Introduction:
Tipranavir (TPV) is the first non-peptidic protease inhibitor (NPPI); it has
demonstrated a uniquely robust resistance profile in single and multiple
protease inhibitor–experienced patients. TPV is administered with low-dose
ritonavir (RTV) to optimize plasma concentrations. TPV is an inducer of, and
RTV is a potent inhibitor of CYP3A4. Coadministration results in net
inhibition of CYP3A4. The interactions between TPV/r and EFV, ZDV, TDF, or
ddI (EC) at manufacturer recommended doses, are reported here.
Methods:
HIV-negative, healthy volunteers were recruited to 1 of 4 open-label,
randomized, parallel-group trials. Subjects in each trial were randomized to
receive either TPV/r 500 mg/100 mg or TPV/r 750 mg/200 mg. Studies of ZDV,
TDF, and ddI had pharmacokinetic (PK) sampling on day 1 for the NRTI alone,
on day 12 or 14 for TPV/r alone (steady state), and on day 13 or 15 for the
drugs in combination. In the EFV trial, PK sampling occurred after both
single dose (days 1, 3, and 5) and at steady state (days 14 and 21).
Results:
The EFV, ZDV, TDF, and ddI trials enrolled 68, 60, 49, and 23 healthy
volunteers, respectively. The PK profile of TPV/r was unchanged by EFV
following a single dose; EFV was also unchanged. Increases in TPV AUC, Cmax,
and C12h were seen at steady state with EFV. TPV/r caused a
56%–61% reduction in ZDV Cmax and a 33%–43% reduction in AUC. ZDV
did not affect the PK of TPV/r. A dose-dependent reduction in TDF Cmax
of 23%–38% was shown, while there was a 17% decrease in TPV at the 500/100
dose and an 11% decrease with the 750/200 dose. No change in the PK profile
of ddI was seen with TPV/r; although no change in TPV/r AUC was seen in this
study, there was a 32% increase in TPV Cmax and a 34% decrease in
TPV C12h.
Conclusions:
When the enteric-coated formulation of ddI is used, administration should be
4 hours apart from TPV/r. Standard doses of EFV, ZDV, TDF and ddI may be
used with TPV/r. |