Lomitapide at supratherapeutic plasma levels does not prolong the Qtc interval--results from a TQT study with moxifloxacin and ketoconazole.

BACKGROUND: The aim of this study was to assess the effect of high plasma levels of lomitapide and its main metabolite on ECG parameters.

METHODS: In this randomized five-way cross-over thorough QT study, 56 healthy subjects were enrolled. Study treatments were administered orally for 3 days in five separate periods in which subjects were dosed with (1) a single dose of 75 mg lomitapide on Day 1 followed by a single dose of 200 mg on Day 3; (2) ketoconazole 200 mg BID; (3) ketoconazole with a single dose of 75 mg lomitapide on Day 3; (4) a single dose of 400 mg moxifloxacin on Day 3 and (5) placebo.

RESULTS: Single doses of 75 and 200 mg lomitapide alone or in combination with ketoconazole caused minor changes in the change-from-baseline QTcI (ΔQTcI), whereas moxifloxacin and ketoconazole caused an increase of ΔQTcI with a peak effect at 1 and 3 hours postdosing, respectively. The largest mean placebo-corrected ΔQTcI (ΔΔQTcI) for lomitapide did not exceed 3 ms (upper bound of 90% CI: 4.7 ms) at any time points postdosing. Ketoconazole caused mild QT prolongation with mean ΔΔQTcI of 5.9 and 6.5 ms at 2 and 3 hours postdosing, and exposure-response analysis demonstrated a significantly positive slope of 1.3 ms per μg/mL (90% CI: 1.0-1.7). Moxifloxacin met the criteria for assay sensitivity.

CONCLUSIONS: Lomitapide does not have an effect on cardiac repolarization. The study's ability to detect small QTc changes was demonstrated with both moxifloxacin and ketoconazole.