Acta Neurol Scand 2015: 132: 346–354 DOI: 10.1111/ane.12416
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers Kropeit D, Johnson M, Cawello W, Rudd GD, Horstmann R. Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers. Acta Neurol Scand 2015: 132: 346–354. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective – To determine whether lacosamide prolongs the corrected QT interval (QTc). Materials and methods – In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. Results – The QTcI mean maximum difference from placebo was 4.3 ms and 6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin ( 0.5 and 2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. Conclusions – Lacosamide (≤800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, doserelated increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures.
Introduction
Lacosamide is a functionalized amino acid, which acts by selective enhancement of the slow inactivation phase of voltage-gated sodium channels (1, 2). Following oral administration, lacosamide shows linear pharmacokinetics (PK) that are constant over time, with low intra- and intersubject variability (3, 4). Lacosamide is metabolized by three cytochrome P450 (CYP) enzymes, CYP2C19, CYP3A4, and CYP2C9 (3, 4) and has an elimination half-life of approximately 13 h. It 346
D. Kropeit1, M. Johnson2, W. Cawello3, G. D. Rudd, R. Horstmann4 1
AiCuris GmbH & Co. KG, Wuppertal, Germany; 2UCB Pharma, Raleigh, NC, USA; 3UCB Pharma, Monheim am Rhein, Germany; 4Consulting Early Development, Bonn, Germany
Key words: Cardiac; Lacosamide; PR interval; QT interval; Safety D. Kropeit, Friedrich-Ebert-Str. 475 / Geb. 302, 42117 Wuppertal, Deutschland Tel.: +49 202 31763 2150 Fax: +49 202 31763 1701 e-mail: [email protected] Accepted for publication April 6, 2015
has a low potential for drug–drug interactions with no clinically relevant changes in plasma concentrations seen in healthy volunteers when coadministered with CYP substrates and inducers (5, 6). Based on in-vitro data, strong inhibitors of CYP2C9 and CYP3A4 may lead to increased systemic exposure of lacosamide (3, 4). Increases in plasma concentration are expected in patients with severe renal impairment or end-stage renal disease (7), and dose titration should be performed with caution in these patients (4). While increases in lacosamide plasma concentration
Lacosamide Thorough QT/QTc Trial have been observed in patients with mild or moderate hepatic impairment, dose adaptation is either not warranted in these patients (4) or limited to a maximum of 300 mg/day (3). The PK of lacosamide in patients with severe hepatic impairment have not been fully evaluated. The cardiac safety of lacosamide (approved as monotherapy and adjunctive treatment for adults aged ≥17 years with partial-onset seizures [POS] in the United States (3) and as adjunctive therapy for adults aged ≥16 years outside the United States (4)) was previously evaluated in preclinical studies, healthy volunteers, and in patients with POS. Safety studies in anesthetized dog and monkey models (8) indicated no effect of lacosamide on ventricular repolarization (no QTc interval prolongation), but detected an effect on atrioventricular (AV) and intraventricular conduction times. Consistent with absence of ventricular repolarization effects, the halfmaximal inhibitory lacosamide concentration (IC50) for the human ether-a-gogo-related gene (hERG) potassium channel (IKr) was >80-fold higher than the maximum unbound drug concentrations at the maximum-recommended human dose (400 mg/day). A 30-fold separation between IKr IC50 and effective unbound therapeutic plasma concentrations is commonly accepted to greatly reduce pro-arrhythmia risk (9); therefore, lacosamide in-vivo and in-vitro data suggest a low risk of QT-interval-related arrhythmias. The efficacy and favorable tolerability of lacosamide was demonstrated in three randomized, placebo-controlled clinical trials (10). Cardiac safety evaluations from pooled populations of POS patients (11) revealed no cardiac-related effects of recommended doses of lacosamide other than a small dose-related increase in PR interval, with no symptomatic consequences. Reported here are the results of a thorough QT/ QTc study in healthy volunteers (trial SP640), conducted in accordance with regulatory guidance for new molecular entities (12). Materials and methods Trial design
Trial SP640 was conducted between June and October 2005 at the PRACS Institute Ltd., Fargo, ND, USA, in accordance with applicable International Conference on Harmonisation (ICH) Good Clinical Practice requirements, Declaration of Helsinki, and local laws. The trial protocol and informed consent were reviewed
by the applicable institutional review board. All volunteers gave written informed consent before trial participation. In this randomized, double-blind, positiveand placebo-controlled, parallel-design trial, healthy volunteers were randomized 1:1:1:1 to multiple oral doses of placebo, lacosamide 400 mg/day (200 mg bid, maximum-recommended daily dose), lacosamide 800 mg/day (400 mg bid, maximum tolerated supratherapeutic dose), or moxifloxacin 400 mg (qd). Lacosamide was initiated at 200 mg bid and escalated to 400 mg bid on Day 3 in the 800 mg/day group. Moxifloxacin (Bayer AG, Germany) served as a positive control to establish QT-interval assay sensitivity. Descriptions of eligibility assessments, sample size calculation, and trial conduct are provided in Supporting Information. Variables assessed
The primary end point was the maximum timematched change from baseline in QT interval with individual correction for heart rate (HR; QTcI). Secondary variables included maximum time-matched changes from baseline in QTc using Fridericia (QTcF) or Bazett (QTcB) methods, time-matched and time-averaged changes from baseline in QTcI, HR, QRS duration and PR interval, outlier values, and treatment-emergent (TE) electrocardiogram (ECG) diagnostic findings. PK, safety, and tolerability variables were also evaluated. ECG acquisition and evaluation
ECGs were acquired using a H-12 ECG continuous recorder (Mortara Instrument, Inc., Milwaukee, WI, USA). Baseline ECGs (n = 36, three at each of 12 time-points) were analyzed 1 day prior to randomization and compared with corresponding treatment ECG interval values acquired on Day 3 (moxifloxacin) or Day 6 (lacosamide, placebo) of treatment at 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours post-dose. For time-matched changes, the baseline value at each time-point was the median of the three values obtained. Details of ECG acquisition, interpretation, and QT value correction are provided in Supporting Information. Safety and PK assessments
Details regarding recording of adverse events (AEs), blood pressure (BP), HR, clinical laboratory 347
Kropeit et al. evaluation, physical examination, and PK data are provided in Supporting Information. Plasma samples for the determination of lacosamide concentration were collected at each of the primary variable time-points on Day 6. Analysis of primary and secondary variables
The primary analysis of the maximum timematched change from baseline in QTcI (calculated per subject) was based on a non-inferiority comparison of each group from baseline to Day 6 (Day 3 for the moxifloxacin group) using the upper limits of 2-sided 90% confidence intervals [CIs; equivalent to a 1-sided 95% CIs as described in ICH E14 Guidance for Industry (12)] with a non-inferiority bound of 10 ms (obtained using an analysis of covariance (ANCOVA) model with effects for treatment, gender, and time-matched baseline QTcI as covariate); all pairwise comparisons were based on the ANCOVA model and were carried out at a nominal 0.05 significance level. Supportive analysis was carried out by assessing non-inferiority at each of the 12 time-matched time-points for Day 3 (moxifloxacin-placebo) and Day 6 (lacosamide-placebo) using a mixed models repeated measures analysis with effects for treatment, subject, gender, time-point, treatment by time-point interaction, and time-matched baseline QTcI as a continuous covariate; a Toeplitz variance– covariance structure was utilized. As a further evaluation of sensitivity, an ANCOVA model with effects for treatment, gender, and timematched baseline as continuous covariates was used to evaluate non-inferiority at each timepoint. The ANCOVA model was also used for exploratory comparisons of time-matched maximum change from baseline for QTcF and QTcB between the lacosamide groups and placebo, and between moxifloxacin and placebo. Summary statistics and exploratory comparisons between groups for time-matched and time-averaged changes from baseline for QTcI, HR, QRS duration, and PR interval were also determined. Results for secondary variables were descriptive because the trial was only powered for the primary QTcI variable. The frequency with which volunteers met change from baseline outlier criteria for each ECG interval, as well as ECG diagnostic findings (present after dosing but not present on any baseline ECG), TEAEs, BP, and clinical laboratory data, were summarized with descriptive statistics. 348
Analysis groups
The Safety Set (SS) included all volunteers who received ≥1 dose of trial medication. The primary analysis was based on the Pharmacodynamic Set (PDS volunteers in the SS with sufficient H-12 data to calculate pharmacodynamic parameters and who completed Day 3 [moxifloxacin] or Day 6 [lacosamide, placebo]). Volunteers with major protocol deviations rendering the ECG data unreliable or incomparable among treatment groups were excluded from the PDS. The PK Set (PKS) comprised all lacosamide SS volunteers with bioanalytical samples collected on Day 6. Pharmacokinetic analysis
PK parameters—area of the concentration over time profile in a dosing interval at steady-state (AUCtau,ss), maximum-measured concentration at steady state (Cmax,ss), and time after administration to reach maximum-measured concentration at steady-state (tmax,ss) of lacosamide and its metabolite were determined for the final day of the treatment period (Day 6) using non-compartmental methods (AUCtau,ss, linear trapezoid rule) and observations (Cmax,ss and tmax,ss). The potential for a pharmacodynamic/pharmacokinetic relationship between time-matched changes in intervals with lacosamide plasma concentrations was explored using a linear regression model with individual subject data. Further details of the PK analyses are provided in the Supporting Information. Results Volunteer disposition, demographics, and baseline characteristics
Of 247 randomized healthy volunteers, 220 (89.1%) completed the trial (Table 1). Twentyseven volunteers discontinued prior to completing dosing and were not included in the PDS; their replacements who completed the assigned dosing regimen were included in the PDS. ECG H-12 data were missing from six volunteers who were excluded from the PDS. Patient demographics were comparable across treatment groups. Electrocardiographic evaluation
QTc interval – The maximum time-matched changes from baseline in placebo-corrected QTcI were 4.3 and 6.3 ms for lacosamide 400 and 800 mg/day, respectively (Table 2). The upper limits of the 90% CIs for both lacosamide dose groups ( 0.5 ms for 400 mg/day and 2.5 ms
Lacosamide Thorough QT/QTc Trial Table 1 Analysis populations, volunteer disposition, and baseline demographics Lacosamide Placebo Randomized and treated, n (%) Safety Set (SS) Discontinued Reason for discontinuation Adverse event Withdrew consent No Holter card available Completed Insufficient ECG data Pharmacodynamic Set (PDS) Pharmacokinetic Set (PKS) Age, mean (SD), years Female, n (%) Weight, mean (SD), kg BMI, mean (SD), kg/m2 Race/ethnicity, n (%) White Black Asian Other
62 (100.0) 62 (100.0) 7 (11.3) 0 4 3 55 1 54 N/A 24.1 32 72.9 24.7 51 2 2 7
400 mg/day
800 mg/day
Moxifloxacin
60 (100.0) 60 (100.0) 3 (5.0)
71 (100.0) 71 (100.0) 17 (23.9)
54 (100.0) 54 (100.0) 0
(6.1) (51.6) (11.9) (3.0)
0 1 2 57 1 56 57 24.7 33 72.9 25.1
(82.3) (3.2) (3.2) (11.3)
54 1 3 2
(6.5) (4.8) (88.7)
(2.8) (15.5) (5.6) (76.1)
(6.4) (55.0) (12.1) (3.1)
2 11 4 54 2 52 53 24.9 43 69.4 23.9
(90.0) (1.7) (5.0) (3.3)
65 3 1 2
(91.5) (4.2) (1.4) (2.8)
(1.7) (3.3) (95.0)
(6.7) (60.6)a (11.9) (3.1)
0 0 0 54 2 52 N/A 25.1 27 75.8 25.5 48 3 2 1
Total 247 (100.0) 247 (100.0) 27 (10.9)
(7.3) (50.0) (13.0) (3.22)
2 16 9 220 6 214 110 24.7 135 72.5 24.7
(6.6) (54.7) (12.3) (3.2)
(88.9) (5.6) (3.7) (1.9)
218 9 8 12
(88.3) (3.6) (3.2) (4.9)
(100.0)
(0.8) (6.5) (3.5) (89.1)
a There was a slightly greater percentage of females in the 800 mg/day lacosamide group because more females than males did not complete treatment through Day 6 and, per protocol, each was replaced with a female who received the same treatment.
for 800 mg/day) were below the +10 ms non-inferiority margin, indicating no increase of QTcI. Assay sensitivity was established using the moxifloxacin group as the change was +10.4 ms with a lower 90% confidence bound of >0 (6.6 ms). Results were similar in males and females (data not shown). The maximum time-matched change from baseline analysis for QTcF and QTcB produced similar results (Table 2). The primary variable (QTcI) results were strongly supported by the assessment of non-inferiority at each of the 12 time-points for Day 3 (moxifloxacin-placebo) and Day 6 (lacosamideplacebo) (Fig. 1A). Likewise, the difference from placebo in time-averaged QTcI change from baseline (mean; 90% CI) showed an increase for the Table 2 ANCOVA for placebo-corrected maximum time-matched change from baseline in QTc interval (Day 6, PDS) Lacosamide 400 mg/day n = 56 QTcI, mean (CI), ms QTcF, mean (CI), ms QTcB, mean (CI), ms
4.3 ( 8.0, 4.4 ( 7.6, 4.5 ( 9.0,
0.5) 1.2) 0.1)
800 mg/day n = 52 6.3 ( 10.0, 2.5) 7.1 ( 10.4, 3.9) 2.9 ( 7.4, 1.7)
Moxifloxacin n = 52 10.4 (6.6, 14.2) 10.4 (7.2, 13.7) 5.0 (0.4, 9.5)
ANCOVA, analysis of covariance; CI, 90% confidence interval; PDS, Pharmacodynamic Set; ms, millisecond. CIs are for treatment differences, based on ANCOVA model with effects for treatment and gender and time-matched baseline QTcI as a covariate.
moxifloxacin group (9.8 ms; 7.4, 12.1) and a slight decrease for lacosamide 400 mg/day ( 2.5 ms; 4.8, 0.2) and 800 mg/day ( 4.5 ms; 6.9, 2.2). Outlier analysis revealed that 15.4%, 7.4%, 5.4%, and 1.9% of volunteers in the moxifloxacin, placebo, lacosamide 400 mg/day, and 800 mg/day groups, respectively, had a QTcI that was ≥450 to 480 ms. The frequency of volunteers exhibiting a QTcI change from baseline ≥30 to 100 ms was greater for both lacosamide groups relative to placebo and not dose related (Table 3). No volunteer had a TE QRS duration >120 ms. PR interval – Compared with placebo, treatment with lacosamide resulted in dose-related timematched changes in PR interval from baseline (Fig. 1D). The maximum mean increase in PR interval occurred at tmax (1 h post-dosing on Day 6) and was 6.3, 13.6, and 18.2 ms for placebo, 400 mg/day and 800 mg/day lacosamide, respectively. These values correspond with
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placebo-subtracted maximum mean increases of 7.3 ms for lacosamide 400 mg/day and 11.9 ms for 800 mg/day. The difference from placebo in time-averaged change from baseline (mean; 95% CI) was also smaller for lacosamide 400 mg/day (6.5 ms; 3.9, 9.0) than 800 mg/day (9.4 ms; 6.8, 12). There was a similar frequency of TE PRinterval outliers for the placebo and lacosamide 400 mg/day groups (Table 3) and a higher frequency of PR-interval outliers in the lacosamide 800 mg/day group. One volunteer from this group had a single PR-interval value >250 ms (251 ms), 1 h following dosing on Day 6; the time-matched baseline value was 193 ms. Other ECG and morphological findings – The most common TE ECG diagnostic finding was sinus tachycardia, observed with similar frequency in the lacosamide and placebo groups. Bradycardia was most frequent in the placebo group (Table 4). A similar percentage of all T-wave findings was observed across treatment groups; however, a higher percentage of volunteers in the lacosamide 800 mg/day group had inverted T-waves, which was not associated with any ischemia-related AE. The frequency of firstdegree AV block (PR interval >200 ms) was
Lacosamide Thorough QT/QTc Trial Table 3 Treatment-emergent outlier analysis (PDS, Treatment Phase)
Table 4 Treatment-emergent ECG diagnostic findings (PDS)a,b
Change from baselinea QTcI,b n (%)
N
120 msd
>140 msd
Placebo Lacosamide 400 mg/day Lacosamide 800 mg/day
54 56 52
16 (29.6) 28 (50.0) 22 (42.3)
0 0 0
0 0 0
PR interval, n (%)
N
>200 ms
>220 ms
>250 ms
Placebo Lacosamide 400 mg/day Lacosamide 800 mg/day
54 56 52
2 (3.7) 2 (3.6) 12 (23.1)
0 1 (1.8) 3 (5.8)
0 0 1 (1.9)
ECG findings (central reader criteria) Sinus tachycardia (HR >100 bpm) Sinus bradycardia (HR 200 ms) Intraventricular conduction defect (QRS duration >110 ms) T-waves Flat Biphasic Inverted Depressed ST segment Prolonged QTc Bazett (>499 ms)
Placebo N = 54 n (%) 30 9 4 1 3
(55.6) (16.7) (7.4) (1.9) (5.6)
0 20 6 16 7 1 3
Lacosamide 400 mg/day N = 56 n (%) 27 1 1 1 2
(48.2) (1.8) (1.8) (1.8) (3.6)
2 (3.6) (37.0) (11.1) (29.6) (13.0) (1.9) (5.6)
17 4 13 6 0 3
(30.4) (7.1) (23.2) (10.7) (5.4)
Lacosamide 800 mg/day N = 52 n (%) 31 3 1 1 11
(59.6) (5.8) (1.9) (1.9) (21.2)
2 (3.8) 19 4 12 15 1 1
(36.5) (7.7) (23.1) (28.8) (1.9) (1.9)
HR, heart rate; bpm, beats per minute; ms, milliseconds. Treatment-emergent ECG findings occurred on any ECG during the treatment phase, but not on any ECG on Day 1. b Treatment-emergent ECG findings reported for more than one subject across groups. a
d
d
d
a
Number of subjects with one or more post-baseline values meeting the criteria when compared to time-matched baseline. b QTc ≥450 ms, ≥480 ms, and ≥500 ms when not present at time-matched baseline (new onset), and increases of >0 to 100 bpm time-point. d Number of subjects meeting criteria at one or more time-points during treatment but not at the corresponding time-matched baseline.
similar between placebo and the lacosamide 400 mg/day group, but higher in the lacosamide 800 mg/day group. There were no reports of second-degree or higher AV block, or bundle branch block. Pharmacokinetic evaluation
The mean plasma concentration of lacosamide increased within 1–2 h (2–4 h for the main metabolite) following dosing. Maximum mean lacosamide concentration (Cmax,ss) was dose proportional: 10.9 lg/ml following 200 mg in the 400 mg/day group and 21.3 lg/ml following 400 mg in the 800 mg/day group. The maximum mean concentration of the metabolite was 1.3 lg/ml and 2.5 lg/ml, respectively. Lacosamide tmax,ss (median = 1 h) was the same for both groups. A dose-proportional increase in AUCs,ss was observed (from 100.3 lg/ml∙hr following lacosamide 400 mg/day to 195.7 lg/ml∙hr following lacosamide 800 mg/day). Normalization of Cmax, ss and AUCs,ss by dose and body weight eliminated small gender differences and produced
nearly identical values among the two lacosamide treatment groups (Cmax,ss,norm: 3.925 vs 3.699 lg/ml*kg/mg, 200 mg bid vs 400 mg bid; AUCs,ss,norm: 36.04 vs 33.96 lg/ml∙h*kg/mg). Summary statistics of PK parameters are provided in Supporting Information Table 2. Pharmacodynamic/pharmacokinetic relationship
There was no relationship between lacosamide plasma concentration and changes in QTcI values (Fig. S1). The concentration–response relationship for PR-interval change is shown in Fig. 2. The regression equation predicts that the maximum steady-state concentrations (~11 lg/ml and ~21 lg/ml) associated with 400 mg/day and 800 mg/day lacosamide would result in a mean PR-interval change from baseline of ~+5.8 ms and ~+9.5 ms. Safety and tolerability
Adverse events – The most common TEAEs (≥10% in any group) were dizziness (6.5% placebo, 10.0% lacosamide 400 mg/day, 54.9% lacosamide 800 mg/day); nausea (1.6%, 8.3%, 26.8%); headache (14.5%, 16.7%, 22.5%); hypoesthesia oral (0.0%, 1.7%, 21.1%); feeling drunk (3.2%, 8.3%, 15.5%); and vomiting (0.0%, 5.0%, 12.7%). One serious TEAE was reported: a spontaneous abortion that occurred 9 days following withdrawal from lacosamide 800 mg/day in a
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Figure 2. Time-matched change in PR interval and lacosamide plasma concentration (Day 6, PDS). Individual data points and the associated regression (solid) line with 95% confidence intervals (dotted lines) for all lacosamide-treated volunteers. For reference and comparison, the spread of the placebo data points for change in PR interval (12 evaluations on Day 6) is shown at zero lacosamide concentration. The vertical dotted and solid lines indicate the mean plasma concentration at tmax for 400 mg/day and 800 mg/day of lacosamide. Pearson coefficient = 0.14. Regression equation: PR change from baseline (ms) = (intercept) 1.661138 + (slope) 0.375588*lacosamide (lg/ml).
41-year-old female who had negative pregnancy tests at baseline and reported the use of a barrier contraceptive method. Two subjects from the lacosamide 800 mg/day group were withdrawn from the trial due to TEAEs: one due to neck pain, the other due to feeling drunk on Day 1, which resolved and was followed by nausea, feeling hot, ear discomfort, and vomiting on Day 3. On the evening of Day 4 (after 2 days of 400 mg lacosamide bid dosing), the same volunteer had moderate syncope that resolved in 2 min. On Day 5, the volunteer developed abdominal pain upper, hematemesis, Mallory-Weiss syndrome, and dizziness that resulted in withdrawal from the trial. Each of these AEs resolved on the day of onset or by the next day. The only cardiac-related TEAEs reported were palpitations [two (3.2%), two (3.3%), and three (4.2%) volunteers in the placebo, lacosamide 400 mg/day, and 800 mg/day groups, respectively] and HR increased (one volunteer in the lacosamide 800 mg/day group). None had a prolonged PR interval during treatment (single maximum PR-interval value was 168 ms). Treatment-emergent ECG findings for these eight subjects were sinus tachycardia (in both placebo subjects and one each in the lacosamide 400 mg/ day and 800 mg/day groups) and flat T-waves in both placebo subjects. Other safety assessments – Results for the single assessment of orthostatic changes in BP and pulse rate were similar in placebo and lacosamide groups on Day 6 and baseline orthostatic assessments. The mean (SD) changes from baseline for supine assessments of systolic BP were –2.5
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(9.8), 1.9 (8.6), and 8.6 (9.7) mmHg in the placebo and lacosamide 400 and 800 mg/day groups. Respective changes in diastolic BP were 2.0 (6.5), 3.9 (7.2), and 10.3 (7.4) mmHg. No volunteers met study criteria for an abnormally high BP. There were no changes in laboratory parameters or physical examination findings attributed to trial medication. Discussion
This thorough QT/QTc trial provides the primary characterization of the ECG and cardiac safety profile of the anti epileptic drug (AED) lacosamide, in healthy volunteers. Serial ECGs throughout the dosing intervals at steady state on Day 6 resulted in a complete systematic assessment of primary (QTcI interval) and secondary ECG variables, as well as PK parameters. The primary maximum timematched change from baseline QTcI analysis, demonstrated that lacosamide did not increase QTcI at either the maximum-recommended (400 mg/day) or a supratherapeutic dosage (800 mg/day). Assay sensitivity was proven using moxifloxacin; therefore, this trial is a negative QTc trial for lacosamide, as per the criteria defined in the ICH E14 Guidance for Industry (12). Time-matched analysis, repeated measure analysis, and time-averaged assessments for QTcI, as well as outlier analyses, were consistent with the primary QTcI analysis. A slight decrease in QTcI was observed in the placebo and lacosamide groups; however, the clinical relevance of this observation is unknown. Decreases in QTc have been reported in thorough QTc trials for lamotrigine (13) and eslicarbazepine (14).
Lacosamide Thorough QT/QTc Trial Analyses of QRS duration did not identify dose-related or clinically relevant changes in lacosamide groups. The time-averaged change from baseline in HR was ~5 bpm greater with lacosamide 800 mg/day compared with placebo or lacosamide 400 mg/day, a difference that was relatively consistent throughout the dosing interval. It is unclear if this observation was due to a direct cardiovascular effect, central nervous system effects (such as dizziness), or a combination of the two. A similar increase in HR over placebo was reported in healthy volunteers in thorough QTc trials of the sodium channel-blocking AEDs lamotrigine (13) and eslicarbazepine (14). A small, dose-related increase from baseline in PR interval, maximal at 1 h (time of tmax), was observed. The relatively flat relationship between lacosamide plasma concentration and change from baseline in PR interval suggests a wide margin of safety with regard to PR interval in healthy volunteers. First-degree AV block was reported with similar frequency in placebo and lacosamide 400 mg/day groups, and with an increased frequency in the lacosamide 800 mg/day group. No associated AEs were reported. Importantly, no volunteer showed second-degree or higher AV block. Small increases in PR interval have been observed with AEDs that act on voltage-gated sodium channel fast inactivation [including carbamazepine (15), lamotrigine (16), and eslicarbazepine (14)] and also those with other mechanisms of action [e.g., pregabalin (17)]. Volunteers with a baseline PR interval >220 ms were excluded; however, those with TE firstdegree AV block and/or TE PR intervals >220 ms were allowed to continue. This did not lead to cardiac-related AEs. If lacosamide increases PR interval through inhibition of slow inactivation of voltage-gated sodium channels, then myocardial ischemia could magnify or potentiate this effect. Thus, precaution is warranted in certain patient populations (3, 4, 11). There have been a few published individual case reports of cardiac-related adverse events in patients with POS treated with lacosamide including bradycardia, second-degree AV block (Mobitz Type I), ventricular tachycardia, sinus node dysfunction, and atrial flutter/fibrillation. These individual case reports are reviewed in more detail in the companion article by Rudd et al. (11). Initiation of lacosamide at the maximum-recommended dosage (400 mg/day) was generally well tolerated. The dose-related and higher incidence of nervous system and gastrointestinal AEs was consistent with results observed with lacosamide treatment in trials in patients with POS (10).
The small increase in BP observed in the lacosamide 800 mg/day group was not associated with AEs and contrasts with the hypotension observed in anesthetized animal models (8). This is the largest PK study lacosamide in healthy volunteers. Lacosamide exposure was dose proportional up to the supratherapeutic dosage of 800 mg/day (400 mg bid). Mean Cmax,ss and AUCs,ss (normalized by dose) were consistent with published data in healthy subjects (18). In this thorough QT/QTc trial in healthy volunteers, lacosamide doses ≤800 mg/day did not prolong the QTc interval; therefore, lacosamide does not affect ventricular repolarization. Secondary outcomes revealed a small, doserelated increase in mean PR interval, not associated with AEs. While there are limitations to the interpretation of any study in healthy volunteers (namely the lack of comorbidities often seen in the patient population, such as existing cardiac conditions, and interactions with concomitant medications), the lacosamide cardiac safety and PK profiles observed in healthy volunteers were consistent with observations in patients with POS receiving adjunctive lacosamide. Acknowledgments Medical writing support was provided by Kristen A. Andersen, PhD of Prescott Medical Communications Group (Chicago, IL) and Jonathon Gibbs, BSc of Evidence Scientific Solutions Ltd (Horsham, UK). Publication management in the form of publication coordination was provided by Azita Tofighy, PhD and Laurent Turet, PhD; employees of UCB Pharma.
Conflict of interests D. Kropeit is a former employee of Schwarz Biosciences, Monheim, Germany (acquired by UCB Pharma). M. Johnson and W. Cawello are employees of UCB Pharma. G.D. Rudd initiated work on this article while an employee of UCB Pharma, Raleigh, NC and completed work on this article as a paid consultant to UCB and, as a retiree, receives deferred compensation and holds UCB stock options. R. Horstmann is a former employee of UCB Pharma, Monheim am Rhein, Germany.
Supporting Information Additional Supporting Information may be found in the online version of this article. Figure S1. Time-matched changes in QTcI interval (Day 6) Table S1. Key trial events and timing. Table S2. Summary statistics for PK parameters derived at steady-state (Day 6) Appendix S1. Materials and methods.
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Kropeit et al. References 1. DOTY P, HEBERT D, MATHY FX, BYRNES W, ZACKHEIM J, SIMONTACCHI K. Development of lacosamide for the treatment of partial-onset seizures. Ann N Y Acad Sci 2013;1291:56–68. 2. ERRINGTON AC, STOHR T, HEERS C, LEES G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008;73:157–69. 3. VIMPATÒ. (lacosamide) Prescribing Information: UCB Pharma, Smyrna, GA, US, 2014. 4. VIMPATÒ. (lacosamide) Summary of Product Characteristics: UCB Pharma, SA, Belgium, 2014. 5. CAWELLO W, MUELLER-VOESSING C, FICHTNER A. Pharmacokinetics of lacosamide and omeprazole coadministration in healthy volunteers: results from a phase I, randomized, crossover trial. Clin Drug Invest 2014;34:317–25. 6. CAWELLO W, SURMANN E, WAITZINGER J. Lacosamide has no effect on the enzymatic activity of CYP3A4. Neurology 2012;78:P01.076. 7. CAWELLO W, FUHR U, HERING U, MAATOUK H, HALABI A. Impact of impaired renal function on the pharmacokinetics of the antiepileptic drug lacosamide. Clin Pharmacokinet 2013;52:897–906. 8. DELAUNOIS A, COLOMAR A, DEPELCHIN B, CORNET M. Cardiac safety of lacosamide: the non-clinical perspective. Acta Neurol Scand 2015. In Press. 9. REDFERN WS, CARLSSON L, DAVIS AS et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res 2003;58:32–45.
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10. CHUNG S, BEN-MENACHEM E, SPERLING MR et al. Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials. CNS Drugs 2010;24:1041–54. 11. RUDD GD, HAVERKAMP W, MASON J et al. Lacosamide cardiac safety: clinical trials in patients with partialonset seizures. Acta Neurol Scand 2015. In press. 12. ICH. Guidance for Industry. E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. October 2005. http:// www.fda.gov/downloads/Drugs/GuidanceComplianceReg ulatoryInformation/Guidances/UCM073161.pdf. (accessed 27 February 2013). 2005. 13. DIXON R, JOB S, OLIVER R et al. Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects. Br J Clin Pharmacol 2008;66:396–404. 14. VAZ-DA-SILVA M, NUNES T, ALMEIDA L, GUTIERREZ MJ, LITWIN JS, SOARES-DA-SILVA P. Evaluation of eslicarbazepine acetate on cardiac repolarization in a thorough QT/ QTc study. J Clin Pharmacol 2012;52:222–33. 15. KENNEBACK G, BERGFELDT L, TOMSON T. Electrophysiological evaluation of the sodium-channel blocker carbamazepine in healthy human subjects. Cardiovasc Drugs Ther 1995;9:709–14. 16. DIXON R, ALEXANDER S, BRICKEL N. Effect of lamotrigine on the PR interval in healthy subjects. Br J Clin Pharmacol 2011;71:961–2. 17. LYRICAÒ. (pregabalin) Prescribing Information. Pfizer, NY, USA, 2012. 18. CAWELLO W, NICKEL B, EGGERT-FORMELLA A. No Pharmacokinetic Interaction Between Lacosamide and Carbamazepine in Healthy Volunteers. J Clin Pharmacol 2009;50:459–71.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers Kropeit D, Johnson M, Cawello W, Rudd GD, Horstmann R. Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers. Acta Neurol Scand 2015: 132: 346–354. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objective – To determine whether lacosamide prolongs the corrected QT interval (QTc). Materials and methods – In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability. Results – The QTcI mean maximum difference from placebo was 4.3 ms and 6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin ( 0.5 and 2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems. Conclusions – Lacosamide (≤800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, doserelated increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures.
Introduction
Lacosamide is a functionalized amino acid, which acts by selective enhancement of the slow inactivation phase of voltage-gated sodium channels (1, 2). Following oral administration, lacosamide shows linear pharmacokinetics (PK) that are constant over time, with low intra- and intersubject variability (3, 4). Lacosamide is metabolized by three cytochrome P450 (CYP) enzymes, CYP2C19, CYP3A4, and CYP2C9 (3, 4) and has an elimination half-life of approximately 13 h. It 346
D. Kropeit1, M. Johnson2, W. Cawello3, G. D. Rudd, R. Horstmann4 1
AiCuris GmbH & Co. KG, Wuppertal, Germany; 2UCB Pharma, Raleigh, NC, USA; 3UCB Pharma, Monheim am Rhein, Germany; 4Consulting Early Development, Bonn, Germany
Key words: Cardiac; Lacosamide; PR interval; QT interval; Safety D. Kropeit, Friedrich-Ebert-Str. 475 / Geb. 302, 42117 Wuppertal, Deutschland Tel.: +49 202 31763 2150 Fax: +49 202 31763 1701 e-mail: [email protected] Accepted for publication April 6, 2015
has a low potential for drug–drug interactions with no clinically relevant changes in plasma concentrations seen in healthy volunteers when coadministered with CYP substrates and inducers (5, 6). Based on in-vitro data, strong inhibitors of CYP2C9 and CYP3A4 may lead to increased systemic exposure of lacosamide (3, 4). Increases in plasma concentration are expected in patients with severe renal impairment or end-stage renal disease (7), and dose titration should be performed with caution in these patients (4). While increases in lacosamide plasma concentration
Lacosamide Thorough QT/QTc Trial have been observed in patients with mild or moderate hepatic impairment, dose adaptation is either not warranted in these patients (4) or limited to a maximum of 300 mg/day (3). The PK of lacosamide in patients with severe hepatic impairment have not been fully evaluated. The cardiac safety of lacosamide (approved as monotherapy and adjunctive treatment for adults aged ≥17 years with partial-onset seizures [POS] in the United States (3) and as adjunctive therapy for adults aged ≥16 years outside the United States (4)) was previously evaluated in preclinical studies, healthy volunteers, and in patients with POS. Safety studies in anesthetized dog and monkey models (8) indicated no effect of lacosamide on ventricular repolarization (no QTc interval prolongation), but detected an effect on atrioventricular (AV) and intraventricular conduction times. Consistent with absence of ventricular repolarization effects, the halfmaximal inhibitory lacosamide concentration (IC50) for the human ether-a-gogo-related gene (hERG) potassium channel (IKr) was >80-fold higher than the maximum unbound drug concentrations at the maximum-recommended human dose (400 mg/day). A 30-fold separation between IKr IC50 and effective unbound therapeutic plasma concentrations is commonly accepted to greatly reduce pro-arrhythmia risk (9); therefore, lacosamide in-vivo and in-vitro data suggest a low risk of QT-interval-related arrhythmias. The efficacy and favorable tolerability of lacosamide was demonstrated in three randomized, placebo-controlled clinical trials (10). Cardiac safety evaluations from pooled populations of POS patients (11) revealed no cardiac-related effects of recommended doses of lacosamide other than a small dose-related increase in PR interval, with no symptomatic consequences. Reported here are the results of a thorough QT/ QTc study in healthy volunteers (trial SP640), conducted in accordance with regulatory guidance for new molecular entities (12). Materials and methods Trial design
Trial SP640 was conducted between June and October 2005 at the PRACS Institute Ltd., Fargo, ND, USA, in accordance with applicable International Conference on Harmonisation (ICH) Good Clinical Practice requirements, Declaration of Helsinki, and local laws. The trial protocol and informed consent were reviewed
by the applicable institutional review board. All volunteers gave written informed consent before trial participation. In this randomized, double-blind, positiveand placebo-controlled, parallel-design trial, healthy volunteers were randomized 1:1:1:1 to multiple oral doses of placebo, lacosamide 400 mg/day (200 mg bid, maximum-recommended daily dose), lacosamide 800 mg/day (400 mg bid, maximum tolerated supratherapeutic dose), or moxifloxacin 400 mg (qd). Lacosamide was initiated at 200 mg bid and escalated to 400 mg bid on Day 3 in the 800 mg/day group. Moxifloxacin (Bayer AG, Germany) served as a positive control to establish QT-interval assay sensitivity. Descriptions of eligibility assessments, sample size calculation, and trial conduct are provided in Supporting Information. Variables assessed
The primary end point was the maximum timematched change from baseline in QT interval with individual correction for heart rate (HR; QTcI). Secondary variables included maximum time-matched changes from baseline in QTc using Fridericia (QTcF) or Bazett (QTcB) methods, time-matched and time-averaged changes from baseline in QTcI, HR, QRS duration and PR interval, outlier values, and treatment-emergent (TE) electrocardiogram (ECG) diagnostic findings. PK, safety, and tolerability variables were also evaluated. ECG acquisition and evaluation
ECGs were acquired using a H-12 ECG continuous recorder (Mortara Instrument, Inc., Milwaukee, WI, USA). Baseline ECGs (n = 36, three at each of 12 time-points) were analyzed 1 day prior to randomization and compared with corresponding treatment ECG interval values acquired on Day 3 (moxifloxacin) or Day 6 (lacosamide, placebo) of treatment at 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, and 24 hours post-dose. For time-matched changes, the baseline value at each time-point was the median of the three values obtained. Details of ECG acquisition, interpretation, and QT value correction are provided in Supporting Information. Safety and PK assessments
Details regarding recording of adverse events (AEs), blood pressure (BP), HR, clinical laboratory 347
Kropeit et al. evaluation, physical examination, and PK data are provided in Supporting Information. Plasma samples for the determination of lacosamide concentration were collected at each of the primary variable time-points on Day 6. Analysis of primary and secondary variables
The primary analysis of the maximum timematched change from baseline in QTcI (calculated per subject) was based on a non-inferiority comparison of each group from baseline to Day 6 (Day 3 for the moxifloxacin group) using the upper limits of 2-sided 90% confidence intervals [CIs; equivalent to a 1-sided 95% CIs as described in ICH E14 Guidance for Industry (12)] with a non-inferiority bound of 10 ms (obtained using an analysis of covariance (ANCOVA) model with effects for treatment, gender, and time-matched baseline QTcI as covariate); all pairwise comparisons were based on the ANCOVA model and were carried out at a nominal 0.05 significance level. Supportive analysis was carried out by assessing non-inferiority at each of the 12 time-matched time-points for Day 3 (moxifloxacin-placebo) and Day 6 (lacosamide-placebo) using a mixed models repeated measures analysis with effects for treatment, subject, gender, time-point, treatment by time-point interaction, and time-matched baseline QTcI as a continuous covariate; a Toeplitz variance– covariance structure was utilized. As a further evaluation of sensitivity, an ANCOVA model with effects for treatment, gender, and timematched baseline as continuous covariates was used to evaluate non-inferiority at each timepoint. The ANCOVA model was also used for exploratory comparisons of time-matched maximum change from baseline for QTcF and QTcB between the lacosamide groups and placebo, and between moxifloxacin and placebo. Summary statistics and exploratory comparisons between groups for time-matched and time-averaged changes from baseline for QTcI, HR, QRS duration, and PR interval were also determined. Results for secondary variables were descriptive because the trial was only powered for the primary QTcI variable. The frequency with which volunteers met change from baseline outlier criteria for each ECG interval, as well as ECG diagnostic findings (present after dosing but not present on any baseline ECG), TEAEs, BP, and clinical laboratory data, were summarized with descriptive statistics. 348
Analysis groups
The Safety Set (SS) included all volunteers who received ≥1 dose of trial medication. The primary analysis was based on the Pharmacodynamic Set (PDS volunteers in the SS with sufficient H-12 data to calculate pharmacodynamic parameters and who completed Day 3 [moxifloxacin] or Day 6 [lacosamide, placebo]). Volunteers with major protocol deviations rendering the ECG data unreliable or incomparable among treatment groups were excluded from the PDS. The PK Set (PKS) comprised all lacosamide SS volunteers with bioanalytical samples collected on Day 6. Pharmacokinetic analysis
PK parameters—area of the concentration over time profile in a dosing interval at steady-state (AUCtau,ss), maximum-measured concentration at steady state (Cmax,ss), and time after administration to reach maximum-measured concentration at steady-state (tmax,ss) of lacosamide and its metabolite were determined for the final day of the treatment period (Day 6) using non-compartmental methods (AUCtau,ss, linear trapezoid rule) and observations (Cmax,ss and tmax,ss). The potential for a pharmacodynamic/pharmacokinetic relationship between time-matched changes in intervals with lacosamide plasma concentrations was explored using a linear regression model with individual subject data. Further details of the PK analyses are provided in the Supporting Information. Results Volunteer disposition, demographics, and baseline characteristics
Of 247 randomized healthy volunteers, 220 (89.1%) completed the trial (Table 1). Twentyseven volunteers discontinued prior to completing dosing and were not included in the PDS; their replacements who completed the assigned dosing regimen were included in the PDS. ECG H-12 data were missing from six volunteers who were excluded from the PDS. Patient demographics were comparable across treatment groups. Electrocardiographic evaluation
QTc interval – The maximum time-matched changes from baseline in placebo-corrected QTcI were 4.3 and 6.3 ms for lacosamide 400 and 800 mg/day, respectively (Table 2). The upper limits of the 90% CIs for both lacosamide dose groups ( 0.5 ms for 400 mg/day and 2.5 ms
Lacosamide Thorough QT/QTc Trial Table 1 Analysis populations, volunteer disposition, and baseline demographics Lacosamide Placebo Randomized and treated, n (%) Safety Set (SS) Discontinued Reason for discontinuation Adverse event Withdrew consent No Holter card available Completed Insufficient ECG data Pharmacodynamic Set (PDS) Pharmacokinetic Set (PKS) Age, mean (SD), years Female, n (%) Weight, mean (SD), kg BMI, mean (SD), kg/m2 Race/ethnicity, n (%) White Black Asian Other
62 (100.0) 62 (100.0) 7 (11.3) 0 4 3 55 1 54 N/A 24.1 32 72.9 24.7 51 2 2 7
400 mg/day
800 mg/day
Moxifloxacin
60 (100.0) 60 (100.0) 3 (5.0)
71 (100.0) 71 (100.0) 17 (23.9)
54 (100.0) 54 (100.0) 0
(6.1) (51.6) (11.9) (3.0)
0 1 2 57 1 56 57 24.7 33 72.9 25.1
(82.3) (3.2) (3.2) (11.3)
54 1 3 2
(6.5) (4.8) (88.7)
(2.8) (15.5) (5.6) (76.1)
(6.4) (55.0) (12.1) (3.1)
2 11 4 54 2 52 53 24.9 43 69.4 23.9
(90.0) (1.7) (5.0) (3.3)
65 3 1 2
(91.5) (4.2) (1.4) (2.8)
(1.7) (3.3) (95.0)
(6.7) (60.6)a (11.9) (3.1)
0 0 0 54 2 52 N/A 25.1 27 75.8 25.5 48 3 2 1
Total 247 (100.0) 247 (100.0) 27 (10.9)
(7.3) (50.0) (13.0) (3.22)
2 16 9 220 6 214 110 24.7 135 72.5 24.7
(6.6) (54.7) (12.3) (3.2)
(88.9) (5.6) (3.7) (1.9)
218 9 8 12
(88.3) (3.6) (3.2) (4.9)
(100.0)
(0.8) (6.5) (3.5) (89.1)
a There was a slightly greater percentage of females in the 800 mg/day lacosamide group because more females than males did not complete treatment through Day 6 and, per protocol, each was replaced with a female who received the same treatment.
for 800 mg/day) were below the +10 ms non-inferiority margin, indicating no increase of QTcI. Assay sensitivity was established using the moxifloxacin group as the change was +10.4 ms with a lower 90% confidence bound of >0 (6.6 ms). Results were similar in males and females (data not shown). The maximum time-matched change from baseline analysis for QTcF and QTcB produced similar results (Table 2). The primary variable (QTcI) results were strongly supported by the assessment of non-inferiority at each of the 12 time-points for Day 3 (moxifloxacin-placebo) and Day 6 (lacosamideplacebo) (Fig. 1A). Likewise, the difference from placebo in time-averaged QTcI change from baseline (mean; 90% CI) showed an increase for the Table 2 ANCOVA for placebo-corrected maximum time-matched change from baseline in QTc interval (Day 6, PDS) Lacosamide 400 mg/day n = 56 QTcI, mean (CI), ms QTcF, mean (CI), ms QTcB, mean (CI), ms
4.3 ( 8.0, 4.4 ( 7.6, 4.5 ( 9.0,
0.5) 1.2) 0.1)
800 mg/day n = 52 6.3 ( 10.0, 2.5) 7.1 ( 10.4, 3.9) 2.9 ( 7.4, 1.7)
Moxifloxacin n = 52 10.4 (6.6, 14.2) 10.4 (7.2, 13.7) 5.0 (0.4, 9.5)
ANCOVA, analysis of covariance; CI, 90% confidence interval; PDS, Pharmacodynamic Set; ms, millisecond. CIs are for treatment differences, based on ANCOVA model with effects for treatment and gender and time-matched baseline QTcI as a covariate.
moxifloxacin group (9.8 ms; 7.4, 12.1) and a slight decrease for lacosamide 400 mg/day ( 2.5 ms; 4.8, 0.2) and 800 mg/day ( 4.5 ms; 6.9, 2.2). Outlier analysis revealed that 15.4%, 7.4%, 5.4%, and 1.9% of volunteers in the moxifloxacin, placebo, lacosamide 400 mg/day, and 800 mg/day groups, respectively, had a QTcI that was ≥450 to 480 ms. The frequency of volunteers exhibiting a QTcI change from baseline ≥30 to 100 ms was greater for both lacosamide groups relative to placebo and not dose related (Table 3). No volunteer had a TE QRS duration >120 ms. PR interval – Compared with placebo, treatment with lacosamide resulted in dose-related timematched changes in PR interval from baseline (Fig. 1D). The maximum mean increase in PR interval occurred at tmax (1 h post-dosing on Day 6) and was 6.3, 13.6, and 18.2 ms for placebo, 400 mg/day and 800 mg/day lacosamide, respectively. These values correspond with
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placebo-subtracted maximum mean increases of 7.3 ms for lacosamide 400 mg/day and 11.9 ms for 800 mg/day. The difference from placebo in time-averaged change from baseline (mean; 95% CI) was also smaller for lacosamide 400 mg/day (6.5 ms; 3.9, 9.0) than 800 mg/day (9.4 ms; 6.8, 12). There was a similar frequency of TE PRinterval outliers for the placebo and lacosamide 400 mg/day groups (Table 3) and a higher frequency of PR-interval outliers in the lacosamide 800 mg/day group. One volunteer from this group had a single PR-interval value >250 ms (251 ms), 1 h following dosing on Day 6; the time-matched baseline value was 193 ms. Other ECG and morphological findings – The most common TE ECG diagnostic finding was sinus tachycardia, observed with similar frequency in the lacosamide and placebo groups. Bradycardia was most frequent in the placebo group (Table 4). A similar percentage of all T-wave findings was observed across treatment groups; however, a higher percentage of volunteers in the lacosamide 800 mg/day group had inverted T-waves, which was not associated with any ischemia-related AE. The frequency of firstdegree AV block (PR interval >200 ms) was
Lacosamide Thorough QT/QTc Trial Table 3 Treatment-emergent outlier analysis (PDS, Treatment Phase)
Table 4 Treatment-emergent ECG diagnostic findings (PDS)a,b
Change from baselinea QTcI,b n (%)
N
120 msd
>140 msd
Placebo Lacosamide 400 mg/day Lacosamide 800 mg/day
54 56 52
16 (29.6) 28 (50.0) 22 (42.3)
0 0 0
0 0 0
PR interval, n (%)
N
>200 ms
>220 ms
>250 ms
Placebo Lacosamide 400 mg/day Lacosamide 800 mg/day
54 56 52
2 (3.7) 2 (3.6) 12 (23.1)
0 1 (1.8) 3 (5.8)
0 0 1 (1.9)
ECG findings (central reader criteria) Sinus tachycardia (HR >100 bpm) Sinus bradycardia (HR 200 ms) Intraventricular conduction defect (QRS duration >110 ms) T-waves Flat Biphasic Inverted Depressed ST segment Prolonged QTc Bazett (>499 ms)
Placebo N = 54 n (%) 30 9 4 1 3
(55.6) (16.7) (7.4) (1.9) (5.6)
0 20 6 16 7 1 3
Lacosamide 400 mg/day N = 56 n (%) 27 1 1 1 2
(48.2) (1.8) (1.8) (1.8) (3.6)
2 (3.6) (37.0) (11.1) (29.6) (13.0) (1.9) (5.6)
17 4 13 6 0 3
(30.4) (7.1) (23.2) (10.7) (5.4)
Lacosamide 800 mg/day N = 52 n (%) 31 3 1 1 11
(59.6) (5.8) (1.9) (1.9) (21.2)
2 (3.8) 19 4 12 15 1 1
(36.5) (7.7) (23.1) (28.8) (1.9) (1.9)
HR, heart rate; bpm, beats per minute; ms, milliseconds. Treatment-emergent ECG findings occurred on any ECG during the treatment phase, but not on any ECG on Day 1. b Treatment-emergent ECG findings reported for more than one subject across groups. a
d
d
d
a
Number of subjects with one or more post-baseline values meeting the criteria when compared to time-matched baseline. b QTc ≥450 ms, ≥480 ms, and ≥500 ms when not present at time-matched baseline (new onset), and increases of >0 to 100 bpm time-point. d Number of subjects meeting criteria at one or more time-points during treatment but not at the corresponding time-matched baseline.
similar between placebo and the lacosamide 400 mg/day group, but higher in the lacosamide 800 mg/day group. There were no reports of second-degree or higher AV block, or bundle branch block. Pharmacokinetic evaluation
The mean plasma concentration of lacosamide increased within 1–2 h (2–4 h for the main metabolite) following dosing. Maximum mean lacosamide concentration (Cmax,ss) was dose proportional: 10.9 lg/ml following 200 mg in the 400 mg/day group and 21.3 lg/ml following 400 mg in the 800 mg/day group. The maximum mean concentration of the metabolite was 1.3 lg/ml and 2.5 lg/ml, respectively. Lacosamide tmax,ss (median = 1 h) was the same for both groups. A dose-proportional increase in AUCs,ss was observed (from 100.3 lg/ml∙hr following lacosamide 400 mg/day to 195.7 lg/ml∙hr following lacosamide 800 mg/day). Normalization of Cmax, ss and AUCs,ss by dose and body weight eliminated small gender differences and produced
nearly identical values among the two lacosamide treatment groups (Cmax,ss,norm: 3.925 vs 3.699 lg/ml*kg/mg, 200 mg bid vs 400 mg bid; AUCs,ss,norm: 36.04 vs 33.96 lg/ml∙h*kg/mg). Summary statistics of PK parameters are provided in Supporting Information Table 2. Pharmacodynamic/pharmacokinetic relationship
There was no relationship between lacosamide plasma concentration and changes in QTcI values (Fig. S1). The concentration–response relationship for PR-interval change is shown in Fig. 2. The regression equation predicts that the maximum steady-state concentrations (~11 lg/ml and ~21 lg/ml) associated with 400 mg/day and 800 mg/day lacosamide would result in a mean PR-interval change from baseline of ~+5.8 ms and ~+9.5 ms. Safety and tolerability
Adverse events – The most common TEAEs (≥10% in any group) were dizziness (6.5% placebo, 10.0% lacosamide 400 mg/day, 54.9% lacosamide 800 mg/day); nausea (1.6%, 8.3%, 26.8%); headache (14.5%, 16.7%, 22.5%); hypoesthesia oral (0.0%, 1.7%, 21.1%); feeling drunk (3.2%, 8.3%, 15.5%); and vomiting (0.0%, 5.0%, 12.7%). One serious TEAE was reported: a spontaneous abortion that occurred 9 days following withdrawal from lacosamide 800 mg/day in a
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Kropeit et al.
Figure 2. Time-matched change in PR interval and lacosamide plasma concentration (Day 6, PDS). Individual data points and the associated regression (solid) line with 95% confidence intervals (dotted lines) for all lacosamide-treated volunteers. For reference and comparison, the spread of the placebo data points for change in PR interval (12 evaluations on Day 6) is shown at zero lacosamide concentration. The vertical dotted and solid lines indicate the mean plasma concentration at tmax for 400 mg/day and 800 mg/day of lacosamide. Pearson coefficient = 0.14. Regression equation: PR change from baseline (ms) = (intercept) 1.661138 + (slope) 0.375588*lacosamide (lg/ml).
41-year-old female who had negative pregnancy tests at baseline and reported the use of a barrier contraceptive method. Two subjects from the lacosamide 800 mg/day group were withdrawn from the trial due to TEAEs: one due to neck pain, the other due to feeling drunk on Day 1, which resolved and was followed by nausea, feeling hot, ear discomfort, and vomiting on Day 3. On the evening of Day 4 (after 2 days of 400 mg lacosamide bid dosing), the same volunteer had moderate syncope that resolved in 2 min. On Day 5, the volunteer developed abdominal pain upper, hematemesis, Mallory-Weiss syndrome, and dizziness that resulted in withdrawal from the trial. Each of these AEs resolved on the day of onset or by the next day. The only cardiac-related TEAEs reported were palpitations [two (3.2%), two (3.3%), and three (4.2%) volunteers in the placebo, lacosamide 400 mg/day, and 800 mg/day groups, respectively] and HR increased (one volunteer in the lacosamide 800 mg/day group). None had a prolonged PR interval during treatment (single maximum PR-interval value was 168 ms). Treatment-emergent ECG findings for these eight subjects were sinus tachycardia (in both placebo subjects and one each in the lacosamide 400 mg/ day and 800 mg/day groups) and flat T-waves in both placebo subjects. Other safety assessments – Results for the single assessment of orthostatic changes in BP and pulse rate were similar in placebo and lacosamide groups on Day 6 and baseline orthostatic assessments. The mean (SD) changes from baseline for supine assessments of systolic BP were –2.5
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(9.8), 1.9 (8.6), and 8.6 (9.7) mmHg in the placebo and lacosamide 400 and 800 mg/day groups. Respective changes in diastolic BP were 2.0 (6.5), 3.9 (7.2), and 10.3 (7.4) mmHg. No volunteers met study criteria for an abnormally high BP. There were no changes in laboratory parameters or physical examination findings attributed to trial medication. Discussion
This thorough QT/QTc trial provides the primary characterization of the ECG and cardiac safety profile of the anti epileptic drug (AED) lacosamide, in healthy volunteers. Serial ECGs throughout the dosing intervals at steady state on Day 6 resulted in a complete systematic assessment of primary (QTcI interval) and secondary ECG variables, as well as PK parameters. The primary maximum timematched change from baseline QTcI analysis, demonstrated that lacosamide did not increase QTcI at either the maximum-recommended (400 mg/day) or a supratherapeutic dosage (800 mg/day). Assay sensitivity was proven using moxifloxacin; therefore, this trial is a negative QTc trial for lacosamide, as per the criteria defined in the ICH E14 Guidance for Industry (12). Time-matched analysis, repeated measure analysis, and time-averaged assessments for QTcI, as well as outlier analyses, were consistent with the primary QTcI analysis. A slight decrease in QTcI was observed in the placebo and lacosamide groups; however, the clinical relevance of this observation is unknown. Decreases in QTc have been reported in thorough QTc trials for lamotrigine (13) and eslicarbazepine (14).
Lacosamide Thorough QT/QTc Trial Analyses of QRS duration did not identify dose-related or clinically relevant changes in lacosamide groups. The time-averaged change from baseline in HR was ~5 bpm greater with lacosamide 800 mg/day compared with placebo or lacosamide 400 mg/day, a difference that was relatively consistent throughout the dosing interval. It is unclear if this observation was due to a direct cardiovascular effect, central nervous system effects (such as dizziness), or a combination of the two. A similar increase in HR over placebo was reported in healthy volunteers in thorough QTc trials of the sodium channel-blocking AEDs lamotrigine (13) and eslicarbazepine (14). A small, dose-related increase from baseline in PR interval, maximal at 1 h (time of tmax), was observed. The relatively flat relationship between lacosamide plasma concentration and change from baseline in PR interval suggests a wide margin of safety with regard to PR interval in healthy volunteers. First-degree AV block was reported with similar frequency in placebo and lacosamide 400 mg/day groups, and with an increased frequency in the lacosamide 800 mg/day group. No associated AEs were reported. Importantly, no volunteer showed second-degree or higher AV block. Small increases in PR interval have been observed with AEDs that act on voltage-gated sodium channel fast inactivation [including carbamazepine (15), lamotrigine (16), and eslicarbazepine (14)] and also those with other mechanisms of action [e.g., pregabalin (17)]. Volunteers with a baseline PR interval >220 ms were excluded; however, those with TE firstdegree AV block and/or TE PR intervals >220 ms were allowed to continue. This did not lead to cardiac-related AEs. If lacosamide increases PR interval through inhibition of slow inactivation of voltage-gated sodium channels, then myocardial ischemia could magnify or potentiate this effect. Thus, precaution is warranted in certain patient populations (3, 4, 11). There have been a few published individual case reports of cardiac-related adverse events in patients with POS treated with lacosamide including bradycardia, second-degree AV block (Mobitz Type I), ventricular tachycardia, sinus node dysfunction, and atrial flutter/fibrillation. These individual case reports are reviewed in more detail in the companion article by Rudd et al. (11). Initiation of lacosamide at the maximum-recommended dosage (400 mg/day) was generally well tolerated. The dose-related and higher incidence of nervous system and gastrointestinal AEs was consistent with results observed with lacosamide treatment in trials in patients with POS (10).
The small increase in BP observed in the lacosamide 800 mg/day group was not associated with AEs and contrasts with the hypotension observed in anesthetized animal models (8). This is the largest PK study lacosamide in healthy volunteers. Lacosamide exposure was dose proportional up to the supratherapeutic dosage of 800 mg/day (400 mg bid). Mean Cmax,ss and AUCs,ss (normalized by dose) were consistent with published data in healthy subjects (18). In this thorough QT/QTc trial in healthy volunteers, lacosamide doses ≤800 mg/day did not prolong the QTc interval; therefore, lacosamide does not affect ventricular repolarization. Secondary outcomes revealed a small, doserelated increase in mean PR interval, not associated with AEs. While there are limitations to the interpretation of any study in healthy volunteers (namely the lack of comorbidities often seen in the patient population, such as existing cardiac conditions, and interactions with concomitant medications), the lacosamide cardiac safety and PK profiles observed in healthy volunteers were consistent with observations in patients with POS receiving adjunctive lacosamide. Acknowledgments Medical writing support was provided by Kristen A. Andersen, PhD of Prescott Medical Communications Group (Chicago, IL) and Jonathon Gibbs, BSc of Evidence Scientific Solutions Ltd (Horsham, UK). Publication management in the form of publication coordination was provided by Azita Tofighy, PhD and Laurent Turet, PhD; employees of UCB Pharma.
Conflict of interests D. Kropeit is a former employee of Schwarz Biosciences, Monheim, Germany (acquired by UCB Pharma). M. Johnson and W. Cawello are employees of UCB Pharma. G.D. Rudd initiated work on this article while an employee of UCB Pharma, Raleigh, NC and completed work on this article as a paid consultant to UCB and, as a retiree, receives deferred compensation and holds UCB stock options. R. Horstmann is a former employee of UCB Pharma, Monheim am Rhein, Germany.
Supporting Information Additional Supporting Information may be found in the online version of this article. Figure S1. Time-matched changes in QTcI interval (Day 6) Table S1. Key trial events and timing. Table S2. Summary statistics for PK parameters derived at steady-state (Day 6) Appendix S1. Materials and methods.
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