Concentration-QTc analysis of soticlestat in healthy adults: An alternative to a thorough QT study

Abstract

Aim: This study aimed to examine the cardiac and overall safety and pharmacokinetic (PK) profiles of soticlestat (TAK-935), an oral, first-in-class selective cholesterol 24-hydroxylase inhibitor.

Methods: Data came from a randomised, phase 1 study of soticlestat in 33 healthy Japanese adults (NCT04461483); 24 adults in Part 1 (single-dose soticlestat 200-1200 mg or placebo) and 9 in Part 2 (soticlestat 100-300 mg twice daily or placebo for 21 days). PK sample collection was paired with 12-lead electrocardiogram data from continuous Holter recordings. The concentration-QTc relationship was analysed using a linear mixed-effects model. QTc prolongation safety margins were determined for two scenarios of calculated high clinical exposures: scenario 1 (NCT05064449) involved coadministration of single-dose soticlestat 300 mg with itraconazole or mefenamic acid and scenario 2 (NCT05098054) involved single-dose soticlestat 300 mg administration in participants with mild/moderate hepatic impairment (implementing a 3-fold dose reduction for moderate severity).

Results: Based on concentration-QTc analysis, placebo-corrected change-from-baseline QT values (90% confidence intervals), corrected for heart rate (Fridericia's method), were 0.94 ms (-2.35, 4.23) for soticlestat and 0.63 ms (-3.15, 4.41) for its N-oxide metabolite plasma concentrations at therapeutic doses (soticlestat 300 mg twice daily); safety margins were >2-fold for scenarios of calculated high clinical exposures. No (Part 1) and five (83.3%; Part 2) participants experienced treatment-emergent adverse events (all mild).

Conclusion: There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety/PK findings aligned with previous soticlestat clinical studies.

Keywords: QT prolongation; TAK‐935; concentration‐QTc analysis; soticlestat.

FIGURE 1

(A) Arithmetic mean (+SD) soticlestat and M‐I plasma concentrations over time for part 1 of the study. (B) Arithmetic mean (+SD) soticlestat and M‐I plasma concentrations over time for part 2 of the study. b.i.d., twice daily; CI, confidence interval; M‐I, N‐oxide metabolite of soticlestat; SD, standard deviation.

FIGURE 2

(A) Placebo‐corrected ΔHR across time for part 1 of the study. (B) Placebo‐corrected ΔHR across time for part 2 of the study. Displayed data are least‐squares mean and 90% CI based on a mixed‐effects model for repeated measures. ΔHR, change‐from‐baseline HR; b.i.d., twice daily; bpm, beats per minute; CI, confidence interval; HR, heart rate.

FIGURE 3

(A) ΔQTcF across time for part 1 of the study. (B) ΔQTcF across time for part 2 of the study. (C) Placebo‐corrected ΔQTcF across time for part 1 of the study. (D) Placebo‐corrected ΔQTcF across time for part 2 of the study. Displayed data are least‐squares mean and 90% CI. ΔQTcF, baseline‐corrected QTcF interval; b.i.d., twice daily; CI, confidence interval; QTcF, QT interval with Fridericia correction method.

FIGURE 4

Model‐predicted placebo‐corrected ΔQTcF (mean and 90% CI) and estimated placebo‐corrected ΔQTcF (mean and 90% CI) across deciles of soticlestat (A) and M‐I (B) plasma concentrations in the study. The solid black line with grey shaded area denotes the model‐predicted mean placebo‐corrected ΔQTcF. The red filled circles with vertical bars denote the estimated mean placebo‐corrected ΔQTcF with 90% CI at the associated median plasma concentration within each decile for soticlestat (A) or M‐I (B). The black circle with vertical bars denotes the mean placebo‐adjusted ΔQTcF with 90% CI for placebo at a concentration of 0. The horizontal red line with notches shows the range of concentrations divided into deciles for soticlestat or M‐I. ΔQTcF, baseline‐corrected QTcF interval; CI, confidence interval; M‐I, N‐oxide metabolite of soticlestat; QTc, corrected QT interval; QTcF, QT interval with Fridericia correction method.

FIGURE 5

Scatter plot of observed soticlestat (A) and M‐I (B) plasma concentrations and estimated placebo‐corrected ΔQTcF in the study. Plotted points denote pairs of observed drug plasma concentrations and estimated placebo‐corrected ΔQTcF by individual. The plotted lines indicate model‐predicted mean placebo‐corrected ΔQTcF (solid red line) and 90% CI (dashed lines). ΔQTcF, baseline‐corrected QTcF interval; b.i.d., twice daily; CI, confidence interval; M‐I, N‐oxide metabolite of soticlestat; QTc, corrected QT interval; QTcF, QT interval with Fridericia correction method.