Thorough QT/QTc Study of Ritonavir‐Boosted Saquinavir Following Multiple‐Dose Administration of Therapeutic and Supratherapeutic Doses in Healthy Participants

Abstract

The effect of saquinavir-boosted ritonavir at therapeutic (1000/100 mg twice daily [bid]) and supratherapeutic (1500/100 mg bid) doses was evaluated in a double-blind, placebo- and positive-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT/QTc study. Least squares mean estimated study-specific QTc (QTcS) change from dense predose baseline (ddQTcS(dense)) was the primary endpoint. Greatest mean increase in ddQTcS(dense) occurred 12 hours postdose for the 1000/100-mg group (18.9 ms) and 20 hours for the 1500/10-mg group (30.2 ms). The upper 1-sided 95% confidence interval was >20 ms from 2 to 20 hours postdose in both groups. ddQTcB(dense) and ddQTcF(dense) were similar to ddQTcS(dense). No QTcS, QTcF, or QTcB measurements were >500 ms. One participant receiving 1000/100 mg and 3 receiving 1500/100 mg had a maximum ddQTcS(dense) >60 ms. More participants with ≥1 adverse event received saquinavir/ritonavir. PubMed search and Roche postmarketing data did not reveal publications or reports directly presenting the effect of saquinavir on QT/QTc or causing torsade de pointes.

Antiretroviral Therapy

“…Saquinavir was shown to cause PR interval and QT prolongation in a dose dependent manner in a healthy volunteer study. 46,47 Cases of torsades de pointes have been reported. Patients with structural heart disease, pre-existing conduction abnormalities, and ischemic heart disease are at an increased risk of cardiac conduction abnormalities.…”

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

“…Blood samples (3 mL) for measurements of plasma saquinavir and ritonavir concentrations were collected from all patients predose and at 2, 4, 6, 8, and 12 h postdose on days 3, 4, 7, 10, and 14, and analyzed using validated liquid chromatography with tandem mass spectrometry detection methods (range 50.0–10,000 ng/mL) as described previously [5]. For saquinavir, assay precision based on the quality control samples ranged from ±4.6 to 7.4 % while accuracy ranged from −0.7 to 2.1 %.…”

“…The dense predose baseline was defined as the average of the three triplicate measurements (nine measurements overall collected at 1, 0.75, and 0.5 h predose on day 1). This is identical to the dense predose baseline measurement as defined in the previous QT study of saquinavir in healthy volunteers [5]. Maximum ∆QTcF dense was described using summary statistics.…”

“…Despite this apparent uncertainty, the results of a previous TQT study in healthy subjects demonstrated significant dose-dependent QT and PR interval prolongation with therapeutic and supratherapeutic doses of saquinavir/ritonavir 1000/100 mg BID and 1500/100 mg BID, respectively [5]. In response to the findings of the TQT study and risk of significant QT prolongation in the first week of treatment with saquinavir/ritonavir 1000/100 mg BID, the recommended dosing regimen for treatment-naïve patients initiating ritonavir-boosted saquinavir therapy was amended in 2011 by the European Medicines Agency.…”

Initiation of antiretroviral therapy at high CD4 cell counts

“…These observations have sparked renewed interest in pro-arrhythmic effects of PIs. The FDA warns that ritonovir boosted lopinavir(97) and saquinavir(98, 99) may be associated with prolongation of the QT interval and elevated risk of polymorphic ventricular tachycardia; however, PI use had minimal effect on the QT interval in SMART after adjusting for race(100). Atazanavir has been associated with a lower risk of QT prolongation, adding further evidence of its favorable CVD risk profile(101).…”