Effects of Temsavir, Active Moiety of Antiretroviral Agent Fostemsavir, on QT Interval: Results From a Phase I Study and an Exposure-Response Analysis

Chakradhar Lagishetty, Katy Moore, Peter Ackerman, Cyril Llamoso, Mindy Magee, Chakradhar Lagishetty, Katy Moore, Peter Ackerman, Cyril Llamoso, Mindy Magee

Abstract

Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure-response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200 mg b.i.d. did not result in a clinically meaningful change from placebo in baseline-adjusted Fridericia-corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg b.i.d., the upper bound of the two-sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2-fold higher than the geometric mean TMR peak plasma concentration (Cmax ) of 1,770 ng/mL in heavily treatment-experienced HIV-1 infected patients administered fostemsavir 600 mg b.i.d. in the phase III BRIGHTE study (NCT02362503).

Conflict of interest statement

All authors are employees of ViiV Healthcare (K.M., P.A., and C.L.) or GlaxoSmithKline (C.L. and M.M.).

© 2020 ViiV Healthcare/GlaxoSmithKline. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
The ddQTcF over time for fostemsavir 1,200 mg q.d., fostemsavir 2,400 mg b.i.d., and moxifloxacin. CI, confidence interval; ddQTcF, difference vs. placebo for change from baseline in Fridericia‐corrected QT interval; FTR, fostemsavir; MOX, moxifloxacin.
Figure 2
Figure 2
Scatterplot of ddQTcF vs. temsavir plasma concentrations for all measurements in subjects receiving fostemsavir 1,200 mg q.d. or 2,400 mg b.i.d. ddQTcF, difference vs. placebo for change from baseline in Fridericia‐corrected QT interval; TMR, temsavir.
Figure 3
Figure 3
Visual predictive check of final model. Circles are observed data; lines are median, 5th, and 95th percentiles of simulated data; shaded area is the 90% CI of simulated data. CI, confidence interval; ddQTcF, difference vs. placebo for change from baseline in Fridericia‐corrected QT interval; TMR, temsavir.
Figure 4
Figure 4
Model‐simulated effect on ddQTcF at increasing temsavir plasma concentrations. Solid line and shaded region represent model‐predicted mean ddQTcF and 90% CI as a function of plasma concentration. Horizontal line with tick marks shows range of concentrations divided into deciles. Circles and vertical bars denote observed means and 90% CIs for ddQTcF with each concentration decile. CI, confidence interval; ddQTcF, difference vs. placebo for change from baseline in Fridericia‐corrected QT interval; TMR, temsavir.

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