Background: ATV is a new protease inhibitor (PI) with excellent anti-HIV activity and a cytochrome P450 (CYP) 3A substrate. EFV is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that induces cytochrome P450 (CYP) 3A.  Addition of EFV to ATV (400-mg once-daily [qd]) reduced ATV exposure 74% vs ATV alone. RTV is a potent inhibitor of CYP 3A4 that, at 200-mg qd, increased ATV exposure 3-fold vs ATV alone.   The objective was to assess the ability of RTV to offset EFV’s inductive effect upon ATV.

Methods: 20 healthy subjects received open-label drugs co-administered with a light meal as follows: ATV alone for 14 days at 400-mg qd followed by addition of RTV at 100 and EFV at 600-mg qd for 14 more days. All had an ATV pharmacokinetic (PK) profile drawn on day 14.  PK profiles for ATV, RTV, and EFV were drawn on day 28. 

Results:  Summary of ATV pharmacokinetic parameters:

 

Treatment (qd)	Cmax* (ng/mL)	Tmax (h)**	Cmin* (ng/mL)	AUC(TAU)* (ng·h/mL)	T-HALF*** (h)
ATV 400	2307.55 (53.09)	4.00 (1.50, 8.00)	149 (101)	18590.72 (48.42)	5.53 (2.13)
ATV 400 (with EFV 600 +RTV200)	5167.97 (31.50)	2.50 (1.00, 5.00)	1149 (74)	63472.97 (38.17)	9.88 (3.40)

*Geometric Mean (CV%) ** Median (Range) reported. ***Arithmetic Mean (SD)

 

The ratios of geometric means (90% confidence intervals, C.I.) for Cmax and AUC(TAU) of  ATV+EFV+RTV vs ATV are: 2.24 (1.86, 2.70) and 3.41 (2.96, 3.94), respectively. No serious laboratory or clinical adverse events were observed during review of preliminary safety data. 

Conclusions:  Addition of RTV at 200-mg qd to ATV+EFV overcame the inductive effect of EFV on ATV but increased ATV exposure by 3-fold vs ATV alone.