Topic 1. Pharmacogenetics of Irinotecan: Scientific and Clinical Impact
of UGT Polymorphism

Camptosar (Irinotecan hydrochloride injection) received accelerated
approval on June 14, 1996 for the treatment of patients with metastatic
carcinoma of the colon or rectum whose disease has recurred or
progressed following initial flurouracil based therapy. Camptosar was
subsequently approved as a component of first-line therapy in
combination with 5-fluorouracil and leucovorin for patients with
metastatic colon or rectal cancer. Camptosar is administered as weekly,
or biweekly, or once every 3-week dosage schedules. In two clinical
trials, irinotecan treatment in combination with 5-fluorouracil and
leucovorin significantly increased the median survival, objective tumor
response rates, and time to tumor progression of patients with
metastatic carcinoma of the colon or rectum. In two multicenter,
randomized trials single-agent irinotecan given once-every-three-week
dosage schedule significantly increased survival of patients with
metastatic colorectal cancer whose disease has recurred or progressed
following prior 5-flurouracil therapy.

The most clinically significant adverse events for patients receiving
irinotecan-based therapy were diarrhea, neutropenia, nausea, vomiting
and alopecia. Irinotecan can induce both early and late forms of
diarrhea and requires dose adjustment based on severity of diarrhea.
Sepsis related death following severe neutropenia is reported in
irinotecan treated patients. Dose adjustment based on neutrophil count
is recommend in the label.

Pharmacokinetic studies of irinotecan have shown large inter-individual
variability of SN-38 exposure (AUC). SN-38 is an active metabolite of
irinotecan and is responsible for the pharmacological and toxic effect
of irinotecan. SN-38 is glucuronidated by Uridine diphosphate-glucuronyl
transferase enzymes (UGT), predominantly by UGT1A1 isoenzyme. UGT1A1 is
a polymorphic enzyme. The TA repeats (5, 6, 7, or 8) in the TATA box of
the UGT1A1 promoter region is inversely correlated with gene
transcription efficiency and overall enzyme activity. The presence of
seven repeats (TA~7~) compared to the normal genotype of six (TA~6~)
repeats results in the variant allele UGT1A1\*28. This allele is
associated with reduced gene expression and reduced glucuronidation in
human liver microsomes. Approximately 10% of the North American
population carry the two deficient alleles (homozygous). In the European
population^1^, the allele frequencies for TA~6~ and TA~7~ are 0.613 and
0.387.

A prospective study^2^ of 66 patients receiving 350 mg/m^2^ every 3
weeks showed homozygous TA~7~ genotype patients had a relative risk of
9.3 (95% CI, 2.4 to 36.4) for grade 4 neutropenia. Fifty percent (3 out
of 6) of the homozygous TA~7~ patients had grade 4 neutropenia compared
to 12.5% heterozygous TA~6/7~ patients (3 out of 24). No patients with
the normal TA~6~ genotype (0 out of 29) had any grade 4 neutropenia.
SN-38 exposure directly correlated with the UGT1A1 genotype (meanS.D:
542 195, 458 380, and 336 168 ng\*h/mL for TA~7~ homozygous, TA~6/7~
heterozygous, and normal genotype). UGT1A1\*28 genotype is associated
with 1.8 to 3.9-fold lower SN-38 glucuronidation compared to patients
with normal genotype. Pretreatment total bilirubin levels which is also
glucuronidated by UGT1A1 was significantly higher in patients with grade
4 neutropenia compared to those without grade 4 neutropenia. The
prevalence of grade 3 diarrhea was only 5% (N=3) and none of the
patients with diarrhea was TA~6~ genotype. In another study^3^ patients
receiving combination regimen of irinotecan and 5-fluorouracil, 5 out of
7 patients (71%) with homozygous TA~7~ genotype had grade 3 or 4
neutropenia compared to 10% patients (3 out of 31) with normal alleles.
The study did not assess the pharmacokinetics of irinotecan. The
occurrence of grade 4 diarrhea was not significantly different in TA~7~,
TA~6/7~, and TA~6/6~ patients. Irinotecan courses had to be postponed in
70% (5 of 7) TA~7~ patients compared to 32% (10 of 31) TA~6/6~ patients.

Marcuello^4^ et al. reported 40% (4 of 10) colorectal cancer patients
with TA~7~ genotype receiving irinotecan based therapy had grade 3 or 4
neutropenia compared to 15% patients with normal alleles (6 or 40). This
study also reported 70% (7 of 10) TA~7~ patients suffered grade 3 or 4
diarrhea compared to 17% (7 of 40) patients with normal alleles. Doses
of irinotecan administered in TA~7~ patients were 1398 mg/m^2^ compared
to TA~6~ patients receiving 1725 mg/m^2^ dose.

In a Phase 2 study^5^, weekly regimen of irinotecan/docetaxel in
previously treated non-small cell lung cancer patients (N= 51) did not
show any correlation between UGT1A1 genotype and toxicity. The
incidences of grade 3 and 4 hematologic toxicity and diarrhea were 10%
and 25%, respectively.

A small prospective pilot study^6^ of 20 patients and a retrospective
analysis^7^ of 118 patients also indicated a higher risk for neutropenia
for TA~7~ homozygous genotype patients.

The Agency appreciates the Clinical Pharmacology Subcommittee's advice
on the scientific and clinical perspectives of the information regarding
the association between irinotecan toxicity and UGT1A1\*28.

### REFERENCES

1.  Beutler E et al. Racial variability in the
    UDP-glucuronosyltransferase 1 (UGT1A1) promoter: A balanced
    polymorphism for regulation of bilirubin metabolism? Proc. Natl.
    Acad. Sci 1998; 95:8170-8174.

2.  Innocenti F et al. Genetic variants in the
    UDP-glucuronasyltransferase 1A1 gene predict the risk of severe
    neutropenia of irinotecan. J Clin Oncol 2004; 22(8); 1382-1388.

3.  Rouits E et al. Relevance of different UGT1A1 polymorphisms in
    irinotecan-induced toxicity: a molecular and clinical study of 75
    patients. Clin Cancer Res 2004; 10:5151-5159.

4.  Marcuello E et al. UGT1A1 gene variations and irinotecan treatment
    in patients with metastatic colorectal cancer. British J Cancer
    2004; 91:678-682.

5.  Font A et al. Weekly regimen of irinotecan/docetaxel in previously
    treated non-small cell lung cancer patients and correlation with
    uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)
    polymorphism. Investigational New Drugs 2003; 21:435-443.

6.  Iyer L et al. UGT1A1\*28 polymorphism as a determinant of irinotecan
    disposition and toxicity. Pharmacogenomics J 2002; 2:43-47.

7.  Ando Y et al. Polymorphisms of UDP-glucuronosyl-transferase gene and
    irinotecan toxicity: A pharmacogenetic analysis. Cancer Res. 2000;
    60:6921-6926.