Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination.
OBJECTIVE
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).


CONCLUSIONS
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.
Michael
Michael
M
Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Victoria, Australia. Michael.Michael@petermac.org
Thompson
Mick
M
Hicks
Rod J
RJ
Mitchell
Paul L
PL
Ellis
Andrew
A
Milner
Alvin D
AD
Di Iulio
Julia
J
Scott
Andrew M
AM
Gurtler
Volker
V
Hoskins
Janelle M
JM
Clarke
Stephen J
SJ
Tebbut
Niall C
NC
Foo
Kian
K
Jefford
Michael
M
Zalcberg
John R
JR
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D012044:Regression Analysis; D019784:Technetium Tc 99m Diethyl-iminodiacetic Acid; D019785:Technetium Tc 99m Disofenin; D017256:Technetium Tc 99m Sestamibi; D000099148:UGT1A1 Enzyme
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D027361:Organic Anion Transporters; D019275:Radiopharmaceuticals; D019784:Technetium Tc 99m Diethyl-iminodiacetic Acid; D019785:Technetium Tc 99m Disofenin; D017256:Technetium Tc 99m Sestamibi; D000099148:UGT1A1 Enzyme; C513055:ABCB1 protein, human