Saquinavir soft-gel capsules (Fortovase®) give lower exposure than expected, even after a high-fat breakfast
- 82 Downloads
Background: The soft-gel capsule (sgc) of saquinavir has been developed in order to improve the poor oral bioavailability of the original hard-gel capsules. However, in a Dutch study population using saquinavir-sgc plasma levels were lower than expected. We hypothesised that this was caused by differences in the amount of fat in the meals of the study populations. Methods: 8-h steady-state plasma curves after observed ingestion of 1200 mg saquinavir-sgc were recorded, concomitantly with a normal breakfast (600 kcal, 33% fat) on the first day, and a high-fat breakfast (1040 kcal, 54% fat) on the second day. Additionally, a comparison was made between saquinavir hard-gel capsules and saquinavir-sgc with or without grapefruit juice (n=1). Furthermore, a comparison between saquinavir-sgc and ritonavir+saquinavir-sgc 400/400 mg bid was made (n=1). Results: Although saquinavir exposure was improved by fat, grapefruit juice or ritonavir, exposure to saquinavir for all recorded curves was lower than expected. A large proportion of trough concentrations was below the efficacy threshold.Conclusion: Intake of saquinavir-sgc with high-fat meals or grapefruit juice may improve the pharmacokinetic profile. However, plasma concentrations may then still be lower than expected and insufficient for good antiviral efficacy. Probably the only way to reach adequate saquinavir concentrations is by combining saquinavir with ritonavir.
Unable to display preview. Download preview PDF.
- 1.Vanhove GF, Gries J-M, Verotta D, Sheiner LB, Coombs R, Collier AC, Blaschke TF. Exposure-response relationships for saquinavir, zidovudine, and zalcitabine in combination therapy. Antimicrob agents chemother 1997;41:2433–8.Google Scholar
- 2.Vella S, Floridia M. Saquinavir-Clinical pharmacology and efficacy. DRUGS 1998;34:189–201.Google Scholar
- 3.F.Hoffmann-La Roche Ltd, Basel, Switzerland. FortovaseR (Saquinavir), Product monograph 1998.Google Scholar
- 4.Hoetelmans RMW. Clinical pharmacology of antiretroviral drugs [Dissertation]. Utrecht: R.M.W. Hoetelmans; 1998. ISBN 90-393-1608-2Google Scholar
- 5.Hugen PWH, Verwey-van Wissen CPWGM, Burger DM, Wuis EW, Koopmans PP, Hekster YA. Simultaneous determination of the HIV-protease inhibitors indinavir, nelfinavir, saquinavir and ritonavir in human plasma by reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 1999;727:139–49.Google Scholar
- 6.Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998;101:289–94.Google Scholar
- 7.Varav H, Holtzer CD. Simultaneous use of two protease inhibitors in HIV infection. American Journal Health-Syst Pharm 1999;56:273–6.Google Scholar
- 8.Kupferschmidt HHT, Fattinger KE, Ha HR, Follath F, Krahenbuhl S. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br Journal Clin Pharmacol 1998; 45:355–9.Google Scholar
- 9.Cameron DW, Japour AJ, Xu Y, Hsu A, Mellors J, Farthing C et al. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 1998;13:213–24.Google Scholar
- 10.Carpenter CJ, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hammer SM et al. Antiretroviral therapy in adults-Updated recommendations of the International AIDS Society-USA Panel. JAMA 2000;283:381–90Google Scholar