Originally published as JCO Early Release 10.1200/JCO.2005.04.8496 on August 8 2006

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Relationship of Hepatic Functional Imaging to Irinotecan Pharmacokinetics and Genetic Parameters of Drug Elimination

Michael Michael, Mick Thompson, Rod J. Hicks, Paul L. Mitchell, Andrew Ellis, Alvin D. Milner, Julia Di Iulio, Andrew M. Scott, Volker Gurtler, Janelle M. Hoskins, Stephen J. Clarke, Niall C. Tebbut, Kian Foo, Michael Jefford, John R. Zalcberg

From the Peter MacCallum Cancer Centre; Division of Haematology and Medical Oncology, Centre for Molecular Imaging, Pharmacology, and Developmental Therapeutics Unit, and Centre for Biostatistics and Clinical Trials, Austin Hospital, Melbourne; Ludwig Medical Oncology Unit, Department of Nuclear Medicine, and Department of Microbiology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia

Address reprint requests to Michael Michael, MD, Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Victoria 8006, Australia; e-mail: Michael.Michael{at}petermac.org

Purpose: The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling.

Methods: Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with ^99mTc-DIDA (acetanilidoiminodiacetic acid)/ ^99mTc-DISIDA (disofenin) and MIBI (^99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly x2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1.

Results: Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. ^99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both ^99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = –215 + 18.68 x bilirubin + 4.27 x MIBI 1-hour RET (P = .009, R² = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015).

Conclusion: Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted.

published online ahead of print at www.jco.org on August 7, 2006.

Supported by in part by a research grant provided by Pfizer Proprietary Ltd.

Presented in part at the Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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• Role for Drug Transporters Beyond Tumor Resistance: Hepatic Functional Imaging and Genotyping of Multidrug Resistance Transporters for the Prediction of Irinotecan Toxicity
  Deanna L. Kroetz
  JCO 2006 24: 4225-4227 [Full Text]

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