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Originally published as JCO Early Release 10.1200/JCO.2005.04.8496 on August 8 2006 © 2006 American Society of Clinical Oncology. Relationship of Hepatic Functional Imaging to Irinotecan Pharmacokinetics and Genetic Parameters of Drug Elimination
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.
Irinotecan has an extremely narrow therapeutic index,1 and marked variability in pharmacodynamics and pharmacokinetics (PK),2-9 that is poorly predicted by BSA-based dosing.9-12 This PK variability has been related to polymorphisms in its hepatic metabolic (CYP3A4, UGT1A1)13-17 and biliary excretory pathways,18,19-22 including biliary canalicular P-glycoprotein (Pgp; ABCB1), MRP-1 (ABCC1),18,23-25 MRP-2 (ABCC2),18,23,24 and BRCP (ABCG2).26,27 In vivo probes of drug metabolism have been evaluated to predict drug clearance.28-33 However, there are no validated methods to predict Ir hepatic excretion. Hepatic nuclear imaging (HNI) may provide a noninvasive method to achieve this aim. Two classes of imaging reagents are relevant to Ir hepatic clearance. First, 99mTc-iminodiacetic acid (IDA) analogs such as 99mTc-DIDA (acetanilidoiminodiacetic acid) or 99mTc-DISIDA (disofenin), have high hepatic extraction through sodium-independent transporter systems including OATP,34,35 and rapid bile canalicular excretion by ABCC1 and ABCC2.36 They have been used to evaluate the functional effects of hepato-biliary disease,34,37-39 providing estimates of hepatic uptake and efflux, but have not yet been correlated to the disposition of cytotoxics that are ABCC1 and ABCC2 substrates. Second, 99mTc-sestamibi (MIBI), a lipophillic agent that enters the hepatocyte by passive diffusion across the plasma membrane and is then sequestered by mitochondria,40-42 is an avid substrate for ABCB1 (Pgp),41,43,44 and to a lesser extent, ABCC1 and ABCC2.45 In vivo it demonstrates rapid uptake from blood and prompt clearance from the liver.46 Its hepatic elimination rate is influenced by single-nucleotide polymorphisms (SNPs) in the ABCB1 gene.47 MIBI hepatic imaging has been correlated to the PK of two cytotoxic ABCB1 substrates.48,49 The aim of this exploratory study was to identify correlations between Ir PK and toxicity with MIBI and IDA HNI parameters. Another aim was to explore the relationship between these parameters and UGT1A1 and ABCB1 polymorphisms.
Patients Patients were required to have: (1) advanced colorectal cancer suitable for Ir therapy; (2) Eastern Cooperative Oncology Group performance status 0 to 2; (3) adequate organ function: (i) hematology: absolute neutrophil count  1.5 x 109/L, platelets 150 x 109/L, (ii) hepatic: serum bilirubin (bili)  1.5x the upper limit of normal (ULN), AST/ALT 1.5x ULN (if hepatic involvement 5.0x ULN), alkaline phosphatase or gamma-glutamyltransferase 2.5x ULN (if hepatic involvement 5.0x ULN), (iii) renal: serum creatinine 160 mmol/L; (4) informed consent. Patients were excluded for (1) chemotherapy within the preceding 4 weeks or radiotherapy to whole pelvis within the preceding 3 months, (2) significant medical comorbidities or nonmalignant acute/chronic hepatic disease, (3) a diagnosis of Gilbert's syndrome. The trial was approved by relevant ethics committees.
Pretreatment Evaluation
HNI IDA analog imaging: Imaging method. Patients fasted for at least 4 hours prior to administration of 250 MBq 99mTc-DIDA or 99mTc-DISIDA (subject to institution). No physiological, pharmacologic, or dietary manipulation was otherwise applied so as to mimic conditions under which chemotherapy might be administered. Patients remained in a supine position postinjection for 60 minutes while the radioactivity was measured in the region of interest (ROI) over the heart, liver (excluding the gall bladder and biliary tree), and kidney. Dynamic scan acquisition of the anterior and posterior abdomen on a dual headed gamma camera occurred with 60 x 1-second frames, then 60 x 60-second frames, representing vascular tracer delivery and the uptake/excretion phases, respectively. Time-activity curves (TACs; counts per min [cpm] versus time), were generated over the ROIs (Fig 1A).
IDA analog imaging: Data processing by noncompartmental analysis of the hepatic TAC. The hepatic ROI activity represented contributions from both the parenchymal and vascular spaces. Parameters calculated using standard noncompartmental PK methods included the terminal rate constant (k), estimated by log-linear regression of the terminal phase, and the terminal elimination half-life, t1/2 = ln(2)/k1. Percent retention at 1-hour (1-hour RET) = 100% x A60/Amax, where A60 and Amax are the activities at 60 minutes and maximal activity, respectively. IDA analog imaging: Data processing by deconvolutional analysis. The above assumes that the activity contribution from the hepatic blood pool is constant and that interpatient variation arises from differences in hepatic uptake.50 It does not separate the simultaneous uptake and excretory functions nor account for the changing tracer blood concentrations presented to the liver due to systemic recirculation.51 Deconvolutional analysis eliminates the latter by simulating a single bolus tracer injection directly into the hepatic blood supply and separates the vascular component from that which is actually taken up by the hepatocyte.51-53 The methodology used was that published previously,51,54 performed by commercial software (KyPlot 32-bit version 2, Beta-13 software; Kyenslab Inc, Tokyo, Japan). The deconvolution function is represented by the equation: L(t) = H(t) x B(t), where liver (L) and blood pool (B) TACs undergo deconvolution to obtain a hepatic clearance function (H). The liver response curve [H(t)] is divided into a vascular phase (activity presented to the liver) and a hepatic retention phase (activity extracted by hepatocytes). An exponential curve of best fit is applied to the liver response curve retention phase, H(t)= AH.e-k1t and is extrapolated backwards to generate a Y-axis intercept [H(t0)] (Fig 1B), being the initial hepatic retention. Parameters derived from the response curve included (1) the hepatic extraction fraction (HEF), a quantitative measure of hepatocyte function reflecting the efficiency of blood clearance by agents primarily excreted by the hepatobiliary route [HEF = H(t0)/Ymax, where Ymax is the response curve peak vascular activity],34,37,39,55 and (2) deconvoluted elimination half-time (td1/2) and ln(2)/k1, where k1 is the terminal constant obtained from the backwards extrapolation. MIBI imaging. Patient preparation was as described in the IDA analog section, with the administration of approximately 800 MBq MIBI. Imaging and data analysis were also performed as in the previous sections.
Pharmacogenetics
ABCB1 Genotyping
UGT1A1 Genotyping
Chemotherapy High-dose loperamide was used for the treatment of delayed-onset diarrhea.59 Dose reductions or omissions were specified during and at the commencement of subsequent cycles.7 Toxicities were described as per the National Cancer Institute Common Toxicity Criteria (version 2.0, 1999).
Patient Evaluation
Pharmacology Studies Analysis of samples. Blood samples were collected and stored on ice. Plasma was separated from erythrocytes by centrifugation at 1,000 x g for 10 minutes at 4°C and stored at –70°C until analysis. Sample preparation and analysis were conducted at low pH, where analytes were converted to their stable lactone forms. Thus total (lactone plus carboxylate) levels were measured. Ir and SN-38 were measured by reverse-phase high-performance liquid chromatography with fluorescence detection at 372 nm (excitation) and 535 nm (emission) using multilevel calibration curves (Ir, 0.5 to 4,000 ng/mL; SN-38, 0.5 to 2,000 ng/mL). Plasma samples were thawed and kept on ice. To each 200 µL sample, 20 µL of 100 mmol/L ammonium acetate buffer (pH 4.0), 400 µL of an ice-cold acidified extraction solution of 50:50 acetonitrile:methanol v/v containing camptothecin (internal standard), and 1/1,000 part concentrated HCl (35.4%) were added. The dried supernatant residue was reconstituted in 200 µL mobile phase and stored at 4°C in the autosampler before injection of 2 to 15 µL onto a 150 mm x 2.1 mm column preceded by a 20 mm x 3.0 mm guard column both packed with Exterra MS C18, 3.5 µm (waters). An isocratic mobile phase at 0.2 mL/min was mixed online at the following ratios of solutions: 10% A, 25% B, and 65% C, where A = 0.75 M ammonium acetate buffer pH 4.0, B = acetonitrile, and C = water. Derivation of PK parameters. Ir area under the curve (AUC) and SN-38 AUC were calculated as per Mick et al.60 Irinotecan clearance was calculated by dividing the Ir dose (mg) by the derived Ir AUC.
Statistical Methods The Spearman rank correlation coefficients (SRCC) were computed for HNI parameters, Ir PK parameters, and liver function tests. Linear regression was used to investigate relationships identified as having a significant correlation coefficient (SPSS 11.0.1; SPSS Inc, Chicago, IL). The Wilcoxon rank sum test was used to compare the distribution of the HNI parameter responses to the toxicity groups and between pharmacogenetic groups (S-plus Version 3.3; MathSoft Inc, Seattle, WA). No adjustments were made for multiple comparisons. All P values were two-sided.
Patient Characteristics Patient characteristics are summarized in Table 1 and were as expected for this population.
Irinotecan Toxicity and Dose Delivery In cycle 1, all 21 patients received the full planned Ir dose. In cycle 2, the mean dose delivery was 214 mg/m2, with 13 of 21 patients receiving full dose therapy. The type and frequency of the toxicities were not unexpected: grade 3 neutropenia, 10%; grade 4 neutropenia, 14%; grade 1-3 delayed onset diarrhea, 19% each; grade 4 delayed onset diarrhea, 0%; febrile neutropenia, 5%.
HNI Parameters
The typical MIBI TAC profile was similar, but with a prolonged t1/2 (109.8 minutes) and hence high 1-hour RET value. As described earlier, there was a strong linear relationship between MIBI 1-hour RET and t1/2 (R2 = 62%). In both cases, there was significant interpatient variation for each parameter, with the coefficient of variation ranging up to 32.5% for IDA and 59.0% for MIBI.
HNI Parameters Versus and Hepatic Biochemistries
HNI Parameters Versus Irinotecan PK and Toxicity The derived PK parameters are summarized in Table 2. Data from five patients were not utilized for technical reasons. The SRCC was significant for SN-38 AUC and bili (0.684, P < .01) and also on linear regression (ANOVA, P = .006).
There were significant positive correlations between SN-38 AUC and both IDA and MIBI 1-hour RET (0.686 and 0.626, P The relationship between the HNI parameters and Ir PK was evaluated by multiple regressions. The effect of bili and MIBI 1-hour RET on SN-38 AUC was found to be significant: SN-38 AUC = –215 + 18.68 x bili + 4.27 x MIBI 1-hour RET (ANOVA, P = .009, R2 = 44.2%). For neutropenia, the variables assessed were grades 0 to 1 versus grades 2 to 4, or grades 0 to 2 versus grades 3, 4, or percentage reduction at the nadir relative to baseline. For delayed diarrhea, grades 0 to 1 versus grades 2 to 3, and grade 0 versus grades 1 to 3 were assessed. There were no significant relationships between these and the HNI parameters. There were trends for increasing neutropenia grade and reduced IDA HEF, similarly for diarrhea and both increased MIBI HEF and reduced t1/2 (data not shown).
ABCB1 and UGT1A1 Genotypes Versus Ir PK and HNI Parameters
Irinotecan PK was available in one patient homozygous for the SNPs in ABCB1 gene exons 12/21, two for exon 26, and two with the UGT1A1*28 genotype. There was no relationship between these genotypes and Ir PK parameters. The HNI parameters were compared across the ABCB1 polymorphisms. For exon 26, the median MIBI dt1/2 was 3.12 v 2.10 hours in patients homozygous for the variant allele (TT) relative to wild-type carriers (CT or CC), respectively (P = .015, Wilcoxon rank sum test). Similarly for exon 12, the MIBI 1-hour RET was 85.9% v 68.2% in homozygous patients (TT) relative to wild-type carriers (CT or CC; P = .019, Wilcoxon rank sum test). No relationship was observed with the UGT1A1 genotype.
HNI potentially represents a potential method for the assessment of hepatic Ir handling. This is achieved through the use of relevant substrates whose hepatic transport parallels that of Ir and the derivation of functional parameters. MIBI hepatic imaging has already been correlated to vinorelbine48 and imatinib PK.49 The study reported here has evaluated both MIBI and IDA analogs in cancer patients. IDA imaging has relevant advantages over MIBI. It is a substrate only for ABCC1 and ABCC2, and it has significantly less muscle uptake,34,61 minimizing effects of body mass. The deconvolutional approach, with its theoretical advantages, has also been used.51-53 Studies have associated the extent of liver dysfunction with reduced blood clearance of IDA or HEF.34,37,50,51,62 In our cohort, the mean HEF was 51.8% for IDA-analogs, relative to a reported 99.0% ± 3.96% standard deviation (SD) for healthy volunteers.51 Similarly, the IDA t1/2 was prolonged (28.8 minutes [SD = 5.2]) relative to a healthy population (19.0 ± 2.5 minutes),34 implying a moderate level of baseline functional impairment. The t1/2 of MIBI was 109.8 minutes (SD, 64.8 minutes) relative to 53.3 minutes (SD, 77.0 minutes) in patients with cancer.47 The differences in half-lives between the tracers may reflect their dissimilar hepatic uptake and physiochemical properties rather than ABCC1 and ABCC2 not being rate limiting for MIBI elimination. The aim of this study was to correlate HNI parameters to Ir PK and toxicity and to UGT*1A1 and ABCB1 polymorphisms. The results here are hypothesis generating and to be interpreted with caution. The sample size is small (21 patients), and adequate Ir PK was only available in 16 patients. The limited sampling model–derived parameters were in the approximate range as previously reported63-66; however, it may have been suboptimal. Subsequent studies had observed a two-fold increase in the reported t1/2 of SN-38,67 signifying the need for any limited sampling model to include a 48-hour time point.68 PK data were available in few homozygous patients, hence we could not confirm the relationships between ABCB1 and UGT1A1 polymorphisms and Ir PK.16,20,69,70 We observed a significant, linear correlation between SN-38 AUC and both IDA and MIBI 1-hour RET (Table 3; P < .05), suggesting that reduced hepatic tracer clearance may be associated with increased SN-38 exposure. These relationships were influenced by a single patient (Fig 2B) who had the lowest 1-hour RET values (ie, low t1/2) and SN-38 AUC of the cohort, which may truly reflect his hepatic function and drug handling. He had significantly reduced hepatic volume from two prior hepatic resections and radiation to the chest wall and liver for recurrent disease. The observed low SN-38 AUC may result from reduced hepatic production, which would not have saturated the excretory pathways. The relationship between HNI parameters and Ir PK was also assessed by multiple regressions. A significant relationship was observed between SN-38 AUC and the baseline bili and MIBI 1-hour RET, accounting for 44% of the SN-38 AUC variation. The relationship between serum bili and Ir clearance and SN-38 AUC has been observed by several groups and partly explained by ABCC2 activity.71-73 The contribution of ABCB1 activity to this is unclear, as MIBI is also an ABCC1 and ABCC2 substrate. There were no significant correlations between HNI parameters and Ir toxicities. The documented trends presented earlier have wide CIs and emphasize the need for larger patient numbers. In this study, we also explored the relationship between the pharmacogenomics of ABCB1 and UGT1A1 and HNI parameters. As expected, no correlation was found for UGT1A1 polymorphisms. However, ABCB1 polymorphisms are possibly reflected functionally by reduced MIBI clearance, but caution is required given the small number of patients homozygous for the variant alleles. The study by Wong et al47 observed a significant decrease in the MIBI elimination rate constant (ie, increased t1/2), from wild-type (CC) to homozygous for the variant (TT) in exon 26 (P < .01) and exon 12 (P = .08). ABCB1 gene polymorphisms have been related to reduced protein content or drug efflux,74,75 though inconsistently.76-80 The aim of individualized dosing is to reduce severe toxicity while optimizing efficacy; this requires an understanding of the variability in drug handling. With regard to Ir, there is considerable need to identify patients at risk for severe toxicity. In this regard, we had set out to correlate functional parameters of HNI, from both MIBI and IDA, with Ir PK and toxicity. We have identified models incorporating these parameters together with serum bili. The findings are hypothesis generating and need to be confirmed in a larger cohort, with more robust PK sampling and pharmacogenomics including ABCC2, BRCP (ABCG2), CYP3A4, and other UGT1A1 gene variants.
The authors indicated no potential conflicts of interest.
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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ABSTRACT
INTRODUCTION
2 test. 
