Boosted saquinavir hard gel formulation exposure in HIV-infected subjects: ritonavir 100 mg once daily versus twice daily
Marta BoffitoDesmond MaitlandLaura DickinsonDavid BackAndrew HillCarl FletcherGraeme MoyleMark NelsonBrian GazzardAnton Pozniak
9
Citation
15
Reference
10
Related Paper
Abstract:
The amount of ritonavir needed to enhance saquinavir hard gel (hg) plasma concentrations is unclear. Reduced ritonavir dosing may help to reduce ritonavir-related side effects and costs. This study examined the pharmacokinetics of twice-daily saquinavir-hg (1000 mg) in the presence of ritonavir 100 mg, dosed twice-daily and once-daily on one single occasion.Eighteen HIV-infected adults taking saquinavir/ritonavir 1000/100 mg twice-daily underwent pharmacokinetic (PK) assessment of saquinavir/ritonavir on day 1 following a morning saquinavir/ritonavir dose. On day 2, PK assessment was repeated when subjects took saquinavir without ritonavir. Drug intake (with a standard meal containing 20 g of fat) was timed on days -1, 1 and 2. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were calculated to assess changes in saquinavir PK parameters.Geometric mean saquinavir AUC(0-12), C(trough), C(max) and elimination half-life on days 1 and 2 were 14 389 and 9590 ng.h/mL, 331 and 234 ng/mL, 2503 and 1893 ng/mL and 2.80 and 2.82 h, respectively. The GMR (95% CI) for these parameters were 0.67 (0.53-0.84), 0.71 (0.48-1.04), 0.76 (0.58-0.98) and 1.01 (0.86-1.18), respectively.Withholding a ritonavir dose significantly reduces overall saquinavir exposure and C(max), but had no impact on the elimination half-life. These data establish the need to administer saquinavir and ritonavir simultaneously.Keywords:
Saquinavir
Ritonavir
Objectives: To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients.
Saquinavir
Atazanavir
Ritonavir
Protease inhibitor (pharmacology)
Cite
Citations (35)
Currently, the optimal boosting dose for saquinavir is unknown. Therefore, we evaluated the pharmacokinetics profiles in a cross over setting comparing saquinavir/ritonavir 1500/50 mg (plus NRTI backbone) to saquinavir/ritonavir 1500/100 mg in the same HIV-infected, Thai individuals. The 50% reduction of ritonavir boosting did not result in a change in the pharmacokinetics of saquinavir, whereas the ritonavir exposure was significantly lower when a dose of 50 mg was administered.
Saquinavir
Ritonavir
Boosting
Cite
Citations (9)
Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.
Ritonavir
Protease inhibitor (pharmacology)
Cite
Citations (417)
The low oral bioavailability of the HIV protease inhibitor (HPI) saquinavir is dramatically increased by coadministration of the HPI ritonavir. Because saquinavir and ritonavir are substrates and inhibitors of both the drug transporter P-glycoprotein (P-gp) and of the metabolizing enzyme CYP3A4, we wanted to sort out whether the ritonavir effect is primarily mediated by inhibition of CYP3A4 or P-gp or both. P-gp is known to limit the bioavailability, brain, testis, and fetal penetration of its substrates, so effective inhibition of P-gp by ritonavir in vivo might open up pharmacological sanctuary sites for saquinavir, with the potential of beneficial effects on therapy, but also of increased toxicity. In vitro, P-gp-mediated transport of saquinavir and ritonavir was only moderately inhibited by both HPIs compared with the potent P-gp inhibitor PSC833. When [14C]saquinavir was orally coadministered with a maximum tolerated dose of ritonavir to wild-type and P-gp-deficient mice, saquinavir bioavailability was dramatically increased in both strains, but P-gp still limited the oral bioavailability of saquinavir, and its penetration into brain and fetus. These data indicate that in vivo, ritonavir is a relatively poor P-gp inhibitor. The highly increased bioavailability of saquinavir because of ritonavir coadministration most likely results from reduced saquinavir metabolism. Importantly, our data indicate that it is unlikely that ritonavir coadministration will substantially affect the contribution of P-gp to pharmacological sanctuary sites such as brain, testis, and fetus. Thus, if one wanted to effectively open these sites for therapeutic purposes, more efficient P-gp inhibitors should be applied.
Saquinavir
Ritonavir
P-glycoprotein
Protease inhibitor (pharmacology)
Cite
Citations (171)
The effect of fluconazole on ritonavir and saquinavir pharmacokinetics in HIV‐1‐infected individuals
Aims To study the effect of fluconazole on the steady‐state pharmacokinetics of the protease inhibitors ritonavir and saquinavir in HIV‐1‐infected patients. Methods Five subjects treated with saquinavir and three with ritonavir received the protease inhibitor alone (saquinavir 1200 mg three times daily, ritonavir 600 mg twice daily) on day 1, and the same protease inhibitor in combination with fluconazole (400 mg on day 2 and 200 mg on days 3 to 8). Pharmacokinetic parameters were determined on days 1 and 8. Results In the saquinavir group, the median increase in the area under the plasma concentration vs time curve was 50% from 1800 µg l −1 h to 2700 µg l −1 h ( P = 0.04, median increase: 900 µg l −1 h; 2.5 and 97.5 percentile: 500–1300), and 56% for the peak concentration in plasma (from 550 to 870 µg l −1 , P = 0.04; median increase: 320 µg l −1 h, 2.5 and 97.5 percentile: 60–450 µg l −1 ). In the ritonavir group, there were no detectable changes in the pharmacokinetic parameters on addition of fluconazole. Conclusions Because of the favourable safety profile of saquinavir, dose adjustments are probably not necessary with concomitant use of fluconazole, as is the case for ritonavir.
Saquinavir
Ritonavir
Protease inhibitor (pharmacology)
Cite
Citations (31)
Saquinavir
Indinavir
Ritonavir
Protease inhibitor (pharmacology)
Cite
Citations (51)
To explore whether steady-state plasma pharmacokinetics of ritonavir and saquinavir change during long-term treatment in HIV-1-infected patients on antiretroviral treatment including ritonavir and saquinavir.The pharmacokinetics of ritonavir and saquinavir were assessed during an 8-h period on two occasions in six HIV-1 infected patients on stable twice daily treatment with ritonavir 400 mg, saquinavir 400 mg and stavudine 40 mg with or without lamivudine 150 mg twice daily.The first study day was 4-12 months (median 7 months) after the start of the current regimen. The second study day was 9-15 months (median 10 months) later. No significant differences were observed for the ritonavir pharmacokinetics between the first and second study day. However, median change in plasma trough level of saquinavir between the two study days was -30% (range -79 to +11%; P = 0.06). Median change in maximum plasma concentration was -40% (range -62 to +34%; P = 0.09). The median change in area under the plasma concentration versus time curve over 0-8 h was -33% (range -53 to +21%; P = 0.06).The exposure to saquinavir decreased over time in HIV-infected patients on stable antiretroviral therapy. These data suggest that regular monitoring of plasma drug concentrations should become part of routine patient care even in apparently compliant patients.
Saquinavir
Ritonavir
Regimen
Stavudine
Cite
Citations (41)
The pharmacokinetics and short-term safety of atazanavir 150 and 200 mg, when coadministered with saquinavir/ritonavir 1600/100 mg once daily, were evaluated. On day 1, atazanavir 150 mg once daily, was added to saquinavir/ritonavir regimens and sampling was performed to evaluate saquinavir, ritonavir, and atazanavir pharmacokinetics (day 11). Atazanavir was increased to 200 mg and pharmacokinetic assessment repeated (day 30). Geometric mean ratios (GMR) and 95% confidence intervals (CI) were used to compare saquinavir, ritonavir, and atazanavir pharmacokinetic parameters in the present study and for 14 of the subjects treated with saquinavir/ritonavir 1600/100 mg once daily without and with atazanavir 300 mg who participated in a previous trial. Geometric mean (GM) saquinavir AUC0–24, Ctrough, and Cmax were 30,589 and 32,312 ng · h/ml, 166 and 182 ng/ml, and 4267 and 4261 ng/ml when coadministered with atazanavir 150 and 200 mg (n = 18). On days 11 and 30, saquinavir and atazanavir Ctrough remained >100 ng/ml in 13/18, 14/18, 18/18, and 17/18 patients. Among the above mentioned 14 subjects, significant increases in saquinavir Ctrough (87%, 92%, 99%), Cmax (40%, 55%, 44%), and AUC0–24 (51%, 60%, 63%) were observed with atazanavir 300, 150, and 200 mg. Ritonavir AUC0–24 and Cmax were significantly increased with the addition of atazanavir 300 mg only. Atazanavir enhances saquinavir and ritonavir by a mechanism that requires elucidation. While saquinavir enhancement was apparently independent of atazanavir dose, atazanavir 300 mg produced an increase in ritonavir Cmax, which is not observed with lower atazanavir doses. Atazanavir-related hyperbilirubinemia was dose dependent. However, higher saquinavir and atazanavir exposure may be required to suppress HIV-resistant strain replication.
Atazanavir
Saquinavir
Ritonavir
Bioequivalence
Cmin
Cite
Citations (18)
To assess the pharmacokinetic interaction between ritonavir and saquinavir.Ritonavir and saquinavir were administered in single doses to six groups of healthy volunteers in a two-way (saquinavir alone and ritonavir plus saquinavir for groups I through V) and a three-way (ritonavir alone, saquinavir alone, and ritonavir plus saquinavir for group VI) crossover manner with the following doses: group I, 200 mg saquinavir and 300 mg ritonavir; group II, 200 mg saquinavir and 600 mg ritonavir; group III, 400 mg saquinavir and 300 mg ritonavir; group IV, 400 mg saquinavir and 600 mg ritonavir; group V; 600 mg saquinavir and 200 mg ritonavir; group VI, 600 mg saquinavir and 600 mg ritonavir.Coadministration of ritonavir markedly increased the area under the plasma concentration-time curve (AUC) and peak concentration of saquinavir (> 50-fold and 22-fold, respectively). For a constant ritonavir dose, the pharmacokinetics of saquinavir were relatively proportional to dose. For a constant saquinavir dose, the increase in saquinavir concentration tended to be less than proportional to ritonavir dose. Ritonavir reduced intersubject variability in the saquinavir AUC from 60% to 28%. The in vivo inhibition constant was 0.025 +/- 0.020 micrograms/ml with noncompartmental estimation and 0.0164 +/- 0.0004 micrograms/ml with nonlinear mixed-effects model compartmental analysis. Saquinavir showed no clinically significant effect on the pharmacokinetics of ritonavir (+6.4% in AUC). The regimens were well tolerated.The large effect of ritonavir on the pharmacokinetics of saquinavir is consistent with a large reduction of saquinavir first-pass metabolism and postabsorptive clearance. Given the limited bioavailability of saquinavir given in the hard gelatin capsule formulation, this drug interaction is expected to have implications in the use of protease inhibitors in the management of human immunodeficiency virus infection.
Saquinavir
Ritonavir
Protease inhibitor (pharmacology)
Cite
Citations (166)