Phenotyping of UGT1A1 Activity Using Raltegravir Predicts Pharmacokinetics and Toxicity of Irinotecan in FOLFIRI

Abstract

Background Irinotecan toxicity correlates with UGT1A1 activity.We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods. Methods Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5. Results SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r =-0.397 p0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P0.005), but not UGT1A1 genotype. Conclusion Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy.