Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Drug Interactions of Aprepitant...
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Transcript of Gastrointestinal Drugs Advisory Committee Meeting March 6, 2003 Drug Interactions of Aprepitant...
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Drug Interactions of AprepitantDrug Interactions of AprepitantDrug Interactions of AprepitantDrug Interactions of Aprepitant
Venkat Jarugula, Ph.D.Clinical Pharmacology and
Biopharmaceutics ReviewerDPE II/OCPB/CDER/FDA
GI Drug Advisory Committee Meeting, March 6, 2003
Venkat Jarugula, Ph.D.Clinical Pharmacology and
Biopharmaceutics ReviewerDPE II/OCPB/CDER/FDA
GI Drug Advisory Committee Meeting, March 6, 2003
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
OutlineOutlineOutlineOutline
• Introduction• Aprepitant as CYP3A4 inhibitor• Effect of other drugs on aprepitant• Drug interaction with 5HT3 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 5HT3 antagonists• Potential for DDI with chemotherapy
drugs metabolized by CYP3A4• Conclusions
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
IntroductionIntroductionIntroductionIntroduction
• 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)
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Effect of Aprepitant on CYP3A4 Effect of Aprepitant on CYP3A4 DrugsDrugs
Effect of Aprepitant on CYP3A4 Effect of Aprepitant on CYP3A4 DrugsDrugs
1
3.3
2.2
1.7
2.5
1.34
0
0.5
1
1.5
2
2.5
3
3.5
AUC ratio
Control
Midazolam
Dexamethasone
Diltiazem
Methylprednisolone(Oral)
Methylprednisolone(IV)
1
3.3
2.2
1.7
2.5
1.34
0
0.5
1
1.5
2
2.5
3
3.5
AUC ratio
Control
Midazolam
Dexamethasone
Diltiazem
Methylprednisolone(Oral)
Methylprednisolone(IV)
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Effect of Other Drugs on Effect of Other Drugs on AprepitantAprepitant
Effect of Other Drugs on Effect of Other Drugs on AprepitantAprepitant
0.09
1
4.8
2
1.3
0
0.51
1.5
22.5
33.5
44.5
5
AUC ratio
Rifampin
Control
Ketoconazole
Diltiazem
Dexamethasone
0.09
1
4.8
2
1.3
0
0.51
1.5
22.5
33.5
44.5
5
AUC ratio
Rifampin
Control
Ketoconazole
Diltiazem
Dexamethasone
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Other Drug InteractionsOther Drug InteractionsOther Drug InteractionsOther 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)
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Drug Interactions With 5-HTDrug Interactions With 5-HT33
AntagonistsAntagonistsDrug Interactions With 5-HTDrug Interactions With 5-HT33
AntagonistsAntagonists
• 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
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Potential for DDI With Chemotherapy Drugs Potential for DDI With Chemotherapy Drugs Metabolized by CYP3A4Metabolized by CYP3A4
Potential for DDI With Chemotherapy Drugs Potential for DDI With Chemotherapy Drugs Metabolized by CYP3A4Metabolized 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
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Potential for DDI with Chemotherapy Drugs Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 Metabolized by CYP3A4 cont’d.cont’d.
Potential for DDI with Chemotherapy Drugs Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 Metabolized by CYP3A4 cont’d.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
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Potential for DDI with Chemotherapy Drugs Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 Metabolized by CYP3A4 cont’d.cont’d.
Potential for DDI with Chemotherapy Drugs Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 Metabolized by CYP3A4 cont’d.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
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Potential for DDI with Chemotherapy Drugs Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 Metabolized by CYP3A4 cont’d.cont’d.
Potential for DDI with Chemotherapy Drugs Potential for DDI with Chemotherapy Drugs Metabolized by CYP3A4 Metabolized by CYP3A4 cont’d.cont’d.
• Proposed package insertPRECAUTION“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 insertPRECAUTION“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
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
ConclusionsConclusionsConclusionsConclusions
• 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
Gastrointestinal Drugs Advisory Committee MeetingMarch 6, 2003
Conclusions Conclusions cont’d.cont’d.Conclusions Conclusions cont’d.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