Pharmacogenomics · CPIC Level A · Topoisomerase I inhibitor

UGT1A1 genotype-guided dosing for irinotecan

CPIC-aligned reference. Educational use only — not a substitute for clinical pharmacology consultation.

TL;DR

UGT1A1 conjugates SN-38 (the active irinotecan metabolite) for biliary excretion. Reduced-function alleles UGT1A1*28 (TA7 repeat homozygous, also Gilbert phenotype) and UGT1A1*6 (G71R, common in East Asian populations) cause SN-38 accumulation, severe neutropenia, and grade 3-4 diarrhea. CPIC Level A recommends genotype-guided starting-dose reduction in poor metabolizers.

Variants tested

  • UGT1A1*28 (rs8175347, TA7 promoter repeat): reduced enzyme expression. Homozygous prevalence ~10-15% in European descent, lower in East Asian.
  • UGT1A1*6 (rs4148323, G71R): primarily East Asian, similar functional effect.
  • UGT1A1*1: wild type (TA6 repeat).
  • UGT1A1*37 (TA8 repeat): rare, similar to *28 effect.

Phenotype mapping

  • Normal metabolizer (UGT1A1 *1/*1): standard dose.
  • Intermediate metabolizer (UGT1A1 *1/*28 or *1/*6): generally standard dose with monitoring; some guidelines suggest mild reduction at higher irinotecan doses (≥180 mg/m²).
  • Poor metabolizer (UGT1A1 *28/*28, *6/*6, *28/*6): reduce irinotecan starting dose, especially at doses ≥180 mg/m².

Dosing recommendation

Pre-treatment UGT1A1 genotyping before high-dose irinotecan regimens (FOLFIRINOX, irinotecan-containing combinations ≥180 mg/m²) is supported by FDA-label revision and CPIC Level A guidance. Practice patterns vary:

  • FOLFIRI (180 mg/m²): genotyping increasingly standard; *28/*28 patients get ~25% dose reduction.
  • FOLFIRINOX (180 mg/m² + oxaliplatin + 5-FU): genotyping strongly indicated due to overlapping toxicities.
  • Lower doses (e.g., weekly schedules at 100-125 mg/m²): clinical benefit of genotyping less clear, though high-risk patients still benefit.

Both UGT1A1 genotyping and DPYD genotyping (for FOLFIRINOX's 5-FU component) can be combined into one pre-treatment PGx workup for pancreatic and colorectal patients.

Evidence

Multiple prospective and meta-analytic studies (Toffoli 2010, Innocenti 2014, FDA label update) demonstrate that UGT1A1*28/*28 confers significantly increased risk of severe neutropenia and diarrhea on standard-dose irinotecan. Genotype-guided dose reduction reduces serious AEs without consistently compromising response. The FDA label includes a dosing-adjustment recommendation for UGT1A1*28/*28 patients.

Caveats

UGT1A1 genotype is one input among several. Concomitant medications affecting UGT1A1 (atazanavir is a strong inhibitor) modify SN-38 exposure. Hepatic dysfunction and bilirubin elevation (a clinical marker of UGT1A1 activity) are also relevant. Some institutions use baseline bilirubin in addition to genotype.

Frequently asked questions

Should we genotype every patient before FOLFIRINOX?
Strongly recommended. FOLFIRINOX has both irinotecan (UGT1A1) and 5-FU (DPYD) components, and the AE burden is already substantial. Combined DPYD + UGT1A1 pre-treatment testing is increasingly standard, especially in pancreatic adenocarcinoma where FOLFIRINOX is first-line for fit patients.
What about UGT1A1*6 in non-East-Asian patients?
*6 is rare in European-descent populations but should be tested in patients of East Asian ancestry. Combined *28 and *6 genotyping gives more complete risk stratification in diverse populations.
Does Gilbert syndrome equate to UGT1A1*28/*28?
Gilbert phenotype is most commonly *28/*28 in European-descent populations. The clinical bilirubin pattern (mild unconjugated hyperbilirubinemia, fasting-exacerbated) often matches the irinotecan risk allele. Bilirubin elevation is suggestive but genotyping is more specific.

Citations