Background: 908, a prodrug of APV, and RTV are HIV-1 PIs. RTV is a potent inhibitor of APV metabolism, even at sub-therapeutic concentrations. The safety and efficacy of 908 700-mg (equivalent to APV 600-mg) BID + RTV 100-mg BID is being studied. EFV is a NNRTI that may be co-administered with 908 and RTV and is a potent inducer of APV metabolism. This study was designed to provide plasma APV PK data to aid in the selection of 908 and RTV doses when coadministered BID with EFV qd.

Methods: Subjects underwent PK sampling over 12h following administration of 908 700-mg BID + RTV 100-mg BID for 14 days. Subjects initiated either 908 700-mg BID + RTV 100-mg BID + EFV 600-mg qd or 908 700-mg BID + RTV 200-mg BID + EFV 600-mg qd immediately following the PK sampling on day 14. After an additional 14 days of dosing, subjects underwent PK sampling over 12 hours.

Results: 5 of 31 subjects prematurely withdrew; 3 for AEs, 1 for seasonal allergies, and 1 withdrew consent.  In addition, 1 subject was excluded from the PK analysis due to non-adherence.

 

Plasma APV PK Parameter Estimates,  Geometric Mean (95% CI)
PK Parameter	908 700-mg BID + RTV 100-mg BID N=25	908 700-mg BID + RTV 100-mg BID + EFV 600-mg qd N=14	908 700-mg BID + RTV 200-mg BID + EFV 600-mg qd N=11
Cmax,ss	6.17 (5.47-6.96)	6.11 (5.18-7.21)	5.60 (4.94-6.36)
AUCt,ss	40.1 (35.1-45.7)	37.0 (31.4-43.7)	37.6 (30.5-46.3)
Ct,ss	2.18 (1.82-2.61)	1.96 (1.62-2.38)	2.01 (1.54-2.63)
t=12 h, Cmax,ss and Ct,ss units are mg/mL and AUCt,ss unit is h·mg/mL

 

The most common AEs were diarrhea/loose stools (45%), headache (26%), fatigue (26%), dizziness/lightheadedness (19%), difficulty in concentrating (16%), rash (16%), and nausea (16%).

Conclusions: Plasma APV concentrations were maintained when RTV 100-mg BID was co-administered with 908 700-mg BID + EFV 600-mg qd. The addition of an extra 100-mg of RTV (i.e. RTV 200-mg BID) did not provide significant additional enhancement of plasma APV concentrations.