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Keywords:

  • antiepileptics;
  • brivaracetam;
  • pharmacodynamics;
  • pharmacokinetics;
  • tolerability;
  • ucb 34714

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported.

• Previous studies have shown that it was well absorbed, had linear kinetics and was well tolerated, and suggested effective doses of 10–80 mg in photoparoxysmal epilepsy.

WHAT THIS STUDY ADDS

• We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses.

AIMS

Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects.

METHODS

Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day−1 (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days.

RESULTS

Brivaracetam was rapidly absorbed (tmax∼2 h) and eliminated (t1/2 7–8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5–8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-β-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily.

CONCLUSIONS

Brivaracetam was well tolerated by healthy male volunteers at doses of 200–800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES

Brivaracetam {(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl] butanamide} is a novel member of the racetam family of anticonvulsants and displays high and selective affinity for the levetiracetam binding site in the brain, now identified as synaptic vesicle protein 2A [1]. We have previously reported three single-dose studies: the first human study [2], mass balance and metabolism [3], and proof of principle in photosensitive epilepsy [4]. We now report the first multiple-dose human study with brivaracetam.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES

Study design

The study was of double-blind, placebo-controlled, parallel-group sequential cohort design. The protocol was reviewed and approved by the Independent Ethics Committee, Manchester, UK and the study was conducted at Medeval Ltd, Manchester, UK in accordance with the latest version of the Declaration of Helsinki. Thirty-six healthy nonsmoking male volunteers of mean (SD) age 28.4 (8.0) years and weight 73.0 (6.3) kg were randomly allocated to one of three cohorts of 12 subjects. In each cohort of 12 volunteers, nine received oral brivaracetam 100, 200 or 400 mg once daily on days 1 and 14 and twice daily on days 2–13 and three received matching placebo, in the form of hard gelatin capsules containing 100 or 200 mg or drug substance or microcrystalline cellulose. The subjects were confined in the clinical unit from the evening before the first dose until 1 day after the last dose.

Evaluation criteria

For pharmacokinetic assessment of brivaracetam and metabolites, blood samples were taken pre-morning dose and at 0.5, 1, 2, 3, 4, 6, 9 and 12 h subsequently on days 1, 7 and 14, with samples at 16 h also on days 1 and 14. Saliva samples were taken at the same time as plasma samples on day 7 only. Pre-morning dose samples were taken on days 2, 5, 6, 8, 12 and 13 and on days 15 and 16 at 24, 36 and 48 h after the last dose. Urine was collected 0–12 h and 12–24 h on days 1, 7, 14 and 15.

In addition to spontaneous adverse events reporting, pharmacodynamics were assessed by daily Addiction Research Center Inventory (ARCI)-49 rating scale [5] and visual analogue scales (VAS) [6] (administered at 0, 1, 3, 9, 12 h on days 1, 7 and 14 and at 3 h on other days) and second-daily neurological assessments including the International Co-Operative Ataxia Rating Scale Examination (ICARS) [7]. Safety was assessed by routine laboratory tests, vital signs, ECG and physical examination.

Drug analysis

Brivaracetam was quantified in plasma, urine and saliva samples after prepurification on solid-phase extraction cartridges, using a previously described liquid chromatography/electrospray ionization/mass spectrometry assay method [2]. The method was extended to the assay of brivaracetam in saliva following 10-fold dilution in reference plasma. Two major urinary metabolites were also quantified [3]: M9 (the product of amide hydrolysis) and M1b (stereospecific ω-1 hydroxylation product on the propyl side-chain). The method for both metabolites had a quantification range of 0.25–10 μg ml−1.

Urinary concentrations of cortisol and 6 β-hydroxycortisol were determined at Cephac Laboratories (Saint Benoit, France) using commercial radioimmunoassay (CORT-CT2; Cis Bio International, Bagnols sur Ceze, France) and enzyme immunoassay (Stabiligen, Villers-les-Nancy, France) kits, respectively.

Pharmacokinetic analysis

Standard noncompartmental methods were used to calculate the following parameters: maximum plasma concentration (Cmax), time of Cmax (tmax), area under the plasma concentration–time curve extrapolated to infinity (AUC) (only after the single dose on day 1), AUC over a dosing interval (AUCτ), terminal elimination half-life (t1/2) (not day 7), apparent plasma clearance (CL/F), apparent distribution volume (Vz/F) (not day 7) and apparent distribution volume at steady state (Vss/F). The fractions of the dose excreted in urine as brivaracetam, and as the metabolites M9 and M1b, fe, were obtained over 24 h (day 1) or 12 h (days 7 and 14). The renal clearance of brivaracetam, CLR, was derived as Ae/AUC, where Ae is the amount of drug excreted in urine. All pharmacokinetic calculations were carried out using WinNonlin 4.0.1 (Pharsight Corp., Cary, NC, USA).

The ratio of the 24-h urinary excretion of 6-β-hydroxycortisol to cortisol was calculated as an indicator of CYP3A4 activity [8].

Statistical analysis

Dose proportionality for AUC and Cmax was explored using a power model [9]. A single factor analysis of variance (anova) with pairwise comparison between doses was applied on the dose-normalized (ln) parameters. Linear regression was performed between the ln transformed parameters and the ln transformed dose.

An anova and pairwise comparisons were performed on CL/F on days 1, 7 and 14, following ln transformation. The ratio of the geometric least square means and its 90% confidence interval (CI) were calculated using ln-transformed parameters for each comparison and dose.

CYP3A4 induction potential was assessed by anova and pairwise comparisons of the 6β-hydroxy cortisol/cortisol ratios obtained from the 24-h urine collections on days 1, 7 and 14.

The correlation between saliva and plasma levels of brivaracetam was evaluated by weighted linear least-squares regression.

All statistical calculations were made using SAS version 8.1 (SAS Institute, Cary, NC, USA) or Proc-StatXact version 4.01 (Cytel Software, Cambridge, MA, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES

All subjects received the study medication and completed the study as planned with no withdrawals.

Tolerability

Adverse events are listed in Table 1. All adverse events were either mild or moderate and almost all were related to the central nervous system (CNS). The most frequently reported adverse events were dizziness and euphoria, and these occurred in a dose-related manner. All subjects at the highest daily dose of 800 mg reported adverse events. At the higher doses, adverse events were most likely to be reported on the first study day with the frequency being similar across all treatment groups (including placebo) from the second day onwards, suggesting rapid tolerance to the adverse effects.

Table 1.  Treatment-emergent adverse events reported by more than one subject by treatment group (ITT population)
 Placebo (n = 9)Brivaracetam daily dose
200 mg (n = 9)400 mg (n = 9)800 mg (n = 9)
  1. AE, adverse event.

Number of subjects reporting AEs (%)7 (78)6 (67)8 (89)9 (100)
Number of AEs27223438
Specific AEs, n (%)
Dizziness1 (11)3 (33)6 (67)8 (89)
Headache2 (22)04 (44)3 (33)
Somnolence2 (22)2 (22)4 (44)1 (11)
Euphoric mood001 (11)4 (44)
Throat irritation03 (33)1 (11)0
Fatigue2 (22)01 (11)2 (22)
Nausea1 (11)02 (22)1 (11)
Hypotension001 (11)1 (11)
Feeling drunk01 (11)1 (11)0
Blurred vision01 (11)1 (11)0
Disturbance of attention1 (11)1 (11)00

Safety

Vital signs showed trends for heart rate (HR) and systolic blood pressure (SBP) to be lower compared with placebo. The mean (SD) HR change from baseline on day 14 at 3 h post dose was +3 (11), −3 (7), −5 (8), −9 (11) beats per minute for placebo, 200, 400 and 800 mg, respectively; the mean (SD) SBP change from baseline was −8 (16), −16 (9), −15 (11), −10 (9) mmHg.

Liver enzymes (aspartate aminotransferase or alanine aminotransferase) above the normal range were sporadically observed in six of the nine subjects receiving placebo; one of the nine subjects receiving 200 mg; two of the nine subjects receiving 400 mg; and none of the nine subjects receiving 800 mg.

No clinically relevant ECG abnormalities or changes from baseline were observed at any time. Bazett's formula was found to provide the optimal correction for QT intervals (QTcB). The distributions of QTcB values and of maximum changes from baseline were similar among the four treatment groups. The number of subjects with an increased QTcB of <30/30–60/>60 ms from baseline at any time during the study was 7/0/2 (placebo), 7/1/1 (200 mg), 5/3/1 (400 mg) and 7/2/0 (800 mg).

Pharmacokinetics

A summary of pharmacokinetic variables is shown in Table 2. Brivaracetam appeared to be well absorbed, with median tmax between 1 and 2 h with low coefficients of variation of Cmax (<25%). The point estimate (90% CI) for ratio of AUC day 14/day 1 was 1.14 (1.11, 1.18) at 800 mg. Coefficients of variation for AUC were low (15–18%), suggesting low between-subject variability.

Table 2.  Plasma and urinary pharmacokinetic parameters after single (day 1) and multiple (days 7 and 14) brivaracetam doses of 200, 400 and 800 mg daily
ParameterBrivaracetam daily dose
200 mg (n = 9)400 mg (n = 9)800 mg (n = 9)
Day 1Day 7Day 14Day 1Day 7Day 14Day 1Day 7Day 14
  • *

    Geometric mean (CV%).

  • AUC extrapolated to infinity on day 1, AUCτ on days 7 and 14.

  • Median (range). fe, fraction of the brivaracetam dose excreted in urine over 24 h (day 1) or over 12 h (days 7 and 14); CLR, renal clearance of brivaracetam; CV%, coefficient of variation of the geometric mean.

Cmax (μg ml−1)*2.2 (14)3.5 (22)3.5 (20)4.7 (10)7.3 (11)7.7 (26)9.0 (23)12.4 (21)13.3 (25)
AUC (μg h−1 ml−1)*27.5 (23)27.7 (21)28.0 (24)56.0 (15)55.2 (14)55.4 (18)104.1 (18)93.1 (22)90.8 (20)
tmax (h)2 (1–4)2 (1–3)2 (1–2)2 (0.5–2)2 (0.5–3)2 (0.5–4)2 (0.5–3)1 (0.5–2)1 (0.5–3)
t1/2 (h)*7.7 (20)7.3 (26)7.3 (16)6.8 (20)7.8 (18)6.3 (21)
MRT (h)*11.8 (17)10.9 (26)11.1 (14)10.3 (19)11.8 (18)9.7 (20)
CL/F (ml min−1 kg−1)*0.83 (21)0.83 (21)0.82 (23)0.82 (14)0.83 (16)0.83 (19)0.83 (16)0.93 (18)0.95 (15)
Vz/F (l kg−1)*0.55 (8.7)0.52 (11)0.52 (7.7)0.49 (6.1)0.56 (8.9)0.52 (10)
fe brivaracetam (%)*4.6 (30)5.1 (47)5.7 (49)5.4 (38)8.2 (23)6.8 (32)6.0 (38)6.6 (41)5.5 (44)
fe M9 (%)*16.5 (39)17.6 (42)22.3 (42)21.7 (34)28.4 (40)26.7 (28)24.3 (25)25.6 (30)25.4 (37)
fe M1b (%)*11.4 (62)15.1 (66)20.6 (55)11.4 (51)21.8 (36)22.3 (40)9.6 (41)19.2 (38)21.3 (48)
CLR (ml min−1 kg−1)*0.04 (30)0.04 (42)0.05 (39)0.04 (42)0.07 (30)0.06 (36)0.05 (45)0.06 (31)0.05 (46)

The induction potential of brivaracetam on CYP3A4 activity was examined by anova analysis of the 6-β-hydroxycortisol/cortisol ratios in 24 h urine. Point estimates (and 90% CIs) for the ratios day 14/1 were: placebo 0.83 (0.62, 1.11); 200 mg day−1 0.87 (0.62, 1.21); 400 mg day−1 1.18 (0.88, 1.57); and 800 mg day−1 1.23 (0.90, 1.69). Hence there appeared to be no clear evidence of CYP3A4 induction.

Urinary recovery of parent drug over one dosing interval was between 5 and 8%, with between 33 and 49% additionally recovered as two metabolites. Renal clearance of parent drug was approximately 3 ml min−1. Considering that binding to plasma proteins is low [3], this suggests that substantial tubular reabsorption must occur.

Saliva concentration–time profiles on day 7 paralleled those in plasma with no hysteresis. Optimal linear least-squares regression fitting was obtained using 1/x2 weighting. There was a strong correlation between saliva and plasma levels (r = 0.97, n = 241) with a slope (standard error) of 0.88 (0.01) and intercept of −0.15 (0.04). This is close to that predicted as a plasma ultrafiltrate given the plasma protein binding of <18% and that brivaracetam is not ionizable.

Pharmacodynamics

The psychometric tests and rating scales indicated that brivaracetam in the high-dose range assessed in this study (200–800 mg day−1) was associated with dose-related sedation and decreased alertness. For subjects on placebo, 200, 400 and 800 mg daily, the mean (SD) area under the change from baseline (ΔAUC0−12 h) on day 7 was 3 (9), 6 (13), 12 (42) 17 (21) for the Pentobarbital-Chlorpromazine-Alcohol Group subscale of the ARCI-49 questionnaire, which measures sedative drug effects. Regarding the VAS alertness scale (for which increased values are associated with reduced alertness), the mean (SD) ΔAUC0−12 h values were −2 (26), 5 (22), 46 (109) and 57 (95). The other subscales of the ARCI-49 (euphoria, psychomimetic and dysphoric changes, amphetamine-stimulating effects, stimulating effects) showed no trends for changes. There were no trends for changes on the calmness VAS scale, ataxia (ICARS) or other neurological examinations.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES

The aim of this study was to assess the safety, tolerability, pharmacokinetics and CNS pharmacodynamic effects of repeated oral doses of brivaracetam in healthy men. Brivaracetam was well tolerated over the dose range 200–800 mg daily for 2 weeks. The safety profile following multiple doses of brivaracetam was consistent with that seen in the previous single-dose study. In both studies, the adverse events typically associated with brivaracetam were those generally expected with a drug that acts on the CNS, such as dizziness and somnolence. In the multiple-dose study, almost all subjects experienced mild or moderate adverse events after the first dose of brivaracetam, but most symptoms resolved the same day. Adverse events occurred less frequently on subsequent days, indicating a degree of tolerance to the adverse effects of brivaracetam. The battery of pharmacodynamic tests supported the finding of mild dose-related sedative effects and was also consistent with the previous study. However, although actively sought, clinically important adverse effects such as ataxia were absent, despite the doses being in excess of those thought necessary for clinical use.

The pharmacokinetic profile of brivaracetam following the first dose in this multiple-dose study was consistent with that seen in the previous single-dose study. There was remarkably little difference in mean values for CL/F, Vss/F, or t1/2 across the three panels in this study. When combined with the low within-group coefficients of variation (typically <25%), this confirms low intersubject variability, which is clinically desirable. Mean values of CL/F on day 1 in this study (0.82–0.83 ml min−1 kg−1) compared well with the range 0.70–1.07 ml min−1 kg−1 over the single-dose range 10–1400 mg in the previous study. Mean values of t1/2 7.3–7.8 h in this study compared well with the range 7.3–8.2 h in the previous study.

The observed limited renal excretion of unchanged brivaracetam (5–8%) together with the presence of significant levels of metabolites in the urine indicates that the compound is predominantly cleared by metabolism. The increase in apparent total body clearance was only modest, indicating that more frequent dosing is not warranted at higher doses of brivaracetam. This study provided no evidence that brivaracetam significantly induces CYP3A4 activity at 200–800 mg daily doses, suggesting a low potential for interaction with drugs that are substrates for this enzyme. Laboratory investigations showed that CYP3A4 plays a minor role in the formation of M1b [3].

Further, photoparoxysmal EEG response was reduced or abolished in subjects with photosensitive epilepsy receiving single doses of 10–80 mg brivaracetam, and all subjects receiving 80 mg exhibited total suppression during 60 h (range 28–72 h) [4]. The present findings suggest that brivaracetam is well tolerated during multiple dosing at daily doses one order of magnitude above the expected clinically effective dose.

Since brivaracetam is a small molecule that is weakly protein-bound and not ionizable, it would be expected to diffuse from plasma to saliva and rapidly equilibrate to a comparable concentration. Saliva concentrations of brivaracetam were highly correlated with plasma concentrations, and the slope was similar to the protein-unbound fraction of brivaracetam. This suggests that brivaracetam diffuses passively through the mucosa. Further, despite larger variability than in plasma, saliva might be a suitable analytic matrix for therapeutic drug monitoring when blood sampling is a limiting factor (e.g. children).

In conclusion, this study has shown that brivaracetam was well tolerated by healthy male subjects at multiple oral doses of 200–800 mg daily for 2 weeks, expected to be one order of magnitude above the clinically effective dose. As expected, adverse events were mostly CNS-related, mild or moderate, and had a rapid onset and short duration. Pharmacodynamic tests identified a sedative effect that only persisted at the highest dose. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality.

This study was funded by UCB Pharma S.A. The authors wish to acknowledge the contributions of Tom Jacobs for statistical calculations and Dominique Tytgat for bioanalytical determinations.

Competing interests: M.-L. Sargentini-Maier and A. Stockis are permanent employees of UCB Pharma S.A.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. REFERENCES
  • 1
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  • 2
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