Download
current and future perspectives on irinotecan pharmacogenomics n.
Skip this Video
Loading SlideShow in 5 Seconds..
Current and Future Perspectives on Irinotecan Pharmacogenomics PowerPoint Presentation
Download Presentation
Current and Future Perspectives on Irinotecan Pharmacogenomics

Current and Future Perspectives on Irinotecan Pharmacogenomics

142 Vues Download Presentation
Télécharger la présentation

Current and Future Perspectives on Irinotecan Pharmacogenomics

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Current and Future Perspectives on Irinotecan Pharmacogenomics ACPS Clinical Pharmacology Subcommittee 3 November 2004 Luis A. Parodi, PhD - Director and Site Head, Clinical Pharmacogenomics Mark E. Morrison, MD, PhD - Medical Director, Team Leader, Camptosar Akintunde Bello, PhD – Associate Director, Clinical Sciences

  2. Presentation Overview • Commitment to safety • Application of pharmacogenomics at Pfizer • Review & analysis of published data • Ongoing studies • Collaboration with FDA

  3. Pharmacogenomics at Pfizer Discovery Development DISEASE TARGET SELECTING PHARMACO- GENOMICS GENETICS RESPONDERS VARIABILITY Improving Early Decision Making Predicting Efficacy and Safety Choosing the Best Targets Better Understanding of Our Targets .

  4. Chronology of Pharmacogenomics Activities Related to Irinotecan • Ca. 1996-7 - Provided irinotecan clinical supplies to NCI in support of early irinotecan pharmacogenomics (PGx) research at University of Chicago • 2000 to present - Supported and sponsored several irinotecan clinical trials with PGx • 2001 to present - Provided grant support to NCCTG for PGx in N9741 Ph-3 mCRC trial • 2002 - Collaboration with Epidauros AG in PGx of drug transporters and metabolizing enzymes • 2004 - Initiating irinotecan neoadjuvant study with PGx component

  5. Irinotecan Disposition & Metabolism NPC & APC Inactive Metabolites Other UGT Isoforms? CYP3A4/5 Carboxylesterases (CE1 & CE2) UGT1A1 Irinotecan SN-38 SN-38G Active Metabolite Inactive Metabolite Parent Drug GI Absorption Biliary Excretion BCRP MDR1 (PGP)? MRP2? C-MOAT? SN-38 SN-38G Glucuronidase (Bacterial) GI Lumen

  6. Key Publications Correlating UGT1A1 7/7 Genotype and Safety *Full citations given in Background Document.

  7. Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 GenotypesUnadjusted Odds Ratio

  8. Severe Neutropenia Risk: 7/7 vs 6/6 + 6/7 GenotypesSummary • No adjustments for known risk factors • There seems to be a statistically significant association in 3 of 4 studies between 7/7 and severe neutropenia • Potential causes for interstudy variation include: • Small sample sizes • Different schedules/dose intensity • Other known risk factors (bilirubin, age, performance status, pelvic radiation) • Difference in population and cancer types treated

  9. Severe (Gr 3+) Diarrhea Risk: 7/7 vs 6/6 + 6/7 GenotypesUnadjusted Odds Ratio • Association between 7/7 and severe diarrhea • 2 of 5 studies show statistical significance

  10. Summary of published data • Comprehensive review of published literature • Evaluate the frequencies of severe neutropenia & diarrhea and genotypes • Conclusion: • Significant association of the UGT1A1 7/7 genotype and the risk of developing Grade 4 neutropenia • The association with severe diarrhea not as consistent between studies • Translation of association data to a predictive performance requires assessing multiple parameters • Sensitivity, specificity, and positive & negative predictive values.

  11. Severe Neutropenia:Translating Associations into a Predictive Test Assumption: Genotyping assay is 100% accurate for detection of UGT1A1*28 allele • Balancing neutropenia and efficacy in 7/7 positive patients: • Neutropenia is generally manageable • Dose reduction may be unnecessary for 50%, with unknown consequences

  12. Ongoing Activities • Ongoing Pfizer sponsored and supported trials aim to: • Better quantify the association between the UGT1A1*28 variant (as well as other genetic factors) and severe neutropenia & diarrhea • Discussions are in progress with FDA on revising the Camptosar label to include pharmacogenomics information

  13. Pfizer-Supported and -Sponsored Trials with a Pharmacogenomic Component* (Nov 2004)

  14. What do we hope to learn from these studies? • Better define magnitude and strength of the association between UGT1A1*28 and safety • Identify other potential covariates of severe neutropenia & diarrhea • Provide information & guidance to health care practitioners to aid in their treatment decisions