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QTc Interval Analyses of Vicriviroc (SCH 417690), a Novel CCR5 Inhibitor
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Reported by Jules Levin
ICAAC Dec 17, 2005 Wash DC
A. Sansone, M. Kraan, and J. Long
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
ABSTRACT
Background: Prolongation of cardiac repolarization occurred with the first-generation CCR5 entry inhibitor SCH 351125. The novel, structurally distinct, second-generation CCR5 antagonist vicriviroc (VVC, formerly SCH 417690) has demonstrated potent antiviral activity with no evidence of adverse cardiac effects. Electrocardiograms (ECGs) from early phase 1 studies were pooled to examine the effect of vicriviroc on QTc interval in healthy and HIV-infected subjects.
Methods: Multiple time-matched ECGs were recorded periodically (0-24 h) after dosing on Days 1, 3, and 5 (singledose studies, 10-150 mg) and on Days 1, 7, 8, and 14 (multiple-dose studies, 10-50 mg BID). All ECGs were over-read by a blinded third party. Time-matched differences on postbaseline days for QTcF were determined as the primary parameter for each subject at each time point relative to baseline (Day -1). Mean values for the differences were tabulated by treatment group and 95% confidence intervals (CI) were calculated for each mean difference.
Results: A total of 190 subjects were included in the analysis (healthy, n=143; HIV-infected, n=47). No subject receiving vicriviroc had a QTcF interval 3500 ms.
Conclusions: These data show that observed changes in the QTc intervals were similar between placebo- and vicriviroctreated subjects and there was no dose-related effect on QTc interval, indicating that vicriviroc does not demonstrate a trend for prolonging cardiac repolarization in healthy or HIV-infected subjects.
Introduction
Vicriviroc is a novel anti-HIV drug that exerts its effect by preventing entry of HIV into the host cell by means of preventing attachment to the CCR5 coreceptor. Since the discovery of the role of the CCR5 chemokine receptor in the process of viral entry, small molecule antagonists of CCR5 have been sought as potential antiretroviral agents. Vicriviroc has demonstrated potent antiviral effects in vitro and as monotherapy in a 14-day study in HIV-infected individuals. In an extensive early development program involving over 400 subjects, vicriviroc has been well tolerated, without apparent dose-limiting toxicities. Prior to conducting a formal definitive ECG study, multiple time matched ECGs were evaluated in the early vicriviroc studies to look for a safety signal. A pooled analysis of ECG data from 7 Phase 1 studies was conducted.
Study Objectives
- Explore changes in QTc interval related to vicriviroc administration compared to baseline
- Correlate ECG findings with vicriviroc dose
- Compare with findings in placebo recipients
METHODS
- Seven Phase 1 studies with multiple time matched ECGs were pooled for the analysis
- ECGs were recorded at specified times after oral doses of vicriviroc ( Table 1)
- Recorded on Days 1, 3, & 5 after single dose (SD)
- Recorded on Days 1, 7, 8, & 14 during multiple dose studies
- All time-matched ECGs were centrally read by a blinded, external, third party, and evaluated individually by study
- In the analysis of each study, the absolute QT interval, QTc interval (Fridericia), PR, RR, QRS, and ventricular rate, including changes from baseline,were listed and summarized using descriptive statistics. The primary pharmacodynamic endpoint for each analysis was the QTc interval change from baseline. Both the Bazett (QTc[B]) and Fridericia (QTc[F]) correction methods were used in each analysis; however, only the QT correction using the Fridericia calculation will be presented in this summary.
- The mean time-matched QTc interval change corrected by the Fridericia formula (QTcF) was calculated over a 12- hour interval individually and then for the each treatment group. For each subject, the difference between each
individual time-matched ECG after dosing relative to Day -1 was calculated. Then, the mean of the time-matched QTc(F) differences was determined for each subject. Summary statistics (mean, median, maximum, and minimum) with 95% Confidence intervals were calculated for the mean QTc(F) change from baseline for each treatment group.
Study population
- 190 subjects
- 143 uninfected volunteers
- 47 HIV infected individuals
- Age: mean 31.6 years (range: 18-64)
- Gender: 149 males; 41 females
- Concomitant medications excluded
- 163 ECGs profiles on vicriviroc; 50 ECGs profiles on placebo
RESULTS
- No dose-related clinical adverse effects
- No cardiac adverse events
- No clinically relevant ECG rhythm changes
- No QTc intervals > 500 msec
Author Conclusions
- Changes observed in time-matched ECGs were similar in vicriviroc and placebo
groups
- No dose-related QTc interval prolongation observed
- No clinically relevant changes in cardiac repolarization or rhythm
- No evidence of QTc prolongaton by vicriviroc was observed in early clinical
studies of HIV infected and uninfected volunteers in single or multiple dose
studies
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