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


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


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)


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)


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


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)


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


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


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




• 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




• 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


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


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

gastrointestinal drugs advisory committee meeting march 6, 2003 drug interactions of aprepitant...

Documents