Steady-State pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients.
BACKGROUND
In vitro synergy and complementary resistance profiles provide a strong rationale for combining fosamprenavir with saquinavir as part of a potent double-boosted protease inhibitor regimen. This study evaluated the steady-state pharmacokinetics of saquinavir 1000 mg twice daily (bid) and fosamprenavir 700 mg bid administered with 2 different doses of ritonavir (100 and 200 mg bid) in HIV-1-infected subjects.


METHODS
On day 1, 12-hour pharmacokinetic profiles for saquinavir/ritonavir (1000/100 mg bid) were obtained for 18 subjects. All subjects were receiving ongoing treatment with a saquinavir/ritonavir-containing regimen. Fosamprenavir 700 mg bid was then added to the regimen, and pharmacokinetic sampling was repeated for all 3 agents at day 11. The ritonavir daily dose was then increased to 200 mg bid, and a 3rd pharmacokinetic profile was obtained at day 22.


RESULTS
The coadministration of fosamprenavir 700 mg bid with saquinavir/ritonavir 1000/100 mg bid resulted in a statistically nonsignificant decrease in saquinavir concentrations (by 14, 9, and 24%, for saquinavir area under the concentration-time curve [AUC]0-12, C(max), and C(trough), respectively). This was compensated for by an increased ritonavir dose of 200 mg bid, which resulted in a statistically nonsignificant increase in saquinavir exposure compared with baseline. Amprenavir levels did not appear to be significantly influenced by coadministration of saquinavir with fosamprenavir. Fosamprenavir significantly reduced ritonavir exposure, but the increased ritonavir dose compensated for this interaction.


CONCLUSIONS
Our findings showed that saquinavir/ritonavir/fosamprenavir was well tolerated over the study period. Saquinavir plasma concentrations were slightly lowered by the addition of fosamprenavir to the regimen. However, the addition of a further 100 mg ritonavir bid restored the small and insignificant decrease.
PK Research Ltd., St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK. marta.boffito@chelwest.nhs.uk
Marta
M
Boffito
Laura
L
Dickinson
Andrew
A
Hill
David
D
Back
Graeme
G
Moyle
Mark
M
Nelson
Chris
C
Higgs
Carl
C
Fletcher
Brian
B
Gazzard
Anton
A
Pozniak
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002219:Carbamates; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005663:Furans; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010755:Organophosphates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019258:Saquinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019562:Viral Load
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D010755:Organophosphates; D012367:RNA, Viral; D013449:Sulfonamides; D019258:Saquinavir; D019438:Ritonavir; C426859:fosamprenavir