Tipranavir NDA 21-814 Drug Interactions

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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

• 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.

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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?