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Session 86 Poster Abstracts
Pharmacology of Protease Inhibitors
Tuesday, 1:30 - 3:30 pm
Poster Hall


607
Atazanavir Enhances Saquinavir Hard Gel Concentrations in a Ritonavir-Boosted Once Daily Regimen.
M Boffito*1, M Kurowski2, G Kruse2, A Hill3, M Nelson1, G Moyle1, A Benzie1, C Higgs1, C Fletcher1, I Hitchcock4, B Gazzard1, and A Pozniak1
1Chelsea and Westminster Hosp., London, UK; 2Therapia GmbH, Berlin, Germany; 3Roche, Welwyn, UK; and 4Bristol-Myers Squibb Co., London, UK

Background:  Atazanavir (ATV) and ritonavir (RTV) have both shown boosting effects on saquinavir (SQV); it is unknown whether the boosting mechanisms are overlapping or independent. Multiple PI combinations might increase PI efficacy and overcome PI resistance. The aim of this study was to investigate the pharmacokinetics of SQV/RTV/ATV 1600/100/300 mg once daily.

Methods:  To 20 HIV+ patients (2 females; mean age 41 years; median CD4 442 cells/mm3) we administered SQV/RTV 1600/100 mg once daily with a 20-g fat meal. On day 2, ATV 300 mg once daily was added to the regimen for 30 days. Safety analysis was performed at screening, D1, 11, 31, and follow-up. One day before and 11 days after addition of ATV, blood was drawn pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose for pharmacokinetics analysis. Geometric mean ratios and 95%CI were used to compare SQV pharmacokinetics parameters measured without and with ATV. SQV/RTV/ATV concentrations were measured by HPLC-MS/MS.

Results:  No significant changes in ALT, AST, glucose, total cholesterol and triglycerides were observed, whereas total and indirect bilirubin increased by 5 times after 10 days of ATV therapy (median, range: 36, 11-139, and 32, 9-128 mmol/L, respectively). Four patients developed scleral icterus and 2 jaundice. SQV and ATV pharmacokinetics data are summarized in the table below. A statistically significant increase in SQV Ctrough (geometric mean ratios, 95%CI: 2.12, 1.72 to 3.50), Cmax (1.42, 1.24 to 1.94) and AUC (1.60, 1.35 to 2.43) was observed. ATV concentrations were in accordance with the ATV concentrations observed in pts with ATV/RTV.

 

SQV and ATV Pharmacokinetic data.

 

Parameter

SQV (+ RTV)

Geom mean (95% CI)

SQV (+ATV/RTV)

Geom mean (95% CI)

ATV (+SQV/RTV)

Geom mean (95% CI)

Ctrough (ng/mL)      

87 (71.9-138.8)

184 (140.3-311.3)

767 (577.2-1426.8)

Cmax (ng/mL)            

2756 (2218.9-4551.2)

3923 (333.4-5349.9)

4982 (4432.3-6235.4)

AUC0-24 (ng.h/mL)

18270 (14951-30357)

29445 (24986-40348)

51036 (44369-64591)

Ctrough=trough concentration; Cmax=maximum concentration; AUC=area under concentration-time curve.

 

Conclusions:  Addition of ATV to SQV/RTV increased SQV AUC, Cmax and Ctrough by 60%, 42% and 112% respectively (p <0.05). RTV and ATV may have independent mechanisms of boosting SQV and other CYP3A4 substrates. 

 

 

Keywords: pharmacokinetics; saquinavir; atazanavir