Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Antiviral Drugs Advisory Committee
FINAL QUESTIONS TO THE COMMITTEE
· 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
· 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
· 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
· 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.
· 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.
· 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)
· Please discuss and recommend future study designs /data acquisition for the heavily pretreated population.