Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

Abstract

We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/l, and the median VL was 4.8 log 10 copies/ml. Median C max , area under the concentration-time curve from 0 to 24 h, and C min plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng ⅐ h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate C min levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.

Cellular Accumulation of Cholyl-Glycylamido-Fluorescein in Sandwich-Cultured Rat Hepatocytes: Kinetic Characterization, Transport Mechanisms, and Effect of Human Immunodeficiency Virus Protease Inhibitors

“…Furthermore, as shown by the data presented in Table 1, the use of day 1 versus day 4 SCRHs appears to offer the advantage of higher CGamF accumulation. A similar phenomenon was observed by Hoffmaster et al Williams and Sinko, 1999;Hoetelmans et al, 2003;Swainston Harrison and Scott, 2005;Marin-Niebla et al, 2007;Ruane et al, 2007. a E max Ϫ E 0 represents the difference between calculated maximum uptake rate (at very low inhibitor concentration) and calculated uptake at maximum extent of inhibition by the specific PI. The results obtained in the present study demonstrate a remarkable difference between CGamF and TC with respect to the transport mechanisms that are primarily mediating hepatic uptake of these substrates (for a schematic summary, see also Fig.…”

Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1

“…As illustrated in Figure 6, the low affinity of digoxin for the OATP2B1 isoform was confirmed with no effect on E3S accumulation. In contrast, the less specific and/or more potent (Williams and Sinko, 1999;Hoetelmans R, 2003;Perry et al, 2005;Swainston Harrison and Scott, 2005;Marin-Niebla et al, 2007;Ruane et al, 2007;Chandwani and Shuter, 2008) **: due to solubility limitations, nelfinavir could only be tested up to a concentration of 20 !M …”

Toxicity of HIV protease inhibitors: clinical considerations

“…Manosuthi et al [6] and Marin-Niebla et al [7] demonstrated that switching to a once-daily boosted saquinavircontaining regimen is well tolerated and does not increase the number of adverse events. However, this switching is not an option for patients receiving rifampicin, as saquinavir plasma levels are significantly lowered [8].…”