1. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Drug Interactions of Aprepitant Venkat Jarugula, Ph.D. Clinical Pharmacology and Biopharmaceutics Reviewer DPE II/OCPB/CDER/FDA GI Drug Advisory Committee Meeting, March 6, 2003 Venkat Jarugula, Ph.D. Clinical Pharmacology and Biopharmaceutics Reviewer DPE II/OCPB/CDER/FDA GI Drug Advisory Committee Meeting, March 6, 2003

2. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 OutlineOutline Introduction Aprepitant as CYP3A4 inhibitor Effect of other drugs on aprepitant Drug interaction with 5HT 3 antagonists Potential for DDI with chemotherapy drugs metabolized by CYP3A4 Conclusions Introduction Aprepitant as CYP3A4 inhibitor Effect of other drugs on aprepitant Drug interaction with 5HT 3 antagonists Potential for DDI with chemotherapy drugs metabolized by CYP3A4 Conclusions

3. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 IntroductionIntroduction Aprepitant is extensively metabolized primarily by CYP3A4 isozyme Inhibits CYP3A4 with aprepitant regimen –(as early as 1 hr after Day 1 dosing) Induces CYP2C9 with aprepitant regimen Induces its own metabolism upon dosing for 2 weeks (autoinduction) Aprepitant is extensively metabolized primarily by CYP3A4 isozyme Inhibits CYP3A4 with aprepitant regimen –(as early as 1 hr after Day 1 dosing) Induces CYP2C9 with aprepitant regimen Induces its own metabolism upon dosing for 2 weeks (autoinduction)

4. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Effect of Aprepitant on CYP3A4 Drugs

5. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Effect of Other Drugs on Aprepitant

6. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Other Drug Interactions Reduces (S)-warfarin levels (induction of CYP2C9) Reduces levels of OC (ethinyl estradiol 40%  ) with 2 week dosing Does not significantly affect P-gp transporter (no effect on digoxin PK) Reduces (S)-warfarin levels (induction of CYP2C9) Reduces levels of OC (ethinyl estradiol 40%  ) with 2 week dosing Does not significantly affect P-gp transporter (no effect on digoxin PK)

7. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Drug Interactions With 5-HT 3 Antagonists Does not significantly affect PK of ondansetron (IV) and granisetron (oral) No PK data with oral ondansetron No PK data with dolasetron –Carbonyl reductase and CYP2D6 main pathways –CYP3A4 minor pathway No safety data on coadministration with dolasetron Does not significantly affect PK of ondansetron (IV) and granisetron (oral) No PK data with oral ondansetron No PK data with dolasetron –Carbonyl reductase and CYP2D6 main pathways –CYP3A4 minor pathway No safety data on coadministration with dolasetron

8. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Potential for DDI With Chemotherapy Drugs Metabolized by CYP3A4 Moderate CYPA4 inhibitor May increase the systemic exposure of chemotherapy drugs metabolized by CYP3A4 and result in serious and life- threatening toxicity Moderate CYPA4 inhibitor May increase the systemic exposure of chemotherapy drugs metabolized by CYP3A4 and result in serious and life- threatening toxicity

9. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 cont’d. No controlled DDI studies except ongoing study with docetaxel (IV) Inadequate DDI information in the literature –Ketoconazole increases the exposure of active metabolite of irinotecan by 100% –Ketoconazole does not inhibit paclitaxel metabolism No controlled DDI studies except ongoing study with docetaxel (IV) Inadequate DDI information in the literature –Ketoconazole increases the exposure of active metabolite of irinotecan by 100% –Ketoconazole does not inhibit paclitaxel metabolism

10. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 cont’d. Some safety data in the NDA –etoposide, paclitaxel, vinorelbine Minimal or no data –irinotecan, ifosfamide, imatinib, vinblastine, vincristine Preliminary PK data –5 patients on IV docetaxel –No significant effect –May not be generalized to other agents Some safety data in the NDA –etoposide, paclitaxel, vinorelbine Minimal or no data –irinotecan, ifosfamide, imatinib, vinblastine, vincristine Preliminary PK data –5 patients on IV docetaxel –No significant effect –May not be generalized to other agents

11. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 cont’d. Proposed package insert PRECAUTION “ EMEND should be used with caution in patients receiving concomitant medicinal products that are metabolized through CYP3A4; some chemotherapy agents are metabolized by CYP3A4”. No data to provide dosage adjustment or appropriate caution Proposed package insert PRECAUTION “ EMEND should be used with caution in patients receiving concomitant medicinal products that are metabolized through CYP3A4; some chemotherapy agents are metabolized by CYP3A4”. No data to provide dosage adjustment or appropriate caution

12. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 ConclusionsConclusions Aprepitant is extensively metabolized, primarily by CYP3A4 Potent CYP3A4 inhibitors increase aprepitant exposure significantly Potent CYP3A4 inducers reduce aprepitant exposure significantly Aprepitant inhibits CYP3A4 mediated metabolism Aprepitant is extensively metabolized, primarily by CYP3A4 Potent CYP3A4 inhibitors increase aprepitant exposure significantly Potent CYP3A4 inducers reduce aprepitant exposure significantly Aprepitant inhibits CYP3A4 mediated metabolism

13. Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Conclusions cont’d. Aprepitant may increase the exposure of chemotherapy drug metabolized by CYP3A4 DDI potential of Aprepitant with chemotherapy drugs metabolized by CYP3A4 is not characterized adequately Aprepitant may increase the exposure of chemotherapy drug metabolized by CYP3A4 DDI potential of Aprepitant with chemotherapy drugs metabolized by CYP3A4 is not characterized adequately