Background:  TPV is the first in a new class of non-peptidic protease inhibitors (NPPIs) and shows potent activity in vitro against broadly PI-resistant HIV strains.  Low-dose RTV is used to increase the plasma concentration of TPV.  TPV induces CYP3A4 activity, while RTV inhibits it.  The study objective was to establish the BID dosing relationship across multiple TPV dosages and 100- or 200-mg of RTV, and to evaluate the net effect of TPV/RTV combinations on CYP3A4 activity. 

Methods:  In an open-label design, 113 HIV-negative subjects were given TPV monotherapy BID for 11 days at the following dosages: 250, 500, 750, 1000, or 1250-mg to establish steady state.  From days 11-32 subjects added 100- or 200-mg of RTV BID.  12-hour PK sampling was obtained on days 11, 18, 25, and 32.  Erythromycin Breath Testing (ERMBT) to assess the CYP3A4 activity was obtained on days 0, 11, 18, 25, and 32. 

Results:  95 subjects had evaluable data through day 32.  RTV 100- or 200-mg co-administration with TPV increased TPV plasma Cmax and AUC at least 4-fold, and Cmin at least 20-fold as compared with TPV monotherapy.  All combinations but TPV 250/RTV 200 resulted in TPV Cmin of at least 20-μM, 10X the protein-adjusted TPV IC50 for multiple PI-resistant HIV-1.

 

Median TPV Cmin (in μM) in the Presence of RTV 0-mg on Day 11 or RTV 100/200-mg on Day 32

	TPV 250 mg	TPV 500 mg	TPV 750 mg	TPV 1000 mg	TPV 1250 mg
RTV 0mg (Day 11)	0.28	0.63	0.69	0.95	1.81
RTV 100mg (Day 32)	--	23	24	76	38
RTV 200mg (Day 32)	15	32	46	59	--

 

ERMBT activity was induced with all doses of TPV monotherapy.  The addition of either 100- or 200-mg of RTV to all doses of TPV completely inhibited ERMBT activity, though RTV 200-mg was associated with more consistent inhibition.  The following adverse events (AEs) were all DAIDS grade I (96%) or II (5%): diarrhea, nausea, vomiting, headache, abdominal pain, and dizziness.  No Grade III/IV events or serious AEs occurred. 

Conclusions:  TPV plasma concentrations were significantly enhanced in the presence of 100- or 200-mg of RTV to levels above the target IC50 for PI-resistant HIV-1.  With each dose combination tested, TPV/RTV led to net inhibition of CYP3A4 activity.  The vast majority of AEs were Grade I and involved the GI tract.