586 
Pharmacokinetics of Saquinavir with Low-dose Ritonavir or Atazanavir Twice Daily in Seronegative Volunteers: ASPIRE II
Jennifer King*1, S Paul Lundy2, T Kakuda3, S Becker4, and E Acosta1
1Univ of Alabama at Birmingham, US; 2Pharma Product Devt, Menlo Park, CA, US; 3Roche, Nutley, NJ, US; and 4AnorMed, Langley, Canada
Background: Dual protease inhibitor (PI) regimens without ritonavir (RTV) are needed for those with PI-induced hyperlipidemia or RTV intolerance. Atazanavir
(ATV) and saquinavir (SQV) have minimal effect on
lipids with divergent resistance profiles potentially making this an ideal
combination. The objective of this study was to evaluate the pharmacokinetics,
safety, and tolerability of twice-daily SQV/ATV combinations.
Methods: ASPIRE II is an open-label, sequential,
3-way crossover study with 10 day washout period between each 10 day treatment regimen.
Treatment arms were SQV/RTV 1000/100 mg twice daily, SQV/ATV 1000/200 mg twice
daily, and SQV/ATV 1500/200 mg twice daily. SQV 500-mg tablets were used for
this study. Following a standardized meal, blood was drawn pre-dose, 1, 2, 3,
4, 5, 6, 8, 10, and 12 hours post-dose on the 11th day after
starting each treatment. ATV, RTV, and SQV plasma concentrations were measured by
validated high-performance liquid chromatography (HPLC) and analyzed using WinNonLin 4.1. Safety labs were collected at screening, on pharmacokinetic
days and follow-up. Wilcoxon Signed Rank Test was used for pair-wise comparisons
and Mann-Whitney U for unpaired comparisons.
Results: A total of 16 seronegative
volunteers (8 male, 8 female) completed all 3 pharmacokinetics profiles. Median
weight was 84.8 kg for men and 62.3 kg for women. Median pharmacokinetics
parameters for the entire cohort are summarized in the table. ATV pharmacokinetics
parameters were similar between periods 2 and 3; ATV AUC12 x 2 was
comparable to AUC24 from seronegative
historical control. SQV pharmacokinetics parameters were significantly higher
in period 1 compared with 2 or 3 (p <0.05
for all comparisons). Women had significantly higher Cmax
and AUC12 for all 3 protease inhibitors compared to men even after
adjusting for weight (p <0.05).
Grade 3 or 4 hyperbilirubinemia was observed in 6 and 2 subjects during period
2 and 3, respectively. Grade 3 diarrhea and nausea was reported in 1 subject
during period 1.
|
|
Period 1
|
Period 2
|
Period 3
|
|
|
SQV 1000
|
RTV 100
|
SQV 1000
|
ATV 200
|
SQV 1500
|
ATV 200
|
|
Cmax (ng/mL)
|
4065
|
1893
|
1322
|
2272
|
1888
|
2557
|
|
Cmin (ng/mL)
|
599
|
255
|
75
|
265
|
129
|
262
|
|
AUC12 (mg•h/L)
|
24.66
|
10.20
|
4.03
|
12.59
|
7.55
|
11.38
|
Conclusions: RTV significantly increases SQV
concentrations relative to ATV. ATV 200 mg twice daily exposure is comparable
to 400 mg once daily. Sex appears to influence exposure to all 3 PI. SQV/ATV
1500/200 mg twice daily should be further evaluated as a RTV-sparing regimen in
HIV-infected, PI-naïve subjects for pharmacokinetics, safety, and efficacy.
|
