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.
BACKGROUND
Saquinavir/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.


OBJECTIVE
To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients.


METHODS
Twenty-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.


RESULTS
The 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.


CONCLUSIONS
Treatment 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.
Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
Marta
M
Boffito
Akil
A
Jackson
Anton
A
Pozniak
Mylene
M
Giraudon
Rohit
R
Kulkarni
Maria Connie
MC
Abelardo
Indravadan H
IH
Patel
Peter N
PN
Morcos
D000328:Adult; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015497:HIV-1; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000453:epidemiology; D008297:Male; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019258:Saquinavir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019258:Saquinavir; D019438:Ritonavir