max diameter, and UGT1A1 status. Plasma and liver tissue samples of irinotecan (CPT-11), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G, were sequentially measured to determine the maximum concentration (Cmax) and the time to Cmax (Tmax). Within the cohort, three patients had wild-type (WT) UGT1A1 genotypes while 2 had variants (VARs). The plasma CPT-11 Cmax was significantly higher for WT and the SN-38 Cmax and AUC for WT was significantly lower versus VAR. No differences in tissue pharmacokinetic parameters were observed between VAR and WT patients.



Commentary


DEBRIRI resulted in four times higher exposure delivered to the tumor and 1000–10,000 times less systemic irinotecan and SN-38 compared to systemic administration of irinotecan. Despite these findings, three patients experienced lymphopenia during the study. Additionally, it does not appear as though the UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI. While DEBIRI imparts a survival benefit compared to systemic therapy with folinic acid, fluoroucil, and irinotecan, the adverse event profile appears to mimic that of systemic therapy. Previous studies have demonstrated the non-significant influence of the UGT1A1 gene polymorphism on the rate of irinotecan-associated toxicity in patients receiving irinotecan based chemotherapy .In accordance, this study demonstrated that predicting the incidence of thrombocytopenia based on UGT1A1 status following DEBIRI is not reliable.

Post Author:
Jacob Bundy, MD, MPH
PGY-1
Department of Surgery
University of Michigan Health System
@JBundyRad

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