Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

 

Antiviral Drugs Advisory Committee

 

May 19, 2005

 

 

FINAL QUESTIONS TO THE COMMITTEE

 

Question 1:

·        Do the data demonstrate that tipranavir/ritonavir (TPV/r) is safe and effective for the multi-drug resistant HIV-1 infected population?

 

•         If no, what additional data are needed to provide evidence of safety and efficacy?

 

•         If yes, please address the appropriate population for TPV/r use considering the following:

–        limited inclusion criteria of the RESIST trials

–        drug-drug interactions

–        resistance information and patterns associated with optimal use

–        safety considerations

 

Question 2:

·        Given the data on transaminase elevations, please provide your recommendations for:

•         TPV/r use in patients with underlying liver disease

•         Monitoring and management of hepatotoxicity during clinical use

•         Future studies

 

Question 3:

·        The limited amount of data in females with HIV infection in the TPV program shows an increased incidence of rash in females.  Please provide your recommendations for:

–        Investigation of this safety signal in future studies with TPV

 

Question 4:

·        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).  Please comment on additional post-marketing drug interaction studies.

 

Question 5:

·        Given the high inter-patient variability in TPV exposures following fixed doses and exposure (blood levels)-virologic response relationships, could a biomarker such as Cmin/IC50 be used for the individualization of TPV/r therapy?  Please discuss the studies that would supplement the data presented today.

 

Question 6

·        Please provide your recommendations regarding the display of TPV/r resistance data/analyses in the TPV package insert that would be useful to clinicians.

 

Background referring to Question 6 on next page

 

 

 

 

(Question 6 Continued: Background)

 

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Question 7:

·        Please discuss and recommend future study designs /data acquisition for the heavily pretreated population.