Brivaracetam Single and Multiple Rising Oral Dose Study in Healthy Japanese Participants: Inﬂuence of CYP2C19 Genotype

Drug Metab. Pharmacokinet. 29 (5): 394–399 (2014). Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX) Regular Article Brivaracetam Single and Multiple Rising Oral Dose Study in Healthy Japanese Participants: Inﬂuence of CYP2C19 Genotype

Armel STOCKIS1,*,ShikikoWATANABE1, Elisabeth ROUITS1,KyokoMATSUGUMA2 and Shin IRIE2 1UCB Pharma, Braine l’Alleud, Belgium 2Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan

Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk

Summary: Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in phase 3 clinical development for epilepsy. A phase 1, single-center, randomized, double-blind, placebo-controlled, single (2.5 100 mg) and multiple (2.550 mg twice daily) rising oral dose study (N01209) was conducted to assess the adverse event profile and pharmacokinetics of brivaracetam in healthy Japanese men, and the influence of the cytochrome P450 (CYP) 2C19 genotype. Plasma and urine were collected serially for analysis of brivaracetam and its three main metabolites: acid, hydroxy and hydroxy acid. Overall, 79/80 randomized participants completed the study. Brivaracetam was generally well tolerated. After single- and multiple-dose administration, brivaracetam was rapidly absorbed, with dose-proportional pharmacokinetics over the dose ranges tested. Steady state was reached after 2 days of repeated dosing. Brivaracetam clearance (averaged across the five single dose levels) was reduced from 0.99 mL/min/kg in homozygous extensive metabolizers (EM; n = 10) to 0.81 mL/min/kg (¹18%) in heterozygous EM (n = 17) and 0.70 mL/min/kg (¹29%) in poor metabolizers (PM; n = 9). Exposure and urinary excretion of hydroxy metabolite were reduced 10-fold in PM participants, compared with EM participants. Results suggest that brivaracetam is hydroxylated by CYP2C19, but this pathway is minor compared with hydrolysis to the acid metabolite.

Keywords: anticonvulsants; clinical pharmacology; CYP2C19; pharmacokinetics; drug clearance

extensively metabolized and entirely eliminated in the urine, Introduction mostly as metabolites, with <10% as unchanged drug. The three Brivaracetam (Fig. 1) is a high-affinity synaptic vesicle protein main metabolites of brivaracetam (Fig. 1) are formed by amidase- 2A (SV2A) ligand1,2) in phase 3 clinical development for epilepsy. mediated hydrolysis of the acetamide group (acid, BRV-AC), CYP- In a wide range of animal models of partial-onset and generalized mediated hydroxylation (hydroxy, BRV-OH), and a combination seizures, brivaracetam demonstrated a potent suppression of of these two pathways (hydroxy acid, BRV-OHAC).11,13,14) The seizure activity.3) The efficacy and safety/tolerability of brivar- metabolites are not pharmacologically active in animal models of acetam were investigated in several phase 2/3 clinical trials at epilepsy (UCB data on file). doses ranging from 5 to 150 mg/day.4–8) Initial in vitro phenotyping assays suggested that brivaracetam Clinical pharmacology studies in European healthy participants hydroxylation into BRV-OH was mainly supported by the CYP2C8 have demonstrated that brivaracetam has a linear and predict- isoform of cytochrome P450, and to a lesser extent by the isoforms able pharmacokinetic profile, with low inter-subject variability.9–12) CYP3A4 and CYP2C19.15) Extensive in vitro inhibition assays Brivaracetam is rapidly and completely absorbed after oral admin- and the results of a gemfibrozil clinical interaction trial demons- istration and has a plasma half-life of approximately 8 h. It is trated that CYP2C8 and CYP2C9 were not involved in this

Received January 22, 2014; Accepted March 25, 2014 J-STAGE Advance Published Date: April 8, 2014, doi:10.2133/dmpk.DMPK-14-RG-010 *To whom correspondence should be addressed: Armel STOCKIS, Ph.D., UCB Pharma, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium. Tel. ©32-2-386-3331, Fax. ©32-2-386-2550, E-mail: [email protected] Primary laboratory of origin: Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan. This work was supported by UCB Pharma, which was responsible for the design and conduct of the study, and collection, management and analysis of the data. UCB Pharma was involved in the preparation and review of this manuscript, and covered all related costs. AS and SW are employees of UCB Pharma. ER was an employee of UCB Pharma when the study was conducted and the clinical study report was prepared. KM and SI received fees from UCB Pharma for their role as clinical investigators in the study. These data were presented in part at the 65th Annual Meeting of the American Epilepsy Society 2011, Baltimore, MD, USA, 2–6 December 2011. Stockis A, Watanabe S, Rouits E, Matsuguma K, Irie S. Double-blind, placebo-controlled single and multiple rising dose study of brivaracetam in healthy Japanese male subjects—inﬂuence of CYP2C19 genotype (Abstract 1.250). Available at: http://www.aesnet.org/go/publications/aes- abstracts/abstract-search/mode/display/st/stockis/sy/2011/sb/All/id/14664

394 Brivaracetam Pharmacokinetics in Japanese Participants 395

followed by twice daily (b.i.d.) dosing from Day 3 to Day 12. Participants remained in the study center from the day before the first dose until at least 48–72 h after the last dose. A follow-up examination was done 1 week after the last dose. All participants provided written informed consent, and the protocol was approved by the Medical Ethics Committee of Kyushu Clinical Pharmacology Research Clinic. Anonymous genotyping was only performed for participants who consented to participate in this part of the study. The study was conducted in accordance with Good Clinical Practice and the principles of the Declaration of Helsinki. Assessments: The tolerability and adverse event profile of brivaracetam were assessed by observed or spontaneously reported treatment-emergent adverse events (TEAEs), physical examina- tions, monitoring of blood pressure and heart rate, 12-lead ECGs and laboratory tests. All participants who consented were genotyped for the two Fig. 1. Structural formulae of brivaracetam and of hydroxy, acid and * * hydroxyacid metabolites CYP2C19 common polymorphisms, / 2 and / 3, using the Invader™ DNA assay method (Third Wave Technologies Inc., Madison, WI). Participants were classified as homozygous extensive metabolizers (EMs; *1/*1), heterozygous EMs (hEMs; *1/*2 biotransformation pathway,13) and suggested that CYP2C19 is the or *1/*3) or PMs (*2/*2, *2/*3or*3/*3). main isoform involved in the hydroxylation of brivaracetam. In the single-dose phase, blood samples were drawn pre-dose This study (N01209) was the first administration of and serially post-dose, and all urine was collected for up to 48 h brivaracetam in a Japanese population. The dose range of (2.5–50 mg) or 72 h (100 mg) after dosing. During the multiple- brivaracetam tested was based on results from clinical studies in dose phase, blood samples were taken immediately before dosing other populations.4,5) The primary objective of this study was to on pre-specified days. Blood samples were drawn serially after establish the tolerability, adverse event profile, and pharmaco- the first dose (Day 1) and following 10 days of multiple dosing kinetics of single and multiple oral doses of brivaracetam in healthy (Day 12), up to 72 h after the last dose. All urine was collected male Japanese adults. An additional objective was to explore over 12- or 24-h intervals, from the first dose until 72 h after the the influence of CYP2C19 genotype on the pharmacokinetics of last dose. Plasma and urine samples were stored at ¹20°C until brivaracetam in a Japanese population. The poor metabolizer (PM) analysis. genotype of CYP2C19 is present in a low percentage of European- Concentrations of brivaracetam, BRV-AC, BRV-OH and BRV- American and African-American populations, but can occur in as OHAC were determined in plasma and urine using liquid chro- many as 20% of the Asian population.16–18) matography with tandem mass spectrometry detection, as describ- ed previously.11) The lower limit of quantification for brivaracetam Methods and its metabolites was 2 ng/mL. Intermediate precision was ¯12% Study design: This was a phase 1, single-center, randomized, and recovery error was ¯8%. double-blind, placebo-controlled, single and multiple rising oral Pharmacokinetic and statistical calculations: Concentra- dose study. The study enrolled healthy Japanese men aged 20–40 tions below the lower limit of quantification were set to zero. years with a body mass index of 17.6 to <26.4 kg/m2. Participants Pharmacokinetic parameters were calculated by non-compartmen- had to be in good health, as determined by medical history, physi- tal methods, using WinNonlinμ version 4.0.1 (Pharsight Corpo- cal examination, vital signs, 12-lead electrocardiogram (ECG) and ration, Mountain View, CA). laboratory tests at a screening visit conducted up to 4 weeks before The maximum plasma concentration (Cmax), time to reach Cmax the first dose. Exclusion criteria included known drug sensitivity or (tmax), area under the plasma concentration-time curve from zero to food allergy, positive urine drug screen, alcohol dependence, heavy the last observation (AUCt), area under the plasma concentration- caffeine intake, smoking (more than four cigarettes per day), use time curve from zero to infinity (AUCinf; single-dose phase only), of any prescription or over-the-counter medication within 2 weeks, AUC over a dosing interval (AUÇ; multiple-dose phase only), or hepatic enzyme-inducing drugs within 2 months, or any other plasma elimination half-life (t1/2), and cumulative urinary excretion investigational product within 4 months prior to study drug (fe, in % of administered dose) were determined for brivaracetam administration, and grapefruit intake during the week before study and its metabolites. Apparent total clearance (CL/F) and apparent drug administration. volume of distribution (V/F) were determined for brivaracetam. Eight successive panels of 10 participants were randomized in Trough plasma concentrations of brivaracetam were determined a double-blind fashion to brivaracetam (eight participants) or a before the morning and evening doses during repeated dosing. matched placebo (two participants). Doses were increased step- The full analysis set (FAS) population was defined as all par- wise, dependent on safety evaluations at the previous dose level. ticipants who were randomized and allocated to treatment, exclud- The first five groups received single oral doses of 2.5, 10, 25, 50 ing those who did not provide written informed consent, did or 100 mg brivaracetam after an overnight fast. After completion not meet inclusion criteria, did not receive study medication or of the single dose part of the study, the last three groups received provided no data after treatment allocation. The per-protocol (PP) a single oral dose of 2.5, 10 or 50 mg brivaracetam on Day 1 population comprised the FAS population, excluding participants

Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX) 396 Armel STOCKIS, et al. with major protocol deviations. The FAS population was used to assess tolerability, and the PP population was used for pharmacokinetic analyses. Dose proportionality for Cmax and AUCinf was assessed using the random intercept power model,19) with subjects as a random effect, using the equation:

ln ðAUCinf or CmaxÞ¼ þ ln ðdoseÞ; where ¡ is the intercept and ¢ is the slope parameter. Dose proportionality was assumed if ¢ was close to 1 and its 90% confidence interval (CI) was entirely contained within the 0.80– 1.25 interval, corrected for dose range.19) The dose-independence of CL/F, V/F, t1/2 and fe was assessed using the same model, under the condition of ¢ = 0. Dose- and body weight-normalized pharmacokinetic parameters after single and multiple brivaracetam doses were pooled for all doses and summarized by genotype. For single-dose data, geometric least squares means ratios were obtained for the PM and hEM groups relatively to the EM group, and the corresponding 90% CIs around the ratios were derived. All statistical analyses were performed using SASμ version Fig. 2. Geometric mean (standard deviation) plasma concentration versus 9.1.3 (SAS Institute Inc., Cary, NC) and Proc StatXactμ version 7.0 time curves of brivaracetam following single-dose oral administration of 2.5, 10, 25, 50 and 100 mg; per-protocol population (Cytel Inc., Cambridge, MA). Results Subject disposition: This study was conducted at a single reported TEAEs, two were PMs, three were hEMs and three were center in Japan between February and May 2008 (single-dose EMs. All TEAEs were of mild intensity, and all but one resolved phase) and June and October 2008 (multiple-dose phase). Eighty before the end of the study. One participant (brivaracetam 10 mg healthy male Japanese participants were enrolled, and all were b.i.d.) was withdrawn from the study due to rash, which resolved included in both the FAS and PP populations. Participants 8 days after onset. Most TEAEs (10/11, 90.9%) were considered randomized to brivaracetam received a single oral dose of 2.5, possibly or probably related to study medication. 10, 25, 50, or 100 mg, or 2.5, 10, or 50 mg b.i.d. (eight participants No physical examination abnormalities were reported, apart in each group). In addition, a total of 10 participants received from those recorded as TEAEs. There were no clinically relevant single doses, and six repeated doses of placebo. Fifty out of 50 findings in vital signs, laboratory tests or ECG measurements. (100%) and 29/30 (96.7%) participants completed the single- and Single rising dose: multiple-dose phases, respectively. One participant (brivaracetam Plasma concentrations and pharmacokinetics 10 mg b.i.d.) was withdrawn from the study due to a TEAE, and Cmax of brivaracetam was reached rapidly after oral administra- did not provide complete pharmacokinetic data. tion and declined mono-exponentially in all dose groups (Fig. 2). Demographic characteristics were similar across dose groups Cmax and AUCinf increased proportionally to the brivaracetam (data not shown). Mean [standard deviation (SD)] age was 22.6 dose over the range 2.5–100 mg (Table 1). Dose-proportionality (2.0) and 24.3 (3.1) years, and mean (SD) weight was 60.2 (6.8) slope estimates (90% CI) were 0.98 (0.94, 1.02) for Cmax and and 61.3 (6.1) kg for the single- and multiple-dose phases, 0.99 (0.95, 1.02) for AUCinf. All other pharmacokinetic param- respectively. eters were similar across brivaracetam dose groups (Table 1). The The CYP2C19 genotype was identified in 69 participants, of geometric mean t1/2 ranged from 8.5 to 9.3 h. Urinary excretion whom 57 had received brivaracetam. Among 36 participants who of brivaracetam was complete by 48 h post-dose, with geometric received single doses of brivaracetam, 10 (27.8%) were EMs, mean fe of unchanged brivaracetam ranging from 7.5% to 10.7% 17 (47.2%) were hEMs and nine (25.0%) were PMs. Among 21 of the dose. participants who received multiple doses of brivaracetam, eight CYP2C19 genotype (38.1%) were EMs, 10 (47.6%) were hEMs and three (14.3%) were Cmax of brivaracetam was similar among EM, hEM and PM PMs. Twelve PM participants received brivaracetam: two 2.5 mg, participants (Table 2). Clearance of brivaracetam was reduced one 10 mg, one 25 mg, three 50 mg, two 100 mg, two 10 mg b.i.d. from 0.99 mL/min/kg in EM participants to 0.81 mL/min/kg and one 50 mg b.i.d. (¹18%) in hEM and 0.70 mL/min/kg (¹30%) in PM participants. Tolerability and adverse event profile: At least one TEAE AUCt and fe of BRV-OH were reduced 10-fold in PM participants, was reported by 8/64 (12.5%) participants after brivaracetam, compared with EM participants. AUCt and fe of brivaracetam and comprising 4/40 after single doses (one 10 mg, one 50 mg and two BRV-AC were slightly increased in PM participants compared with 100 mg), 4/24 during multiple doses (one 10 mg b.i.d. and three EM and hEM participants. 50 mg b.i.d.), and 1/16 (6.3%) participants after placebo (multiple Comparison with non-genotyped European population dose). The only TEAEs reported by more than one participant were Dose- and body weight-normalized plasma concentration versus diarrhea (one placebo and three 50 mg b.i.d.), and somnolence (two time curves of brivaracetam and BRV-OH following single doses 100 mg). Among the eight brivaracetam-treated participants who of brivaracetam were compared with previous data from non-

Table 1. Geometric mean (CV%) pharmacokinetic parameters of brivaracetam following single-dose oral administration (2.5–100 mg; PP population)

Brivaracetam (mg) 2.5 10 25 50 100 (n = 8) (n = 8) (n = 8) (n = 8) (n = 8) n 2/4/2/0 1/5/1/1 3/4/1/0 1/2/3/2 3/2/2/1 (EM/hEM/PM/missing)

Cmax (ng/mL) 87 (17.8) 373 (18.0) 900 (18.8) 1,921 (20.2) 3,083 (17.3) a tmax (h) 0.5 (0.3–0.5) 0.5 (0.5–1.0) 0.5 (0.5–1.5) 0.5 (0.5–2.0) 1.5 (0.5–1.5) AUCinf (ng0h/mL) 865 (18.9) 3,606 (13.5) 7,649 (20.5) 18,358 (18.2) 32,203 (14.1) t1/2 (h) 9.3 (15.5) 9.2 (11.9) 8.5 (22.4) 9.3 (12.9) 8.8 (19.2) fe (% of dose) 8.2 (25.5) 10.7 (20.6) 7.5 (27.2) 8.6 (29.3) 10.0 (24.4) CL/F (mL/min/kg) 0.82 (16.8) 0.81 (18.0) 0.85 (18.2) 0.78 (13.1) 0.85 (19.2) V/F (L/kg) 0.66 (5.0) 0.65 (11.4) 0.62 (6.2) 0.63 (4.7) 0.65 (4.6) aMedian (range). AUCinf: area under the plasma concentration-time curve from zero to inﬁnity, Cmax: maximum plasma concentration, CL/F: apparent total clearance, CV: coefﬁcient of variation, EM: extensive metabolizer, fe: cumulative urinary excretion, hEM: heterozygous extensive metabolizer, PM: poor metabolizer, PP: per-protocol, t1/2: plasma elimination half-life, tmax: time to reach Cmax, V/F: apparent distribution volume.

Table 2. Dose-normalized geometric mean (CV%) pharmacokinetic parameters of brivaracetam and metabolites following single-dose oral administration (2.5–100 mg) by CYP2C19 genotype (PP population)

EM hEM PM (n = 10)b (n = 17)b (n = 9)b

Brivaracetam Cmax 2.17 (23) 2.08 (21) 2.31 (21) (µg/mL)a 0.96 [0.83; 1.11]c 1.06 [0.90; 1.26]c Brivaracetam CL/F 0.99 (13) 0.81 (9) 0.70 (10) (mL/min/kg) 0.82 [0.76; 0.88] 0.70 [0.65; 0.76] Brivaracetam t1/2 7.4 (15) 9.2 (7) 10.8 (6) (h) 1.25 [1.17; 1.33] 1.45 [1.35; 1.56] a AUCt (µg0h/mL) Brivaracetam 16.6 (13) 20.0 (9) 23.1 (9) 1.21 [1.13; 1.29] 1.39 [1.29; 1.50] BRV-OH 2.55 (33) 0.97 (103) 0.19 (59) 0.38 [0.24; 0.60] 0.07 [0.04; 0.13] BRV-AC 0.75 (107) 0.91 (64) 1.08 (66) 1.20 [0.76; 1.90] 1.43 [0.84; 2.42] BRV-OHAC 0.29 (22) 0.20 (91) 0.31 (16) 0.69 [0.45; 1.06] 1.06 [0.65; 1.72]

fe (% of brivaracetam dose) Brivaracetam 7.8 (32) 9.2 (28) 9.6 (21) 1.18 [0.98; 1.42] 1.23 [0.99; 1.52] Fig. 3. Geometric mean plasma concentration (normalized to a dose of BRV-OH 19.1 (33) 10.5 (17) 1.7 (41) 1 mg/kg) versus time curves of brivaracetam and BRV-OH by CYP2C19 0.55 [0.45; 0.67] 0.09 [0.07; 0.11] genotype in healthy male Japanese subjects (per-protocol population) and BRV-AC 28.6 (18) 33.7 (11) 37.0 (5) non-genotyped healthy European subjects 1.18 [1.09; 1.28] 1.30 [1.18; 1.42] BRV-OH: brivaracetam hydroxy metabolite, EM: homozygous extensive BRV-OHAC 12.5 (8) 13.5 (9) 14.0 (19) metabolizer (n = 10), hEM: heterozygous extensive metabolizer (n = 17), 1.08 [1.00; 1.17] 1.12 [1.02; 1.23] PM: poor metabolizer (n = 9), European: geometric mean plasma concen- 13) aNormalized to a dose of 1 mg/kg. trations are from Nicolas et al. (n = 25). bGenotype was missing in 4/40 participants (see Table 1). cGeometric means ratio [90% confidence interval] versus homozygous EM. AUCt: area under the plasma concentration-time curve from zero to the last observation, BRV-AC: brivaracetam acid metabolite, BRV-OH: brivaracetam Multiple rising dose: hydroxy metabolite, BRV-OHAC: brivaracetam hydroxyacid metabolite, Cmax: maximum plasma concentration, CL/F: apparent total clearance, CV: coefficient Plasma concentrations and pharmacokinetics of variation, EM: extensive metabolizer, f : cumulative urinary excretion, hEM: e Cmax and AUÇ were proportional to the brivaracetam dose over heterozygous extensive metabolizer, PM: poor metabolizer, PP: per-protocol, the range 2.5–50 mg b.i.d. (Table 3). Steady state was reached by t1/2: plasma elimination half-life. approximately the second day of repeated dosing (Fig. 4). CYP2C19 genotype The plasma concentration versus time curves for brivaracetam genotyped healthy male European adults.13) Brivaracetam plasma on day 10 of b.i.d. dosing indicated that exposure was slightly profiles from Japanese EM, hEM and PM participants were similar higher in hEM than EM participants. Complete pharmacokinetic to those of non-genotyped European participants (Fig. 3). BRV- data were only available for two PM participants, but suggested OH plasma concentration versus time curves from Japanese EM that exposure to brivaracetam was higher in this group compared and hEM participants were also similar to those of the European with hEM and EM participants. Dose-normalized (1 mg/kg) Cmax participants, while those obtained from Japanese PM participants of brivaracetam increased from 2,556 ng/mL in EM to 3,052 ng/mL showed approximately 10-fold lower plasma concentrations (+19%) in hEM participants, and dose-normalized AUÇ increased (Fig. 3). from 14,653 to 18,617 ng0h/mL (+27%). Clearance of brivaracetam

Table 3. Geometric mean (CV%) pharmacokinetic parameters of brivar- respectively, the most frequent being diarrhea (three participants) acetam on Day 10 of twice-daily oral administration (2.5–50 mg b.i.d.; PP population) and somnolence (two participants). The tolerability and adverse event proﬁle was comparable with that previously reported in Brivaracetam (mg b.i.d.) healthy European volunteers.9,10) 2.5 10 50 The pharmacokinetic proﬁle of brivaracetam observed in this (n = 8) (n = 7) (n = 8) study was consistent with that previously reported in healthy male n 3/2/0/3 3/3/1/0 2/5/1/0 9) (EM/hEM/PM/missing) European adults following single and multiple oral doses. In our

Cmax (ng/mL) 113 (14.5) 508 (35.7) 2,477 (16.5) study, brivaracetam was absorbed rapidly under fasting conditions, Cmin (ng/mL) 35 (20.4) 125 (29.8) 670 (27.8) and displayed linear and dose-proportional pharmacokinetics over a – – – tmax (h) 0.5 (0.3 1.5) 0.5 (0.3 1.0) 0.5 (0.5 1.5) the dose ranges tested. Elimination was also rapid with a half-life 0 AUÇ (ng h/mL) 702 (12.8) 2,785 (26.2) 14,239 (16.1) in Japanese participants of ³9 h, comparable with that observed t (h) 9.4 (8.5) 8.7 (17.2) 8.6 (16.4) 1/2 in the European population (³8 h).9,10) Similarly to previous fe (% of dose) 13.4 (23.6) 12.5 (31.2) 12.3 (30.0) 9,10,14) CLSS/F (mL/min/kg) 0.93 (10.0) 1.00 (26.2) 0.97 (11.7) studies, only a small proportion of the brivaracetam dose V/F (L/kg) 0.45 (11.2) 0.47 (17.9) 0.46 (10.5) (8–11%) was eliminated unchanged in the urine, confirming that aMedian (range). the compound is extensively metabolized. AUÇ: area under the plasma concentration-time curve over a dosing interval, A genotype analysis was performed to investigate the role of b.i.d.: twice daily administration, Cmax: maximum plasma concentration, Cmin: CYP2C19 in the metabolism of brivaracetam, and to determine minimum plasma concentration, CLSS/F: apparent total clearance at steady state, CV: coefficient of variation, EM: extensive metabolizer, fe: cumulative urinary whether CYP2C19 polymorphism has any impact on its pharmaco- excretion, hEM: heterozygous extensive metabolizer, PM: poor metabolizer, kinetics. Other studies have shown that CYP2C19 PM genotype PP: per-protocol, t1/2: plasma elimination half-life, tmax: time to reach Cmax, can have significant effects on the pharmacokinetics of drugs that V/F: apparent distribution volume. are CYP2C19 substrates, potentially affecting clinical outcome.20) Across the single- and multiple-dose phases of our study, 32% of participants were EMs, 45% were hEMs and 23% were PMs. This distribution is similar to that reported for the Japanese population: EMs 32–49%, hEMs 36–46% and PMs 15–24%.16–18) Comparison of dose- and body weight-normalized pharmacokinetic parameters following single doses of brivaracetam revealed small differences between hEM and EM participants, and more marked differences between PM and EM participants. Results following multiple doses of brivaracetam were broadly in agree- ment with the single-dose data, but were limited by the small number of PM participants included in this phase of the study. Following single doses of brivaracetam, plasma and urine concentrations of BRV-OH were around 10-fold lower in PM than EM participants, together with a slight increase in the formation of BRV-AC and BRV-OHAC. Clearance of brivaracetam was reduced by 29% in PM compared with EM participants. Taken together, these observations indicate that the hydroxylation pathway is suppressed in PM participants, signifying that this pathway is mediated by CYP2C19. Plasma and urine concentrations of BRV- OHAC were little affected by a 10-fold decrease in the formation of BRV-OH, indicating that BRV-OHAC is mainly formed from BRV-AC. Although little BRV-OH was produced by PM partici- Fig. 4. Geometric mean (standard deviation) plasma trough concentration versus time curves of brivaracetam at steady state during repeated oral pants, there was only a 29% reduction in clearance of brivaracetam, administration (2.5–50 mg b.i.d.; per-protocol population) indicating that hydroxylation has a minor role in the disposition of b.i.d.: twice daily. brivaracetam. No clinically relevant change in the pharmacokinetics of brivaracetam would thus be expected in participants with impaired CYP2C19 metabolism. In support of this finding, was reduced from 1.14 mL/min/kg in EM to 0.90 mL/min/kg although the numbers were small, this study provided no evidence (¹21%) in hEM participants. Brivaracetam fe increased from that the PM genotype was associated with a higher incidence of 10.4% of dose in homogeneous EM to 13.8% of dose (+33%) in adverse events. It is not anticipated that CYP2C19 PM screening or hEM participants. AUÇ of BRV-OH was reduced from 2,903 ng0h/ dose adaptation would be required for Asian patients treated with mL in EM to 1900 ng0h/mL (¹35%) in hEM participants, while brivaracetam. fe was also reduced from 39.6% to 27.5% of dose (¹31%). Further confirmation of the lack of clinical relevance of any differences in the pharmacokinetics of brivaracetam based on Discussion CYP2C19 genotype was provided by comparison of our results Brivaracetam was well tolerated by healthy male Japanese adults with data obtained in a European population. In a previous phase 1 following single- (2.5–100 mg) and multiple-dose (5–100 mg/ drug-interaction study, 25 healthy male European adults each day for 10 days) administration. TEAEs were reported by 4/40 and received a single 150 mg dose of brivaracetam.13) Genotyping was 4/24 participants after single and repeated doses of brivaracetam, not done in this study but, based on metabolic profiles, it was

Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX) Brivaracetam Pharmacokinetics in Japanese Participants 399 assumed that the European population comprised participants with Br. J. Pharmacol., 154: 1662–1671 (2008). 4) French, J. A., Costantini, C., Brodsky, A. and von Rosenstiel, P.: hEM and EM phenotypes. There were no obvious differences in Adjunctive brivaracetam for refractory partial-onset seizures: a random- dose- and body weight-normalized brivaracetam plasma concen- ized, controlled trial. Neurology, 75: 519–525 (2010). tration versus time curves between Japanese EM, hEM and PM 5) Van Paesschen, W., Hirsch, E., Johnson, M., Falter, U. and fi participants, and European participants. In the latter, brivaracetam von Rosenstiel, P.: Ef cacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial-onset seizures: A phase IIb, ran- geometric mean Cmax (normalized to a dose of 1 mg/kg) was 2.12 domized, controlled trial. Epilepsia, 54:89–97 (2013). µg/mL, CL/F was 0.79 mL/min/kg, and t1/2 was 8.1 h; normalized 6) Kwan, P., Trinka, E., Van Paesschen, W., Rektor, I., Johnson, M. E. and AUC of brivaracetam, BRV-OH, BRV-AC and BRV-OHAC were Lu, S.: Adjunctive brivaracetam for uncontrolled focal and generalized 0 epilepsies: Results of a phase III, double-blind, randomized, placebo- 21.0, 2.10, 1.64 and 0.46 µg h/mL, respectively; the corresponding controlled, flexible-dose trial. Epilepsia, 55:38–46 (2014). cumulative urinary excretions reached 8.3, 12.9, 27.2 and 14.2% 7) Ryvlin, P., Werhahn, K. J., Blaszczyk, B., Johnson, M. E. and Lu, S.: of dose, respectively.13) Unsurprisingly, the profile for the European Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double-blind, randomized, placebo-controlled trial. participants fell between that of the Japanese EM and hEM Epilepsia, 55:47–56 (2014). participants. For BRV-OH, the plasma concentration versus time 8) Biton, V., Berkovic, S. F., Abou-Khalil, B., Sperling, M. R., Johnson, curves were similar for Japanese EM and hEM participants and M. E. and Lu, S.: Brivaracetam as adjunctive treatment for uncontrolled European participants, while the Japanese PM participants showed partial epilepsy in adults: A phase III randomized, double-blind, placebo- controlled trial. Epilepsia, 55:57–66 (2014). markedly lower plasma concentrations of this metabolite. 9) Rolan, P., Sargentini-Maier, M. L., Pigeolet, E. and Stockis, A.: The Our study has several limitations that should be taken into pharmacokinetics, CNS pharmacodynamics and adverse event profile of account in interpretation of the results. Doses of brivaracetam brivaracetam after multiple increasing oral doses in healthy males. Br. J. Clin. Pharmacol., 66:71–75 (2008). higher than 100 mg daily were not tested and tolerability at higher 10) Sargentini-Maier, M. L., Rolan, P., Connell, J., Tytgat, D., Jacobs, T., doses cannot be extrapolated; however, good tolerability was Pigeolet, E., Riethuisen, J. M. and Stockis, A.: The pharmacokinetics, observed for up to 800 mg/day in healthy European volunteer CNS pharmacodynamics and adverse event profile of brivaracetam after studies.9) Most participants provided a DNA sample for genotyp- single increasing oral doses in healthy males. Br. J. Clin. Pharmacol., 63: 680–688 (2007). ing, which was carried out retrospectively without randomization 11) Sargentini-Maier, M. L., Sokalski, A., Boulanger, P., Jacobs, T. and according to metabolizer status. Few PMs were included in the Stockis, A.: Brivaracetam disposition in renal impairment. J. Clin. multiple-dose phase. Pharmacol., 52: 1927–1933 (2012). 12) Stockis, A., Sargentini-Maier, M. L. and Horsmans, Y.: Brivaracetam In summary, brivaracetam was well tolerated in healthy male disposition in mild to severe hepatic impairment. J. Clin. Pharmacol., 53: Japanese adults. The observed differences between extensive and 633–641 (2013). poor metabolizers suggest that brivaracetam is hydroxylated by 13) Nicolas, J. M., Chanteux, H., Rosa, M., Watanabe, S. and Stockis, A.: Effect of gemfibrozil on the metabolism of brivaracetam in vitro and in CYP2C19, but that this pathway is minor compared with hydroly- human subjects. Drug Metab. Dispos., 40: 1466–1472 (2012). sis to the acid metabolite. As such, the potential for CYP2C19- 14) Sargentini-Maier, M. L., Espie, P., Coquette, A. and Stockis, A.: mediated drug-drug interactions with brivaracetam is expected to Pharmacokinetics and metabolism of 14C-brivaracetam, a novel SV2A – be low. ligand, in healthy subjects. Drug Metab. Dispos., 36:36 45 (2008). 15) Whomsley, R., Dell’Aiera, S., Brochot, A., Espie, P. and Delepine, X.: Identification of the cytochrome P450 isoforms responsible for the Acknowledgments: The authors thank Muriel Boulton (UCB hydroxylation of brivaracetam. AAPS J., 9: 3408 (2007). Pharma, Belgium) and Katsumi Yoshida (UCB Pharma, Japan) for 16) Goldstein, J. A., Ishizaki, T., Chiba, K., de Morais, S. M., Bell, D., Krahn, P. M. and Evans, D. A.: Frequencies of the defective CYP2C19 statistical analysis support, and Jennifer Stewart, M.Sc. (QXV alleles responsible for the mephenytoin poor metabolizer phenotype Communications, Macclesfield, UK) and Laurent Turet, Ph.D. in various Oriental, Caucasian, Saudi Arabian and American black (UCB Pharma, Brussels, Belgium) for writing assistance. populations. Pharmacogenetics, 7:59–64 (1997). 17) Inomata, S., Nagashima, A., Itagaki, F., Homma, M., Nishimura, M., References Osaka, Y., Okuyama, K., Tanaka, E., Nakamura, T., et al.: CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general 1) Bialer, M., Johannessen, S. I., Levy, R. H., Perucca, E., Tomson, T. and anesthesia. Clin. Pharmacol. Ther., 78: 647–655 (2005). White, H. S.: Progress report on new antiepileptic drugs: A summary of 18) Kimura, M., Ieiri, I., Mamiya, K., Urae, A. and Higuchi, S.: Genetic the Eleventh Eilat Conference (EILAT XI). Epilepsy Res., 103:2–30 polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a (2013). Japanese population. Ther. Drug Monit., 20: 243–247 (1998). 2) Kenda, B. M., Matagne, A. C., Talaga, P. E., Pasau, P. M., Differding, E., 19) Smith, B. P., Vandenhende, F. R., DeSante, K. A., Farid, N. A., Welch, Lallemand, B. I., Frycia, A. M., Moureau, F. G., Klitgaard, H. V., et al.: P. A., Callaghan, J. T. and Forgue, S. T.: Confidence interval criteria for Discovery of 4-substituted pyrrolidone butanamides as new agents with assessment of dose proportionality. Pharm. Res., 17: 1278–1283 (2000). significant antiepileptic activity. J. Med. Chem., 47: 530–549 (2004). 20) Bogman, K., Silkey, M., Chan, S. P., Tomlinson, B. and Weber, C.: 3) Matagne, A., Margineanu, D.-G., Kenda, B., Michel, P. and Klitgaard, H.: Influence of CYP2C19 genotype on the pharmacokinetics of R483, a Anti-convulsive and anti-epileptic properties of brivaracetam (ucb CYP2C19 substrate, in healthy subjects and type 2 diabetes patients. Eur. 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A. J. Clin. Pharmacol., 66: 1005–1015 (2010).