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

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).

• Authors: Chakradhar Lagishetty, Katy Moore, Peter Ackerman, Cyril Llamoso, Mindy Magee
• Journal: Clinical and translational science (Clin Transl Sci) Vol. 13 Issue 4 Pg. 769-776 (07 2020) ISSN: 1752-8062 [Electronic] United States
• PMID: 32027457 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 ViiV Healthcare/GlaxoSmithKline. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Anti-HIV Agents
• Organophosphates
• Piperazines
• Prodrugs
• fostemsavir

Topics

• Adolescent
• Adult
• Anti-HIV Agents (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Drug Resistance, Multiple, Viral
• Drug Therapy, Combination
• Electrocardiography (drug effects)
• Female
• HIV Infections (drug therapy)
• HIV-1 (drug effects)
• Humans
• Long QT Syndrome (chemically induced, diagnosis)
• Male
• Middle Aged
• Organophosphates (administration & dosage, adverse effects)
• Piperazines (administration & dosage, adverse effects)
• Prodrugs (administration & dosage, adverse effects)
• Young Adult