# Presentation: 852875

## Scientific and Clinical Impact of UGT1A1 Polymorphism: EvidenceNAM Atiqur Rahman, Ph.D.Acting Deputy Director, Division of Pharmaceutical Evaluation 1Office of Clinical Pharmacology and BiopharmaceuticsCenter for Drug Evaluation and ResearchFood and Drug Administration

**Advisory Committee for Pharmaceutical Science****Gaithersburg, Maryland****November 03, 2004**

## PRESENATION OUTLINE

**TPMT Pharmacogenetics and **
**	****PURENITHOL Drug Label**
**Irinotecan Pharmacogenetics: Scientific and Clinical Evidence**** **

## TPMT Pharmacogenetics and Purinethol Label

## TPMT Pharmacogenetics and Purinethol Label

**____________________________________________________**
**In a study of 142 patients with Acute Lymphoblastic Leukemia, 100% homozygous deficient patients required substantial dose alteration to prevent toxicity during continuation of therapy compared to 35% heterozygous patients and 7% patients with wild-type alleles.**
**_________________________________________________**

## TPMT Pharmacogenetics and Purinethol Label

**Potential benefit of avoiding myelosuppression by reducing the dose of 6-MP in presence of other myelosuppressive drugs.**
**___________________________________________**
**Potential for secondary malignancy for patients with low TPMT activity.**

## TPMT Pharmacogenetics and Purinethol Label

**Clinical Pharmacology**
-  **Includes a subsection describing the frequency of TPMT polymorphism in the Caucasian and African Americans and the effect of the mutation on 6-MP metabolism**
**Warning**** **
**Under “Bone Marrow Toxicity” subsection, includes a warning for substantial dose reductions generally required for homozygous-TPMT deficient patients**
**Laboratory Test**
**Includes a subsection “****TPMT Testing****” informing on the availability of the tests and the variant alleles associated with low TPMT activity.**

## TPMT Pharmacogenetics and Purinethol Label

**Adverse Reactions**
**Includes under “Hematologic” subsection, particular susceptibility of TPMT-deficient patients to hematologic toxicity. **
**Dosage and Administration**
**Includes a specific subsection on “Dosage in TPMT-deficient Patients”. Informs about severe toxicity with conventional doses of Purinethol and reemphasizes that substantial dose reduction is generally required for TPMT-deficient patients. **

## Pharmacogenetics of Irinotecan:Scientific and Clinical Evidence

**Indicated as a component of first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum.**
**Indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.**

## Efficacy: First Line Therapy

**Source: Package Insert**

## Efficacy: Second Line Therapy

**Source:Package Insert**

## Metabolic Pathways 

**Irinotecan**

- -

**APC**

- inactive

- NPC

- inactive

**SN-38**

**CYP3A4**

**CYP3A4**

**CES 1/2**

**UGT1A1**

**SN-38G**

**SN-38G**

- UGT1A6

- UGT1A9

## UGT1A1 Pharmacogenetics

**UGT1A1 has more than 30 variant alleles. **
**UGT 1A1*28 is a variant allele**** **
- Variation in the TA repeats in the promoter region
- Normal allele: 6 TA repeats (6/6)
- Variant allele: 7 TA repeats (7/7)
- UGT 1A1*28 is associated with reduced gene expression and reduced glucuronidation in human liver microsomes.

## Genotype Versus Phenotype

_**Genotype and Phenotype**_
_**_______________________**_
**Genotype****	****Glucuronidation**
**6/6****	****	****851±545**
**6/7****	****	****699±361**
**7/7****	****	****199±118**
**_______________________**
**Mean ± Standard Deviation**

**Fisher et al. Pharmacogenetics, 2000**

## UGT1A1 Pharmacogenetics

## Retrospective Analysis

**Data from phase 2/3 studies of Irinotecan weekly regimens. Dose range: 100-150 mg/m****2. ****Due to lack of individual PK data, mean AUC’s were used.**

**Risk of neutropenia and severe diarrhea increases with SN38 exposure**

## Genetic Variants in the UDG-glucuronosyltransferase 1A1 Gene Predict the Risk of Severe Neutropenia of Irinotecan

**Study Design:**
**N=66 patients (solid tumor or lymphoma)**
**10 colorectal patients**
**350 mg/m****2 **** every 3 weeks (90 minute infusion)**
**Toxicity assessed during cycle 1 of the treatment**
**PK samples collected up to 25.5 hours**
**Nonparametric trend tests were used to assess the relationship of genotype and ANC nadir, PK, and  pretreatment bilirubin levels.**

**Innocenti  et al. J Clin Oncol, 2004**

## Highlights of the Study

**Prospective study**
**Size of the study **
**Single agent therapy**
**Toxicity assessment in the first cycle**
**PK conducted adequately**

## Genotype and SN-38 AUC

**p-values are based on analysis of log-transformed data**

## SN38 AUC-ANC Nadir Relationship

**6/6**

**6/7**

**7/7**

**Single doses of 300-350 mg/m****2**** were given to 86 patients**

- Grade 4

## Genotype and Neutropenia

## Results 

**Prevalence of Grade 4 neutropenia was 9.5%**
**Prevalence of severe diarrhea was 5%**
**One-patient died of neutropenia related sepsis; had the highest bilirubin level and 7/7 genotype  **

## Results (Cont.)

**Grade 4 neutropenia was more common (p=0.001) in patients with 7/7 genotype patients**
**The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4)  for the 7/7 genotype patients**
** **
**Pretreatment total bilirubin levels were significantly higher in 7/7 genotype patients**
**No association between genotype and diarrhea (3 patients with grade 3 diarrhea was 7/7 or 6/7 patients) **

## Conclusions

**	****“****UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia.”**

## UGT1A1 Gene Variations and Irinotecan Treatment in Patients with Metastatic Colorectal Cancer

**Study Design:**
**N=95 patients (metastatic colorectal cancer)**
**Four chemotherapy regimens containing irinotecan **
**Toxicity assessed during the entire treatment cycles**
**PK samples were not collected.**
**Logistic regression was used to assess if genotype independently predict toxicity**

**Marcuello et al. British J Cancer, 2004**

## Genotype and Neutropenia and Diarrhea

## Results 

**Prevalence of grade 3/4 neutropenia was 21%**
**Prevalence of severe diarrhea was 31% **

## Results

**A strong correlation between genotype and diarrhea (P=0.01)**
**No significant association between genotype and grade 3/4  neutropenia**
**Mean pretreatment total bilirubin levels were significantly higher (P=0.001) in 7/7 genotype patients**
**Cumulative Irinotecan dose administered in 7/7 patients was 1398 mg/m****2**** compared to 1725 mg/m****2**** in 6/6 patients. **

## Conclusions

**“ ****Irinotecan studies have paved the way for new genetic-based ways of applying chemotherapeutic treatments in a more rational manner.”**

## Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity: A Molecular and Clinical Study of 75 Patients

**Study Design:**
- N=75 patients (metastatic colorectal cancer)
- Two Irinotecan containing chemotherapy regimens
- IRIFUFOL (85 mg/m2 weekly)
- FOLFIRI (180 mg/m2 biweekly)
- Toxicity assessed either weekly or biweekly
- No PK samples collected in this study
- Statistical differences were tested Non-parametric Kruskal-Wallis Test

**Rouits et al. Clin Can Res, 2004**

## Genotype and Neutropenia

## Genotype and Susceptibility to AEOverall Toxicity

## Results and Conclusions

**Prevalence of grade 3/4 neutropenia was 30%**
**Prevalence of severe diarrhea was 7%**
**No association between genotype and diarrhea**
**Significant association between genotype and grade 3/4  neutropenia**
**Patients with deficient alleles required hospitalization**

## Other Studies

**Mathijssen et al. Clin Cancer Res, 2003**
**PK Study in 65 patients to explore relationship between irinotecan disposition and variant genes.**
**Genes explored: MDR-1, MRP-1, MRP-2, CES1, CES2, CYP3A4, CYP3A5, UGT1A1, XRCC1**
**No significant correlation between UGT1A1*28 and irinotecan disposition**
**Two 7/7 genotype patient in this study**
**Paoluzzi et al. J Clin Pharmacol Ther, 2004**
**PK Study in 94 patients to explore relationship between irinotecan disposition and variant genes.**
**Genes explored:UGT1A1 and UGT1A9**
**AUC ratio of SN-38G/SN-38: 6/6>6/7>7/7**
**Five patients with 7/7 genotype**

## Other Studies

**Font et al. Invest New Drugs, 2003**
**A phase 2 study to evaluate the activity of docetaxel and irinotecan in 51 advanced NSCLC patients**
**No correlation between genotype and toxicity**
**7 patients with 7/7 genotype**
**Ando et al. Cancer Res, 2000**
**Retrospective analysis of 118 patients with various cancers treated with irinotecan containing regimen**
**UGT1A1*28 is a significant predictor of severe toxicity**
**7 patients with 7/7 genotype**
**55% patients with grade 4 neutropenia also had grade 3/4 diarrhea**
**73% patients with grade 3/4 diarrhea also had grade 3/4 neutropenia**

## Other Studies

**Sai et al. Clin Pharmacol Ther, 2004**
**A PK study in 88 cancer and 107 cardiovascular patients**
**Highly significant association between *28 haplotype and reduced AUC ratio and increased total bilirubin**
**Three patients with 7/7 genotype**
**Iyer et al. Pharmacogenom J, 2002**
**A prospective pharmacogenetic study PK in 20 cancer patients treated with irinotecan**
**A significant reduction in SN-38 glucuronidation rates **
**Lower ANC in 7/7 genotype patients**
**Four patients with 7/7 genotype**

## Risks Factors

**Known Predictive Factors for Toxicity (potential dose reduction)**
**Age (>/=65yrs, monitor; 70 yrs, dose reduce)**
**Prior pelvic and abdominal radiotherapy**
**Performance status of 2**
**Increased bilirubin level**
**Proposed Predictive Factor for Toxicity **
**	****(suggested dose reduction)**
**UGT 1A1 genotype**
**Likely Predictive Factor for Toxicity**
**SN-38 exposure**

## Utility of  UGT1A1 Polymorphism in the Use of  Irinotecan

**Excluding 7/7 patients from standard dose of irinotecan treatment will reduce the overall incidence of grade 4 neutropenia from 10.1% to 5.7%.**
**7/7 genotype patients may get a alternate irinotecan regimen?**
**Genotypic testing combined with bilirubin levels will allow better patient selection for Irinotecan therapy. Physicians will be better informed about use of Irinotecan as a single agent or in  combination therapy.**
**Genotypic testing will allow 7/7 genotype patients with a choice for equally efficacious alternate therapy.**

## ACKNOWLEDGEMENT

_**Office of Clinical Pharmacology and **_
_**Biopharmceutics**_
**Dr. Larry Lesko**
**Dr. Shiew-Mei Huang**
**Dr. Felix Frueh****	****	****	****	**_**Division of Onoclogy Drug **__**	**__**	**__**	**__**	**__**	**__**	**__**Products**_
_**Division of Pharmaceutical **__**	**__**	**_**Dr. Grant WIlliams**
_**Evaluation 1**__**	**__**	**__**	**__**	**_**Dr. Richard Pazdur**
**Dr. Roshni Ramchandani**
**Dr. Yanning Wang**
**Dr. Brian Booth**
**Dr. Joga Gobburu**
**Dr. Mehul Mehta**