May 19, 2005 FDA Antiviral Drugs Advisory Committee Meeting

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Tipranavir NDA 21-814

Drug Interactions

Yuanchao (Derek) Zhang, Ph.D.Clinical Pharmacology Reviewer

Office of Clinical Pharmacology and Biopharmaceutics

CDER, FDA

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Outline

• Potential for TPV/r to alter concentrations of other drugs

• Potential for other drugs to alter TPV/r concentrations

• Examples of unknown drug interactions• Question for the Antiviral Drugs Advisory

Committee

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Potential for TPV/r to alter concentrations of other drugs

• In vitro drug metabolism (effect of TPV)– TPV is a CYP3A inducer and inhibitor.– TPV is an inhibitor of CYP1A2, CYP2C9,

CYP2C19, and CYP2D6.

• In vivo net effect of TPV/r (500/200 bid)– Inhibition of CYP3A– Potential net effect of TPV/r on CYP2D6 is

inhibition (RTV inhibits CYP2D6).– Net effect of TPV/r on CYP1A2, CYP2C9 and

CYP2C19 is not known (RTV may induce CYP1A2 and CYP2C9).

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Potential for TPV/r to alter concentrations of other drugs

• In vivo effect on P-gp transporter– TPV is a P-gp inducer.– Net effect of TPV/r is P-gp induction.

– Data supporting this conclusion• Loperamide interaction study• Clarithromycin interaction study• Protease inhibiter interaction data• Multiple-dose TPV/r PK study with 14C-TPV

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Potential for TPV/r to affect other drugsSummary

• Inhibition of CYP3A- Administration of TPV/r can increase plasma concentrations of drugs metabolized by CYP3A.

• In vitro TPV and RTV inhibit CYP2D6- TPV/r likely inhibit CYP2D6 (may increase concentrations of drugs metabolized by CYP2D6).

• Effect on CYP1A2, CYP2C9 and CYP2C19 is not known.

• Induction of P-gp- Administration of TPV/r can decrease plasma concentrations of P-gp substrates.

• Effect on dual CYP3A and P-gp substrates- It depends…

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Potential for TPV/r to alter concentrations of other drugs

• Competing effects of TPV/r on CYP3A and P-gp make prediction of in vivo drug interactions difficult– Expect concentrations of CYP3A

substrates to increase– Expect concentrations of P-gp substrates

to decrease

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Potential for TPV/r to affect CYP3A and P-gp dual substrate drugs

• Net effect will vary depending on the relative affinity of the co-administered drugs for CYP3A and P-gp and the extent of intestinal first-pass metabolism/efflux

– CYP3A seems to be dominant for atorvastatin absorption (Atorvastatin concentrations increase to 5-9 fold).

– P-gp seems to be dominant for absorption of other RTV-boosted protease inhibitors (Amprenavir concentrations decrease 50%, lopinavir concentrations decrease 50-70%, saquinavir concentrations decrease 80%).

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Potential for other drugs to alter TPV/r

• TPV is a CYP3A substrate.

• TPV is a P-gp substrate.

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Potential for other drugs to alter TPV/r Summary

• Co-administration of TPV/r and drugs that induce CYP3A and/or P-gp may decrease TPV plasma concentrations.

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Potential for other drugs to alter TPV/r Summary

• Co-administration of TPV/r and drugs that inhibit CYP3A may not further increase TPV plasma concentrations.

– This conclusion is supported by results of a multiple-dose TPV/r PK study with 14C-labeled TPV.

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Potential for other drugs to alter TPV/r Summary

• Co-administration of TPV/r and drugs that inhibit P-gp may increase TPV plasma concentrations.

– TPV/r + fluconazole increased TPV concentrations– TPV/r + clarithromycin increased TPV concentrations

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Examples of unknown drug interactions

1. Anticoagulant (warfarin)– TPV/r may increase or decrease warfarin

concentrations (competing effects on CYP2C9).

2. Calcium channel blockers– Cannot predict effect of TPV/r (competing effects

on CYP3A and P-gp)

3. Anti-diabetic agents– The effect of TPV/r on CYP2C8, which metabolizes

most glitazones, is not known.– Sulfonylureas are metabolized by CYP2C9,

interaction is possible.

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Question for the Antiviral Drugs Advisory Committee

Current information indicates the net effect of TPV/r on substrates of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 is not known, and there are competing effects of TPV/r on CYP3A (inhibition) and P-glycoprotein (induction). What additional drug interaction information is important for the safe use of TPV/r in the target population?