A B S T R A C T PurposeWe aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients. Patients and MethodsPharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m 2 (n ϭ 20) and 350 mg/m 2 (n ϭ 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated. ResultsAlmost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48CϾT, SLCO1B1*1b, ANC baseline levels, sex, and race (P Ͻ .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 -24CϾT, SLCO1B1*5, HNF1A 79AϾC, age, and CPT-11 dose (P Ͻ .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684TϾC, ABCB1 IVS9 -44AϾG, and UGT1A1*93 (P ϭ .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes. ConclusionOn the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.

Purpose-To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTAlthough all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptPatients and Methods-A prospective clinical study of 80 patients with non-small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5were genotyped, and their effects on pharmacokinetics and toxicities were evaluated.Results-A novel diplotype of two polymorphic loci in the ABCG2 promoter involving −15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration.Conclusion-Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.