In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 26 ( 2006-09-10), p. 4228-4235
Abstract:
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 99m Tc-DIDA (acetanilidoiminodiacetic acid)/ 99m Tc-DISIDA (disofenin) and MIBI ( 99m Tc-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 ×2, 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. 99m Tc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99m Tc-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 × bilirubin + 4.27 × MIBI 1-hour RET (P = .009, R 2 = 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.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2005.04.8496
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2006
detail.hit.zdb_id:
2005181-5
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