Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients

Abstract

BackgroundSaquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations.ObjectiveTo explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients.MethodsTwenty-three HIV-1-infected treatment-naïve patients received saquinavir/ritonavir 500/100 mg BID on days 1–7 and 1000/100 mg BID on days 8–14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia’s formula (∆QTcFdense) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days.ResultsThe mean maximum ∆QTcFdense was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ∆QTcFdense ≥30 ms (on day 10); the highest mean ∆QTcFdense was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated.ConclusionTreatment initiation with the modified saquinavir/ritonavir regimen in treatment-naïve HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment.

N-Propargylamines: versatile building blocks in the construction of thiazole cores

“…Ritonavir (norvir), is an HIV protease inhibitor. It works by blocking the growth of HIV [ 8 – 9 ]. Tiazofurin is a C-nucleoside analogue with antineoplastic activity and acts by inhibition of the guanosine triphosphate (GTP) biosynthesis through a reduction of PI and PIP kinase activity [ 10 – 14 ] ( Fig.…”

The first case of HIV-2 in Scotland

“…Unfortunately, the patient developed a prolonged QTc interval on her ECG on saquinavir, increasing from 436 to 474 ms. This is a well described side effect of saquinavir and one reason why it no longer a first line PI in HIV-1 treatment [ 39 ]. The decision was taken to switch her PI from saquinavir to darunavir.…”

Current evidence for the risk of PR prolongation, QRS widening, QT prolongation, from lopinavir, ritonavir, atazanavir, and saquinavir

“…We obtained 5 studies which consist of 172 participants that reported about the risk of antivirals in changing QRS wave length (Table 3). [22,24,25,27,29] One study in HIV patients already treated with antiviral drugs reported treatment using ATV/r (300 mg/ 100 mg) could prolong QRS wave length in 2 hours after first dose and persisted after 1 month. [22] Another study in HIV patients treated with NRTI, reported that combination of daily ATV 300 mg, and twice daily LPV/r (400-800 mg/100-200 mg) for 12 to 20 days prolonged QRS wave statistically significant.…”