Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects

Abstract

Aim: To characterize the effects of lamotrigine on QT interval in healthy subjects.

Methods: Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic-pharmacodynamic (PK-PD) modelling.

Results: Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo -7.48 ms, 90% CI -10.49, -4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK-PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied.

Conclusions: Therapeutic doses of lamotrigine (50-200 mg b.d.) were not associated with QT prolongation in healthy subjects.

Figure 1

Scatter plots of (a) uncorrected QT, (b) QTcF and (c) QTcB vs. the RR interval

Figure 2

Difference from placebo in adjusted mean QTcF by time. Lamotrigine 50 mg bd vs. Placebo (□), Lamotrigine 150 mg bd vs. Placebo (▴), Lamotrigine 200 mg bd vs. Placebo (○), Moxifloxzcin SD vs. Placebo SD (♦)

Figure 3

Difference from placebo in adjusted mean QRS by time. Lamotrigine 50 mg bd vs. Placebo (□), Lamotrigine 150 mg bd vs. Placebo (▴), Lamotrigine 200 mg bd vs. Placebo (○), Moxifloxacin SD vs. Placebo SD (♦)

Figure 4

Difference from placebo in adjusted mean heart rate by time. Lamotrigine 50 mg bd vs. Placebo (□), Lamotrigine 150 mg bd vs. Placebo (▴), Lamotrigine 200 mg bd vs. Placebo (○), Moxifloxzcin SD vs. Placebo SD (♦)

Figure 5

Scatter plot of circadian-corrected individual heart rate corrected QT interval (QTci) vs. plasma concentration for lamotrigine (a) and moxifloxacin (b) in male subjects. The solid lines represent the population medians and the dashed lines the 5th and 95th percentiles of predicted QTci vs. concentration relationship. Similar results were obtained in female subjects