The utility of in-vivo functional and genetic parameters of drug elimination for the estimation of irinotecan (Ir) clearance (CL)

Abstract

2034 Background: Dosing nomograms based upon metabolic phenotype/genotypes may reduce the marked interpatient variability in the clearance (CL) of cytotoxics in cancer patients (pts). Irinotecan (Ir) is a relevant model drug, its active moiety (SN38), undergoes glucuronidation by uridine diphosphoglucuronyl transferase (UGT)-1A1, and with its metabolites is excreted via biliary membrane transporters P glycoprotein (Pgp) and MRP. The aim of this trial was to correlate functional imaging of biliary excretion, and significant polymorphisms in the genes coding for Pgp (exons 12, 21, 26) and UGT-1A1(*28) with Ir pharmacology. Methods: Eligible pts had colorectal cancer, adequate organ function, ECOG PS 0–2. Pre-therapy all pts had bloods taken for Pgp single nucleotide polymorphism (SNP) analysis and UGT 1A1*28 carriage and underwent hepatic 99mTc-DIDA and -MIBI scans, measures of biliary MRP and Pgp function, respectively. DIDA and MIBI hepatic extraction fraction (HEF), CL, elimination half-time and % retention at 1-hr were calculated. Pts received Ir 125mg/m2/90-min, Leucovorin 20mg/m2, 5FU 500mg/m2 bolus, days 1 & 8, q 3weekly. Plasma was taken for Ir and metabolite analysis on day 1 of cycle 1, using a limited sampling model. Results: 21 pts accrued, M:F = 16:5, Mean age 61 yrs. Mean Ir CL = 14.1 L.hr-1.m-2(CV: 20%), SN38 AUC = 253.9 ng.hr.ml-1 (CV: 56%) (n= 17). Ir CL failed to correlate with either hepatic imaging mode. SN38 AUC inversely correlated with DIDA hepatic clearance (R2 = 0.36). Pts hetero- and homozygous for Pgp exon 21 and 26 SNPs demonstrated a trend to increased SN38 AUC and similarly for pts hetero- (n = 7) and homozygous (n = 2) for UGT 1A1*28. The frequency of delayed diarrhea in cycle 1 was, Grade 0/1: n = 13 pts, Grade 2: 4, Grade 3: 4. A trend to increased DIDA HEF and % retention at 1-hr and MIBI HEF in pts with grade 2/3 diarrhea was noted relative to pts with grade 0/1 diarrhea. Conclusions: Functional hepatic imaging together with Pgp and UGT polymorphisms have shown potentially useful correlates with Ir and SN38 pharmacology and with further appraisal may allow for individualised dosing of this and other relevant cytotoxics. No significant financial relationships to disclose.