Effects of the HIV-1 maturation inhibitor GSK3640254 on QT interval in healthy participants

Abstract

GSK3640254 (GSK'254) is a novel HIV-1 maturation inhibitor with pharmacokinetics supporting once-daily (QD) therapy for HIV-1 treatment. This thorough QT/corrected QT (QTc) study evaluated the effect of GSK'254 on cardiac repolarization. In this two-part, randomized study, healthy participants received GSK'254 or placebo QD for 7 days (part 1) to determine safety and pharmacokinetics of a 500-mg supratherapeutic dose. Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400-mg moxifloxacin dose on Day 7 (all with a moderate-fat meal). Concentration-QTc analyses modeled the relationship between GSK'254 plasma concentrations and placebo-adjusted change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF). Of 50 participants enrolled, 48 completed the study (part 1, 8/8; part 2, 40/42). Least-squares (LS) mean change from baseline in QTcF for GSK'254 100 mg followed the placebo pattern across time points (maximum LS mean ΔΔQTcF, 1.7 ms); the upper bound of the 90% CI remained <10 ms. Maximum LS mean ΔΔQTcF for GSK'254 500 mg exceeded the 10-ms threshold: 10.6 ms (90% CI 7.75-13.38). Neither GSK'254 dose had clinically relevant effects on heart rate or cardiac conduction. By concentration-QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL^-1 . No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100-mg dose.

Keywords: QT prolongation; antiretrovirals; drug safety; phase I.

FIGURE 1

Study design. Treatment T: potential therapeutic dose of GSK'254 100 mg QD. Treatment ST: supratherapeutic dose of GSK'254 500 mg QD. Treatment P: placebo QD. Treatment M: placebo QD on Days 1–6 and a single dose of moxifloxacin 400 mg on Day 7. GSK'254, GSK3640254; QD, once daily; QTc, corrected QT. ^aWashout was ≥7 days minus 4 h to allow for scheduling flexibility in the clinic.

FIGURE 2

Goodness‐of‐fit plot of the QTc model. The solid black line and gray shaded region denote the model‐predicted mean (90% CI) ΔΔQTcF, which is calculated from the equation ΔΔQTcF ≈ 0.61 + 0.0025 × GSK'254 concentration. The red filled circles with error bars denote the estimated mean ΔΔQTcF with 90% CI at the associated median plasma concentration within each GSK'254 concentration decile. The blue open circle with error bars denotes the mean ΔΔQTcF with 90% CI for placebo. The horizontal red line with notches shows the range of GSK'254 concentrations divided into deciles. The black dashed line denotes the 10‐ms threshold. QTc, corrected QT; ΔΔQTcF, placebo‐adjusted change from baseline in QT interval corrected using Fridericia's formula.

FIGURE 3

Model‐predicted ΔΔQTc interval at geometric mean GSK'254 concentrations associated with 100‐ and 500‐mg doses. The solid black line and gray shaded region denote the model‐predicted mean (90%) ΔΔQTcF, which is calculated from the equation ΔΔQTcF ≈ 0.61 + 0.0025 × GSK'254 concentration. The points plotted denote the estimated mean (90%) ΔΔQTcF at geometric mean GSK'254 C_max. The black dashed line denotes the 10‐ms threshold. C_max, maximum concentration; ΔΔQTcF, placebo‐adjusted change from baseline in QT interval corrected using Fridericia's formula.