Safety and Pharmacokinetics of Once-Daily Regimens of Soft-Gel Capsule Saquinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Negative Adults

doi:10.1128/AAC.44.10.2672-2678.2000

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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 antiretroviraltreatment regimens (HAART). Previous studies demonstrated thatcombined therapy with ritonavir and saquinavir allows a decreasein frequency of saquinavir dosing to twice daily. In this study,we evaluated the safety and pharmacokinetics of combining once-dailydoses of the soft-gel capsule (SGC) formulation of saquinavir(saquinavir-SGC) and minidose ritonavir. Forty-four healthy HIV-negativevolunteers were randomized into groups receiving once-daily dosesof saquinavir-SGC (1,200 to 1,800 mg) plus ritonavir (100 to 200mg) or a control group receiving only saquinavir-SGC (1,200 mg)three times daily. Saquinavir-SGC alone and saquinavir-SGC-ritonavircombinations were generally well tolerated, and there were nosafety concerns. Addition of ritonavir (100 mg) to saquinavir-SGC(1,200 to 1,800 mg/day) increased the area under the concentration-timecurve (AUC) for saquinavir severalfold, and the intersubject peakconcentration in plasma and AUC variability were reduced comparedto those achieved with saquinavir-SGC alone (3,600 mg/day), whiletrough saquinavir levels (24 h post-dose) were substantially higherthan the 90% inhibitory concentration calculated from HIV-1 clinicalisolates. Neither increasing the saquinavir-SGC dose to higherthan 1,600 mg nor increasing ritonavir from 100 to 200 mg appearedto further enhance the AUC. These results suggest that an allonce-daily HAART regimen, utilizing saquinavir-SGC plus a moretolerable low dose of ritonavir, may be feasible. Studies of once-dailysaquinavir-SGC (1,600 mg) in combination with ritonavir (100 mg)in HIV-infected patients areunderway.

^* 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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