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 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), 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.

Trial registration: Clinicaltrials.gov NCT00808184.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT Flow Diagram for trial.

Fig 2. The raltegravir-raltegravir glucuronide (parent-metabolite) compartment model.

N1 denotes the first hypothetical transit compartment up to Nn compartment. ktr is the transit rate constant. ka is the absorption rate constant from the hypothetical drug depot compartment to plasma. CL/V (or k) is the elimination rate constant of raltegravir. FMET is the fraction of raltegravir clearance for the formation of raltegravir glucuronide. VM, the distribution volume of the metabolite, was fixed to 1. As such, FMET is estimated as the ratio of the formation rate of glucuronide to VM. CLM is the glucuronide clearance.

Fig 3. Scatterplot and linear correlation between nadir absolute neutrophil count (ANC) and rate constant of formation of raltegravir glucuronide from raltegravir (K23).

The regression equation is ANC = 129.2 + 89461.5*K23. R is 0.598 (p = 0.00158).

Fig 4. Box-plot showing the association between the rate constant of formation of raltegravir glucuronide from raltegravir (K23) and presence or absence of dose delay amongst the patients.

Fig 5. Box-plots showing the statistically insignificant associations between the nadir absolute neutrophil count and UGT1A1 genotypes.