1. May 19, 2005FDA Antiviral Drugs Advisory Committee Meeting 1 Tipranavir NDA 21-814 Drug Interactions Yuanchao (Derek) Zhang, Ph.D. Clinical Pharmacology Reviewer Office of Clinical Pharmacology and Biopharmaceutics CDER, FDA

2. 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. 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. 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 14 C-TPV

5. 5 Potential for TPV/r to affect other drugs Summary 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. 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. 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. 8 Potential for other drugs to alter TPV/r TPV is a CYP3A substrate. TPV is a P-gp substrate.

9. 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. 10 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 14 C-labeled TPV.

11. 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. 12 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.

13. 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?