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Antimicrobial Agents and Chemotherapy, October 2000, p. 2672-2678, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Safety and Pharmacokinetics of Once-Daily Regimens of
Soft-Gel Capsule Saquinavir plus Minidose Ritonavir in Human
Immunodeficiency Virus-Negative Adults
J. Michael
Kilby,1
Greg
Sfakianos,1
Nick
Gizzi,2
Peggy
Siemon-Hryczyk,2
Eric
Ehrensing,1
Charles
Oo,2
Neil
Buss,3 and
Michael S.
Saag1,*
Division of Infectious Diseases, Department
of Medicine, University of Alabama at Birmingham, Birmingham,
Alabama1; Roche Laboratories, Nutley,
New Jersey2; and F. Hoffmann-La Roche,
Basel, Switzerland3
Received 20 December 1999/Returned for modification 16 April
2000/Accepted 20 July 2000
Human immunodeficiency virus type 1 (HIV-1) protease inhibitors
have dramatically improved treatment options for HIV infection, but
frequent dosing may impact adherence to highly active antiretroviral treatment regimens (HAART). Previous studies demonstrated that combined
therapy with ritonavir and saquinavir allows a decrease in frequency of
saquinavir dosing to twice daily. In this study, we evaluated the
safety and pharmacokinetics of combining once-daily doses of the
soft-gel capsule (SGC) formulation of saquinavir (saquinavir-SGC) and
minidose ritonavir. Forty-four healthy HIV-negative volunteers were
randomized into groups receiving once-daily doses of saquinavir-SGC
(1,200 to 1,800 mg) plus ritonavir (100 to 200 mg) or a control group
receiving only saquinavir-SGC (1,200 mg) three times daily.
Saquinavir-SGC alone and saquinavir-SGC-ritonavir combinations were
generally well tolerated, and there were no safety concerns. Addition
of ritonavir (100 mg) to saquinavir-SGC (1,200 to 1,800 mg/day)
increased the area under the concentration-time curve (AUC) for
saquinavir severalfold, and the intersubject peak concentration in
plasma and AUC variability were reduced compared to those achieved with
saquinavir-SGC alone (3,600 mg/day), while trough saquinavir levels (24 h post-dose) were substantially higher than the 90% inhibitory
concentration calculated from HIV-1 clinical isolates. Neither
increasing the saquinavir-SGC dose to higher than 1,600 mg nor
increasing ritonavir from 100 to 200 mg appeared to further enhance the
AUC. These results suggest that an all once-daily HAART regimen,
utilizing saquinavir-SGC plus a more tolerable low dose of ritonavir,
may be feasible. Studies of once-daily saquinavir-SGC (1,600 mg) in
combination with ritonavir (100 mg) in HIV-infected patients are underway.
*
Corresponding author. Mailing address: UAB 1917 Clinic,
908 20th Street South, Birmingham, AL 35294. Phone: (205) 934-7349. Fax: (205) 934-8490. E-mail: msaag{at}uab.edu.
Antimicrobial Agents and Chemotherapy, October 2000, p. 2672-2678, Vol. 44, No. 10
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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