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Session 113 Poster Abstracts
Pharmacology of Protease Inhibitors
Wednesday, 1:30 - 3:30 pm
Hall A


655    
Pharmacokinetics of Once-daily Saquinavir Hard-gel Capsule with Low-dose Ritonavir or Full-dose Atazanavir in Seronegative Volunteers: ASPIRE I
Stephen Becker*1, M Tse1, F Sterman1, T Kakuda2, and E Acosta3
1Pacific Horizon Med Group, San Francisco, CA, USA; 2Roche, Nutley, NJ, USA; and 3Univ of Alabama at Birmingham, USA

Background:  Previous pharmacokinetic studies of saquinavir (SQV)/atazanavir (ATV) have either used the soft-gel formulation of SQV or the addition of low-dose ritonavir (RTV), optimal dosing of SQV/ATV without RTV has not been established. Furthermore, recent studies suggest an influence of sex on SQV pharmacokinetics.

Methods:  ASPIRE I 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 1600/100 mg once daily, SQV/ATV 1600/400 mg once daily, and SQV/ATV 2000/400 mg once daily. Following a standardized meal, blood was drawn pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post-dose on the 11th day after starting each treatment. ATV, RTV, and SQV plasma concentrations were measured by validated HPLC and analyzed using WinNonLin 4.1. Wilcoxon Signed Rank Test was used for pair-wise comparisons and Mann-Whitney U for unpaired comparisons. Safety labs were collected at screening, on pharmacokinetic days and follow-up.

Results:  All 3 pharmacokinetic profiles were completed by 13 seronegative volunteers (6 male, 7 female) completed. Median age and weight was 41 years and 85.5 kg for the males, and 27 years and 55.5 kg for the females. Median pharmacokinetic parameters for the entire cohort are shown in the table. ATV pharmacokinetic parameters were similar between periods 2 and 3 and comparable to historic parameters. SQV pharmacokinetic parameters were significantly higher in period 1 than in 2 or 3 (p < 0.05 for all comparisons). Men had significantly lower Cmax and AUC24 for all 3 protease inhibitors (PI) than women after adjusting for weight (p < 0.05). Grade 3 hyperbilirubinemia was observed in 0, 2, and 7 subjects during periods 1, 2, and 3, respectively. Gastrointestinal disturbances were reported in 7, 3, and 4 subjects during periods 1, 2, and 3, respectively.

 

 

Period 1

Period 2

Period 3

 

SQV 1600

RTV 100

SQV 1600

ATV 400

SQV 2000

ATV 400

Cmax (ng/mL)

3,782.8

1,493.3

1,519.2

4,122.6

2,499.9

4276.3

Cmin (ng/mL)

87.1

27.3

<25

153.7

30.0

130.2

AUC24 (mg·h/L)

26.79

9.88

7.06

22.18

10.61

23.36

 

Conclusions:  RTV significantly increases SQV concentrations relative to ATV. SQV does not alter ATV concentrations. Sex appears to influence exposure to all 3 PI. SQV/ATV 2000/400 mg once daily reaches pharmacologically active exposure for both PI and should be further evaluated in HIV-infected, PI-naïve subjects for pharmacokinetics and efficacy.

 

Keywords: Pharmacokinetics; Saquinavir; Atazanavir