PII‐20

BACKGROUND PK variability of the anticancer agent CPT‐11 is high. Life‐threatening grade 3 ‐ 4 diarrhea is seen in up to 25% of patients and has been related with CPT‐11 PK and UGT1A1‐status. Aim of this study was to evaluate the association of ABCC2 polymorphisms and haplotypes with CPT‐11 disposition and diarrhea. METHODS 105 European Caucasian cancer patients who were previously assessed for CPT‐11 PK (90‐min infusion; three‐weekly), toxicity and UGT1A1*28 , were genotyped for ABCC2 using Pyrosequencing (table 1). RESULTS Frequencies of wild type alleles and haplotypes (13 identified in 85 patients) are given in table 1. ABCC2*1 was associated with slower CPT‐11 clearance (28.4 vs 33.9 L/h; P=.005). In 67 patients who received the recommended single agent dose (350 mg/m 2 or 600 mg), ABCC2*1 was negatively correlated with grade 3–4 diarrhea (P=.040). A 3‐fold reduced risk (30% vs 10%) was unrelated to UGT1A1*28 since severe diarrhea manifested itself in particular in patients homozygous for the UGT1A1*1 allele (P=.011). CONCLUSIONS This study suggests that the ABCC2*1 haplotype is associated with CPT‐11 related diarrhea, maybe as a consequence of altered CPT‐11 excretion via the bile into the gut, and hence less local activation into the active metabolite, SN‐38. As its protective effect on diarrhea is seen predominantly in patients not at risk for diarrhea due to UGT1A1*28 , additional studies of the relationships of ABCC2 genotypes to CPT‐11 PK and toxicity are warranted.Frequencies wild type alleles (p) of 6 ABCC2 polymorphisms, and constructed haplotypes (%; N=85). polymorphism p haplotype %−1549G > A 0.60 GGCGTC ( ABCC2*1 ) 35−1019A > G 0.45 GGCATC 19−24C > T 0.84 AATGTT 151249G > A 0.79 AACGTT 12IVS26 −34T > C 0.96 AACGTC 83972C > T 0.67 AACGCC 5Clinical Pharmacology & Therapeutics (2005) 79 , P41–P41; doi: 10.1016/j.clpt.2005.12.145