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

BackgroundIrinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods.MethodsTwenty-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.ResultsSN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 pConclusionRaltegravir 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.Trial RegistrationClinicaltrials.gov NCT00808184