Pharmacokinetics of Once-Daily Saquinavir Hard-Gelatin Capsules and Saquinavir Soft-Gelatin Capsules Boosted With Ritonavir in HIV-1-Infected Subjects

Peter G. Cardiello, Tarkika Monhaphol, Apicha Mahanontharit, Rolf P. van Heeswijk, David Burger, Andrew Hill, Kiat Ruxrungtham, Joep M. Lange, David A. Cooper, Praphan Phanuphak


J Acquir Immune Defic Syndr. 2003;32(3) 

In This Article

Abstract and Introduction

Objective: To investigate the pharmacokinetics of once-daily saquinavir (SQV) hard-gelatin capsule (HGC)/ritonavir (RTV), 1600/100 mg, compared with once-daily SQV soft-gelatin capsule (SGC)/RTV, 1600/100 mg.
Methods: We evaluated 13 randomly selected HIV-1-infected subjects taking once-daily SQV SGC/RTV, 1600/100 mg, plus dual nucleoside reverse transcriptase inhibitors (NRTIs) in this pharmacokinetic (PK) substudy. Subjects took 1 week of SQV HGC/RTV and NRTIs, followed by steady-state SQV PK determinations. Subjects then changed to SQV SGC/RTV and NRTIs for 1 week, followed again by steady-state SQV PK determinations. Area under the plasma concentration versus time curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin), time to Cmax, and elimination half-life were calculated.
Results: There was no significant difference in AUC values between HGCs and SGCs, with a median (plus interquartile range [IQR]) of 50.0 (42.6-71.5) versus 35.5 (28.0-50.2) mg/L/h, respectively (p = .056). Intersubject variability resulted in 4 of 13 subjects on the SQV SGCs and 2 of 13 subjects on the SQV HGCs having a Cmin below the minimum effective concentration of 0.05 mg/L.
Conclusion: Once-daily SQV HGCs, 1600 mg, boosted with once-daily RTV, 100 mg, resulted in PK parameters that were similar to those observed with 1600 mg of SQV SGC/100 mg RTV once daily. Once-daily SQV HGC/RTV, 1600/100 mg, may be easier to use in developing countries and may increase access where drug costs can be less, the capsule size is smaller, and the need for refrigeration is lessened.

Although the use of saquinavir (SQV) along with other antiretroviral drugs to manage the effects of HIV infection has proved to be highly effective, the original formulation of SQV as a hard-gelatin capsule (HGC, Invirase) had limited bioavailability when used as the sole protease inhibitor.[1] Subsequent development of the soft-gelatin capsule (SGC, Fortovase) formulation increased bioavailability, mainly by the addition of the glyceride capmul, which improved the dissolution of the active drug in the small intestine.[2,3]

Ritonavir (RTV) has been shown to boost the levels of SQV by several processes.[4,5,6] Although there has been pharmacokinetic (PK) research on using once-daily SQV SGC at a dose of 1600 mg boosted with once-daily RTV at a dose of 100 mg, the data on the steady-state PK of 1600 mg of SQV HGC boosted with 100 mg of RTV once daily are lacking.[7,8]

Disadvantages with the SQV SGC compound are the requirement for refrigeration, larger pill size, and increased gastrointestinal disturbance possibly caused by capmul in the formulation.[9] Although most subjects taking SQV are using the SGC formulation, subjects in the developing world could still potentially benefit from the use of the HGC formulation, which is stable at room temperature and has a lower cost. These characteristics make SQV HGC a more convenient and accessible medication with possible increased tolerability. We report on the PK of once-daily SQV SGC/RTV, 1600/100 mg, compared with once-daily SQV HGC/RTV, 1600/100 mg, both in combination with dual nucleoside reverse transcriptase inhibitors (NRTIs).