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Tipranavir NDA 21-814 Drug Interactions

Tipranavir NDA 21-814 Drug Interactions. Yuanchao (Derek) Zhang, Ph.D. Clinical Pharmacology Reviewer Office of Clinical Pharmacology and Biopharmaceutics CDER, FDA. Outline. Potential for TPV/r to alter concentrations of other drugs Potential for other drugs to alter TPV/r concentrations

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Tipranavir NDA 21-814 Drug Interactions

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  1. Tipranavir NDA 21-814Drug Interactions Yuanchao (Derek) Zhang, Ph.D. Clinical Pharmacology Reviewer Office of Clinical Pharmacology and Biopharmaceutics CDER, FDA FDA Antiviral Drugs Advisory Committee Meeting

  2. 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

  3. 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).

  4. 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

  5. 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…

  6. 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

  7. 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%).

  8. Potential for other drugs to alter TPV/r • TPV is a CYP3A substrate. • TPV is a P-gp substrate.

  9. 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.

  10. Potential for other drugs to alter TPV/rSummary • 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.

  11. 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

  12. Examples of unknown drug interactions • Anticoagulant (warfarin) • TPV/r may increase or decrease warfarin concentrations (competing effects on CYP2C9). • Calcium channel blockers • Cannot predict effect of TPV/r (competing effects on CYP3A and P-gp) • 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.

  13. 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?

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