Table 1: Pharmacokinetic parameters of LCM following single oral administrations of 400,
`600, and 800mg LCM in healthy male subjects.
`
`
`
`
`
`
`-
`
`8.53
`
`14.16
`
`288.09
`(3.5.9)
`
`293.224
`(35-5)
`
`18.43
`
`
`
`
`
`AlECwm {pg’mL*i1) Geomatrit mean
`
`
`
`AECcom} (gamma)
`
`Cw; (pigmi)
`
`1m {b}
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`{20.2}
`
`13.84
`
`{16.5)
`
`{I 6.1)
`
`13.143
`
`{8.1}
`
`(26.0}
`
`EZQCC
`
`(11.4)
`
`Giff (Uh)
`
`Geometric mean
`raw"
`
`mama mew—m mm
`
`(31mg; (Uh)
`
`Arithmetic. mean
`
`iSD
`
`
`
`CV=coefficient 9f wriation; LCM=1acmamitie; SD=staudacrd dexdaficm
`a
`In 3 of the 13 subjects rewiring LCM in the 890mg group, the docs: was, reduced in Treatment E’en'od 3».
`Tim ofthe 3 subjects received 3091113 and 1 subject received 500mg LCM instead of 898mg.
`The geometric CV96} was calculated additionally and is mat reported in the .8958? Clinical Trial Repefi.
`
`b
`
`Table 2: Summary of Urinary PK
`
`
`
`first aim adoémg
`
`
`
`M
`15.6 :l: 53
`3&5»:- 132
`54.51- mm:
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`rm 3- 0.3
`
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`
`
`‘
`3.12 a alter-mama N s it
`"
`Mhmrmmgnaai
`flats mum mm 18.2,. T5313? mg 5'
`
`Comments: AUC(0—tz), AUC(0-oo), and Cmax as well as Ae increased proportionally with the
`administered dose.
`
`NDA -’/‘
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`3‘4}
`
`'
`
`150
`
`

`

`Other PK parameters (tmax, tl/2, total body clearance [CL/f], and renal clearance [CLrenal]) of
`LCM were unchanged at the different doses.
`
`The dose—proportional increase of AUC(0—oo) and Cmax was demonstrated for AUC and Cmax
`of LCM with the dose between 400 mg and 800 mg.
`
`PK conclusion: Lacosamide was absorbed with a tmax occurring between 1.0 and 4.0 hours
`after dosing and a terminal half-life of approximately 13 hours. AUC and CmaX of LCM
`increased proportionally with the dose between 400 mg and 800 mg.
`
`4.2.2.2 Dose Proportionalz'ty Studies—Multiple Doses
`
`4.2.2.2.] Study SP836: Double-blind,randomized, placebo-controlled, parallel group, 7-day
`oral ascending dose study to determine the tolerability andpharmacokinetic profile
`ofSPM 927
`
`
`Study Type: Multiple dose study.
`
`but
`
`Clinical Investigator: Mm: ,_
`Maw
`
`;- --——~~M—~—_mm
`
`Objectives: The primary objective was to investigate the safety and tolerability of multiple oral
`doses of SPM 927 in healthy male subjects. The secondary objective was to determine the PK
`profile of SPM 927 following multiple oral dose administration.
`
`Study Design: This was a randomized, double-blind, placebo-controlled, parallel-group Phase 1
`trial in healthy male subjects using SPM 927 capsules hand-filled with the pure drug substance.
`Twenty-one subjects were randomized to 3 groups of 7 subjects. In each group, 6 subjects were
`randomized to 100 mg SPM 927 once daily on 7 consecutive days, 200mg once daily on 7
`consecutive days, or 200 mg twice daily on 6 consecutive days and in addition once daily on Day
`7. One subject in each group was randomized to placebo.
`
`Blood sampling times: Samples (7 ml) were collected at the following times:
`Interval
`Subjects 1‘7 (100 mgod {Group 1]
`Subjects 15—21 (200 mg bid {Group .31)"
`Sub em 8-14 (206 In; 0d Grou 2
`
`
`
`pre dose; 0.5, 1, 2, 3, 4, 6. 8. i0, 12. 16‘, &
`m--- dose
`
`pro AM‘dose; 0.5, 1, 2, 3, 4. 6. 8, I0, 12 (pm PM dose). 8:
`24hstAMdosc
`
`Day t
`
`Day?
`
`Day 9
`
`Day to
`
`we dose; 0.5, I, 2, 3, 4, 6, 8, 10, 12, 16* &
`24 h ost dose
`
`pr: dose; 0.5, l, 2, 3, 4, 6. 8. lo. 12, 16. &24 h pas! dose:
`
`X (48 hours post finat dose)
`
`X (72 hours post final dose)
`
`-‘ as detailed in protocol amendment 1; also, measurements added at 48 hr & 72 hr post final dose for Groups 1 & 2
`
`NDA A
`Lacosamide FiIm—Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`3(4)
`
`15]
`
`

`

`Urine sampling times: Urine was collected at the following times: pre-dose, 0-4, 4-8, 8-12, and
`12—24 h post dose on Days 1 and 7.
`
`Criteria for Evaluation: PK parameters (AUC, Cmax, Tmax, t1/2) of SPM 927.
`
`Analflical Methodology: Same as Study SP835
`
`Data Analysis: PK parameters were calculated by non-compartmental or model-free methods.
`Descriptive statistics were computed for pertinent pharmacokinetic parameters for each
`treatment. An analysis of variance (ANOV A) was performed and the 90% confidence intervals
`were generated for the ratio of fed/fasted for Cmax, AUC0_t and AUC0_...,, Cmax, and AUCOM were
`natural-log (In) transformed prior to analysis.
`
`Results:
`
`Study Population: 21 male Caucasian subjects were enrolled and they all completed the trial.
`The mean age of the subjects was 32 years (range, 19-39 years).
`
`Pharmacokinetics: Mean PK profiles of SPM 927 for all the treatments are shown in Figures 1
`and 2. Trough concentrations of SPM indicate that with a twice-daily dosing regimen with 200
`mg LCM, steady state was reached after 72 hours.
`
`Descriptive statistics for PK parameters of shown Table 1.
`
`Figure 1. Mean Plasma Concentrations of SPM 927 After Oral Administration of SPM to '
`Healthy Volunteers.
`
`Wm Wm
`1m
`:3
`121550
`
`W 103: mg
`15—5—2: m
`mm 280 mg m1.
`
`
`
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`
`24
`
`as
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`93 m m ass
`72‘
`Tm 4h; 3%“) my 1 Dose
`
`252 m
`
`NDA r—'
`Lacosamide Film-Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`b .
`(a)
`
`i
`
`>
`0-
`
`5L)
`.2
`‘3
`
`n.
`
`g
`
`152
`
`

`

`Figure 2. Mean Urinary Concentrations of SPM 927 Afier Oral Administration of SPM mg to
`Healthy Volunteers.
`’
`Com {Light}120
`
`73:2;
`
`
`27333328332
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`mmysammwom
`
`Table 1: Summary of PK Parameters
`
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`-
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`2... Ne mama: m palm
`
`NDA -“""
`Lacosamide Film-Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`33(4)
`
`153
`
`

`

`Comments: The PK parameters AUC(0-tz), AUC(0-oo), and Cmax increased proportionally with
`the administered daily doses of 100, 200, and 400mg. Tmax and t1/2 were unchanged at the
`different doses. Dose proportionality of AUC and Cmax was also shown by plotting mean Cmax,
`AUC(0-tz), and AUC(0—oo) against the daily dose and by the ratios of mean AUC(O-tz) and
`Cmax values between dose groups.
`
`Steady state was reached after 72 hours of dosing with a twice-daily oral dosing regimen
`
`PK conclusion: The analysis of AUC(O-tz), AUC(0—oo), and Cmax of LCM showed dose-proportional
`increases for these parameters. The maximum plasma concentration was reached between 0.5
`and 6 hours afier dosing. The terminal half-life of LCM was approximately 13 to 14 hours.
`
`4. 2. 2. 2.2 Study SP588: Multiple dose tolerance study with ascending oral doses ofSPM 927
`(Harkoseride) in healthy male Caucasian volunteers
`
`
`Study Type: Multiple dose study.
`
`a
`
`Clinical Investigator:
`J——’:
`
`#5
`
`“(Bit
`
`Objectives: To evaluate the safety, tolerability, PD effects, and pharmacokinetics of oral
`multiple doses of SPM 927.
`
`Study Design: This was a randomized (within group), double-blind, placebo—controlled,
`sequential parallel-group study in subjects with single- and multiple-dose administration of LCM
`capsules filled with powder blend. Thirty-three subjects in total were enrolled in 2 sequential
`groups with ascending dose levels. The higher dose level in the second group was only
`administered after an evaluation of tolerability and safety data from the first group. Sixteen
`subjects were enrolled in the first group and randomized to 300 mg LCM as single dose on Day 1
`and twice daily for 13.5 days on Days 3 to 16 (12 subjects) or matching placebo treatment (4
`subjects). Seventeen subjects were enrolled in the second group and randomized to 500 mg LCM
`as'single dose on Day 1 and twice daily for 13.5 days on Days 3 to 16 ( 12 subjects) or matching
`placebo treatment (5 subjects). The dose regimen in the second group could be altered during the
`trial for tolerability and safety reasons.
`
`Blood sampling times: Serial blood samples (7 ml) were collected post close on Days 1 16 and
`at several times on other days.
`
`Urine sampling times: Urine was collected on Days 1, 3 and 16 at the following times: pre-
`dose(only on Day 1), 0-4, 4-8, 8-12, and 12-24 h post dose; over 24 hours on Days 2 and 17; and
`0—12 hours after evening dose on day 15..
`
`NDA i”
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`[1(4)
`.
`
`154
`
`

`

`Criteria for Evaluation: PK parameters (AUC, Cmax, Tmax, t1/2) of SPM 927.
`
`Analy_tical Methodology : Same as Study 587
`
`Data Analysis: PK parameters were calculated by non—compartmental or model-free methods.
`Descriptive statistics were computed for pertinent pharmacokinetic parameters for each
`treatment. An analysis of variance (ANOV A) was performed and the 90% confidence intervals
`were generated for the ratio of fed/fasted for Cmax, AUC0_t and AUCo_...., Cmax, and AUC0_... were
`natural—log (In) transformed prior to analysis.
`
`Results:
`
`Study Population: 33 male Caucasian subjects were enrolled. Fourteen and Twelve subjects
`completed the single dose and multiple dose of 300 mg SPM respectively while 10 and 4
`completed the single and multiple dose of 500 mg SPM respectively.
`
`Pharmacokinetics: PK parameters were derived from non—compartmental analysis. Trough
`concentrations of SPM indicate that with a twice-daily dosing regimen with 200 mg LCM,
`steady state was reached alter 72 hours.
`
`The following figure shows mean plasma concentrations of LCM over 48 hours after
`administration of a single dose of 300 mg and 500 mg LCM.
`
`Figure 1. Mean plasma concentration-time curve of LCM (mean and standard deviation)
`after administration of a single dose of 300 mg and 500 mg LCM.
`)
`
`1&8"
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`Groupmt momma/:14} -------
`
`Gmpfl 560mg {Nam}
`
`Descriptive statistics for PK parameters of shown Tables 1 to 4.
`
`NDA =4"
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`b‘4)
`
`155
`
`

`

`Table 1: Single Dose PK (MeaniSD or Median (range))
`
`
`AUCO—n-last
`
`[quml]
`
`A1100...
`Cm”
`
`[pg‘h/ml]
`[pg/ml}
`
`tmax '
`
`tuz "
`CWF
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`Vle
`
`MRT'
`
`{11]
`
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`[Uh]
`
`[I]
`
`'
`
`[h]
`
`Data source: Section 13.1, Table 10.2.3.1
`
`309 mg
`N=14,
`rou l/ll
`
`104.9 :1: 13.8
`
`111.9i16.0
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`
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`
`11.6 (8.1-1 7.7)
`2.7 i 0.4
`
`45.1 :1: 9.4
`
`17.1 (12.0-24.4)
`
`500 mg
`rou ll
`N=10
`168.7 2 52.9
`
`190.1 1 85.4
`
`10.4 i 3.0
`
`1.0 (0.5-2.0)
`
`13.3 (15.6-19.1)
`3.1 i 1.6
`
`57.1 1 22.7
`
`19.4 (12.5-28.0)
`
`Table 2: Multiple Dose PK (MeaniSD or Median (range))
`
`300 mg
`(N=12. Group I)
`Day 15
`Day 16
`' ht
`da
`
`400 mg
`(N=7, Group 11)
`Day 16
`Day 15
`da
`
`500 mg
`(11:4. Group 1|)
`Day 16
`Day 15
`03
`Bibi
`
`171.1
`i 32.7
`19.2
`i 3.7
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`12.2
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`8.7
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`
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`13.1
`
`(12.1—
`
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`4 0
`(296)
`
`2.6
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`38.6
`
`‘ 18.0
`(12.9.
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`55.9)
`24.5)
`39.3)‘
`Data source: Section 13.1, Tables 10.2.3.3 and 10.2.3.4
`111:13; 211:2; 3N=3
`
`20.4)
`
`AUC12.,24h
`Eug’h/mll
`{WOO—.121) [pg*h/ml]
`
`Cmax [pg/ml}
`
`len [991ml]
`
`tmax* [h]
`
`1112* {’1}
`
`Chen": {1131}
`
`MRT’ {1:3
`
`1 0
`(132)
`12.4
`
`{8.1—1 7.4)
`2.4
`$0.4
`
`.
`
`2.6
`10.4
`26.1
`
`
`
`NDA
`Lacosamide Film-Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`b(4)
`
`156
`
`

`

`Table 3: Single Dose Urinary PK of SPM 927 (MeaniSD)
`
`Time
`0 h
`
`0 — 4 h
`4 — 8 h
`
`8 —— 12 h
`
`12-24h
`
`24—36h
`
`36—48 h
`
`Total
`
`300 mg
`
`500 mg
`
`Amount excreted {mg}
`2.5 :t 0.0
`
`29.3 115.8
`47.2 218.9
`
`39.4 :15.8
`
`31.0190
`
`12.3133
`
`6.7i4.1
`
`'
`
`N
`10
`
`10
`10
`
`10
`
`10
`
`10
`
`9
`
`Amount excreted [mg]
`2.5 i 0.0
`
`60.3 i: 70.0
`59.4 d: 20.6
`
`54.2 i 25.5
`
`48.7.2312
`
`23.71184
`
`16.6:123
`
`167.3 a; 53.4
`
`(10)
`
`.
`
`263.7 i 132.7
`
`Renal clearance [1111}
`1.5;t0.4
`
`N
`' 10
`
`Renat clearance [l/h}
`1.4i0.4
`
`N
`1.3
`
`13
`13
`
`13
`
`13
`
`13
`
`11
`
`(13)
`
`N
`13
`
`N=number of subjects
`Data source: Section 13.1, Table 10.2101
`
`Table 4: Multiple Dose Urinary PK of SPM 927 (MeaniSD) '
`
`
`
`
`
`500 mg (N=4, group ll)300 mg (N612. group I) 400 mg (N37, group II)
`
`”Fume
`
`0 — 4 h
`
`4 - a n
`a .. 12 h
`
`Total (Ou‘l 2m
`
`'
`
`56.7 1 23.3
`
`88.7 i 30.1 .
`92.3 :t: 77.6
`
`237.7 1 88.5
`
`Amount excreted {mg}
`
`51.5 i 32.1
`
`64.3 i 45.5
`74.0 «2 74.2
`
`189.8 .4: 145.3
`
`103.3 :t: 28.2
`
`124.5 4; 27.6
`125.7 i 53.2
`
`353.6 i 96.1
`
`12 ~ 24 h
`
`72.2 a: 26.1
`
`48.6 i 48.1
`
`101.9 :1: 58.8
`
`55.6 i: 43.4
`17.1 $16.0
`‘
`29.0 216.3
`24 .. 36 h
`36 ~ 48 h 22.4 t 13.3 19.4 i 8.6 6.4 i 5.8
`
`
`
`
`
`
`
`Renal clearance {lib}
`
`«no.4
`' 1.8 10.6
`2.1 :03
`
`Data source: Section 13.1, Tables 10.2.1113
`
`The PK characteristics after single-dose administration of 300 and 500mg LCM in this trial were
`comparable to those observed in SP587 (single-dose administration of 400, 600, and 800mg
`LCM).
`
`No relevant differences were apparent for tmax, tl/2, and CLrenal between single- and multiple—
`dose (over 13 days) administration of LCM.
`
`NDA ._....
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`h‘4)
`
`157
`
`

`

`Trough concentrations indicate that steady state was reached within 3 days.
`
`Conclusions: The PK characteristics of LCM in this trial were consistent with those obtained in
`previous trials. AUC and Cmax increased proportionally with the administered dose. The PK
`characteristics did not change during multiple dosing, ie, multiple-dose pharmacokinetics could
`be predicted from single dose data. The analysis of AUC(0tz), AUC(0co), and Cmax of LCM
`showed dose-proportional1ncreases for these parameters.
`
`4.2.3 Special Population Studies
`
`4.2.3.1
`
`Renal Impairment— Study SP641.‘ Open, non-randomized, sequential group
`comparison to investigate the pharmacokinetics, safety, and tolerability 0f100mg
`SPM 92 7 in male andfemale subjects with renal impairment including subjects
`requiring dialysis compared with male andfemale healthy subjectsfollowing single-
`dose administration
`
`—_——————h__
`
`June 4, 2004 to November 22, 2004
`Study Period:
`Sample Analysis Periods: November 22, 2004 to February 18, 2005 (plasma)
`December 13, 2005 to December 16, 2005 (urine)
`SCHWARZ BIOSCIENCES GmbH, Department of Bioanalytics,
`Alfred-Nobel-StraBe 10, 40789 Monheim am Rhein, Germany
`
`Analytical Site:
`
`APPEARS THlS WAY
`ON ORIGINAL
`
`NDA ' -"
`Lacosamide Film—Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`b(4)
`
`I58
`
`

`

`
`
`Name of company:
`SCH‘NARZ BIOSCIENCES
`GmbH
`
`{For Nafionai Aymara}! Use
`Individual study {able
`referring 1'0 par: of the dossier Om‘y)
`NA
`
`Name of Yinisiaed i’l-oduct:
`Nor applicabie
`
`Volume: Not aypliczble
`
`
`
`Page: Not applicabie
`Name. of Active Ingredient:
`
`Lacosamide '
`
`
`
`
`Title of trial: Open, non—Immomized, sequential goup comparison to investigate the
`pinarnncokiuetics, safety, and tolerabih'ty of {Wang SFM 927 in male and female subjects with
`renai impairment inciuding subjecis requiring diaiysis compared with mails and female healthy
`subjects following singie—dose admiifistration
`
`
`, Investigators:W “(4)
`Trial sites: 2 sites in Germany
`
`Studied period (years): —
`First subject emailed: 04 Jim 2804
`Last subject completed: 22 Nov 2004
`
`Phase. of deveiupment: Phase 1
`
`Objectives: Primary objective of Part 1 of the triaE was to evaluate the pharmacoidneiics of
`hecsanfide in subj eds wiih mild to sevea‘e renal impairment, strafified according to their creafioine
`clearance approxiimteiy 2 to 7 days prior to dosing, and healthy subjems (incfividualfiy matched to
`subjects from Group 4 for age, body mam index {BM}, 3:16 gender) following singie—dose
`aziminisflation of 100mg Iacosamide. A comparison of phmnmcok'inetic (PK) parameters was
`petfonned to assess whether renal impaitmem is associated wiih changes in phannacoidnetics.
`
`Primary objective of Pan 2 of the m: was to evaiuate the phzmuacokmetics of lacosamide in
`subjects with endstage renal disease remixing dialysis under dialysis and non-dialysis conditions
`following single—dose administration of 100mg Iawsamide.
`
`As secondary objectives further phannacokinetics ofthe main metabolite of lacesamide and the
`safay and tolerabiliiy of :11: treatment were emiuaied.
`
`Methodology: This was an open-label: non-randomized, non-controlled, sequential group
`comparison trial ix: ’2 parts in subjects with renal imminent and in healthy xxmjects.
`
`Park I was a sequential group comparison trial Male and female subjects {healthy and'wiih semi
`impairment) were assigned to 1 of 4 groups according to their creatinine clearances (Chg)
`(Groups I to 4). A11 subjects roceivecf a, single-dose of 150mg lacosamide.
`
`Part 2 was a trial with 2 toaiments in a. Ext-é order (A—B). Make and femaie subjects with endstage
`tenet disease requiring dialysis (Gmup 5) received the foliowing treatments:
`Treatment A: shag/1e dose of 100mg lamaamide on diaiysis—free day (1 day before dialysis)
`
`Treatment B: singie ciose of 100mg lacosamide 2.5 hours before the start ofhemodialysis (dmation
`
`ofhanodialysis: 4 hours)
`
`ND;A ’—
`
`Lacosamide Film-Coated Tablets
`
`.
`
`81(4)
`
`.
`
`159
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`

`

`Number 91‘ subjects {planned and analyzed): Thirty-two meme were enrolled in Part 1 as
`pianned (in 4 groups of 8 subjects)... Eight safiijects were enrolled in PM 2 as Qimed (Group 5}. M
`sub}eats compieted the trial and were enlist for PK and safety anaiy‘sis.
`
`Diagnosis and main criteria far inclusian: Subjects were healthy or had inmaired remi fimetion
`(mild moderate, severe, or enfitage renal impairment requiring dialysis} and were assigned in
`groups accordnig to their CLQ vaiues at the Eligibiiity Assessment. Healthy subjects (Group 1) were.
`individually matched to subjects firm} Group 4 far age= BMI. and gender.
`
`Test product, {lose and mode of administration, batci: 3111111563“: Single oral Idese of lamsamide
`180mg film—coated tabiet; drug prodeet batch number: 223920; pack batch number: 20030204
`
`Bnration {if treatment: Single dose
`
`Refez‘ence therapy, {1952. and mode of administration, batch number: None
`
`
`
`Criteria fer evahm‘fion:
`
`Pharmaeekinetics: Pinnalj; PK parameters were:
`
`E’s—H1; AUCMI}, AUQM}m, Em, and Cwm of Eacosamide
`
`Rafi: AUCWz}, AUC{B—iz}mem Cm. Cmmm of lacosamide
`
`Secondary PK parameters were:
`
`Past 1: Cit) and {my ef iacosarnide, CUf, CIR, and Egg of lacesannde, 3133mm, Aficwuggm, {3mg
`Cmmmm, CLR, and in (film main metabolite (39M £2809), a...“ and tiflmaf lacosannde and
`SPM. 12809
`
`Part 2: C(t} and tau of lacosamide, CRT and In of iacasamide, Amiga}, AUCgszjam Cm,
`Emma and ha of SPM 12309. cancentration of lacosamide and SPM 12809 in diaiysis inlet and
`male“: fine at t=6 hours {3.5 hours after start of dialysis) to calculate E (extractinn rate) dufiilg
`dialysis, concentration of lacosamide and 5PM 12.809 in the diaiysis fluid at i=4 hours (1.5 hours
`sfier start if dialysis)and at the end of dia’iyeis to calmfate (ELM
`
`Saint's: Subjective ioierabiliiy, adverse events (AE3), detemnnation of changes in iaberam
`parametefs, and influence on Vital Sign parameters [pulse rate} blood pressure} and
`eleetmcardiogram (ECG)
`
`Rationale for the study: Lacosamide is eliminated primarily Via renal excretory mechanisms.
`Data from previous studies show that about 40% of the administered dose were excreted renally
`as unchanged lacosamide and another 30% were excreted as the main metabolite, SPM 12809.
`In addition, a 20% polar fraction was excreted in urine. Impaired renal function may alter the
`pharmacokinetics of drugs with such mechanisms of excretion and the dosage regimen may need
`to be adjusted in patients with renal impairment. Pharmacokinetic characterization in subjects
`with renal impairment would provide rational recommendations for dosing in renal impairment
`patients.
`
`Dose selection: In this trial a dose of 100mg, which represents the lowest therapeutic dose, was
`chosen for safety considerations. The proposed therapeutic doses are 50-“ mg twice daily.
`The classification of renal function and stratification were based the FDA 1998 renal guidance.
`
`W“ -
`
`NDA —/
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`,
`
`b‘4)
`
`’
`
`160
`
`

`

`Group 1:
`
`C143; ESGmhimin {heaithy subjects)
`
`Group 2:
`Group 3:
`
`Group 4:
`
`80mL’min >CLQ 250mm (subjects with mild renal impairment)
`fiflmhimifl MILE: 23Omfonin (subjects with moderate renal impairment)
`
`CLCI iSQmLa’min (subjects with severe renal impairment, not on dialysis between
`2 weeks before EA and end of the trial)
`
`In Seen? 4 the Whole range of ISLCr values had to be covered, it; iii subjects with
`{3L3 mines of 2.8—3fimijrnin and 4 mbjects with {3L3 <29mUmin were enrolled.
`
`Subjects of Group 4 were included onfy afler uneventfigl treafinent of at. least 6 subjects with
`mild {Group 2} or moderate (Group 3) rem} dwfimetion.
`
`Healthy subjects {Group 1) were hiéividuafly matched by age, BMI, and gender to atbjects of
`Group 4.
`
`Group 5:
`
`Subjects with endstage .renai disease {CLgfilSmUmfi}, determined 2 to 3 days
`before first. dosmg} treated with extracerporai hemodialysis for at least 4 months
`
`Subjects for Part 2 were only enrolled at Site 1.
`
`The materials used for dialysis in Part 2 (eg, filters and tubes) were not examined for a possible
`interference with the analytes because this was not necessary in the opinion of the responsible
`analyst. In addition, no discrepancy Was found between the results for the extraction rate, the
`amount excreted in the dialysis fluid, and the reduction of AUC(0-tz) for lacosamide and SPM
`12809.
`
`Nith a
`dialysator type
`'2‘“
`For the high-flux hemodialysis in Part 2 of the trial, a
`blood flow rate of 300mL/min and a dialysate flow rate of SOOmL/min was used. Samples for
`PK evaluation were drawn from the dialysis inlet and dialysis outlet line 4 hours afier the start of
`dialysis and from the dialysis fluid 4 and 6.5 hours after the start of dialysis.
`
`, b“
`
`
`
`Subjects: Eight subjects were enrolled in each of the 5 groups. All subjects were valid for safety
`and PK analyses (Table 1). All subjects were White. Subjects in Group 1 were individually
`matched to subjects in Group 4.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`'
`NDA — .
`Lacosamide F ilm-Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`M4)
`
`.
`
`161
`
`

`

`Table 1. Demographic Summary.
`
`Demographic characteristics of Groups 1 ta 5 — SS
`
`,
`
`.
`
`..
`
`.
`
`.
`
`Group I
`
`Gran? 2
`(11:8)
`
`
`
`.-
`
`2
`6
`
`Group 3
`
`Group 5
`{PM}
`
`Group 4
`
`4
`4
`
`
`
`
`
`
`
`Mean-£313
`$233-$128
`56:_4:l:8.2
`
`
`
`43.1233
`37.92111?
`47.52102
`
`(range)
`(44-66)
`{25—53}
`(37—55)
`{38—68)
`(21:54)
`
`
`
`
`
`Mean-i833
`
`11184101
`175.1235 MESH}
`
`
`
`
`169.8i85
`
`Body height
`
`(can)
`
`{range}
`(1.70-1373
`(135—189)
`
`
`
`
`
`
`71.8:b13.7
`73.52141}
`71529.5
`83-08102
`Bodyweight Memsn 16.22148
`
`(59.101;(range) (54.1131) {71-99} {57—86) {60.104}
`
`
`
`
`(kg)
`
`
`
`
`
`
`
`21123. 1
`MeaniSD
`
`{range}
`(23—33}
`
`
`Bbzfi=bady mass index; SD=standard deviation; SS=Safety Set
`
`{169—181)
`
`(131—182)
`
`(160—184)
`
`l?2.0i8.?
`
`25.1%:32
`
`2461:6153
`
`24.3i4l
`
`{20—32}
`
`(21—33)
`
`(21—33)
`
`
`
`
`
`Group I=heaItky subjects; Group 2=subjects 111211 mild renal impairmem; Group 3=subjeets with moderate
`renal impairment; Group 4=vflubjects with sex.are renalampm’zmeat Gmup 3=suljeets with wastage renal
`rksease. requiring hemadiaiysis.
`
`Table 2.
`
`unable
`
`Creatinine clearance {mLfmin} in Grange i to ‘3 at Eligibility Assessment — SS
`
`
`
`Statutes:-- ,
`M)
`G1pup 3
`G:911p-’1
`G10:11) I
`
`
`
`
`
`earame
`
`8230-14210
`
`52. 80—77. 18
`
`30 113-47.80
`
`ID .40428. 81’}
`
`8.012}-17!’.8-0a
`
`SS=811fet} Set
`
`Gran}: 1=heairl1} subjects; Group 2=511bjeets with 11311:! renal impanment; Group 3=sul1§jeets with moderate
`renal impairment; Group 4=suh§ectr5 with aerate renal impairment; Group 5=subjects with aldstage renal
`disease requiring hemodiafysis
`“mam: Subject 39505 7.1110 had a creatinine clearance of 17.813111112211211 at EA. the range cfvafues in 616111) 3
`was Sflfl-HSOmUmin.
`
`Sample Collection:
`Plasma samples:
`For quantification of lacosamide and its metabolite, 17 venous blood samples of 6 mL were
`collected from predose to 96 hours post dose in Part 1. 30 samples of 4mL were collected in Part
`2 (15 samples per treatment) (see Table 3 below). Samples for PK evaluation were drawn from
`the dialysis inlet and dialysis outlet line 4 hours after the start of dialysis and from the dialysis
`fluid 4 and 6.5 hours after the start of dialysis (Table 3). Two samples of about 1.5mL were
`collected for each time point. The dialysis fluid was collected in a Container and weighed after 4
`
`p
`NDA /-'*—‘
`Lacosamide Film—Coated Tablets
`
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`-
`{“4}
`
`162
`
`

`

`and 6.5 hours to determine the collected volume. The total volume collected after 4 and 6.5 hours
`
`and the concentrations of lacosamide and SPM 12809 in the dialysis fluid were used to calculate
`the amounts excreted by dialysis at these timepoints.
`Table 3.
`
`TABfiLAR SCHEDULE FOR SAMPLING FOR PHAWACOKINETICS {PART 2)‘
`
`Day {(1)
`
`Time schedule
`E a
`E.
`:
`
`Time seheéule
`{min postdose)
`
`
`
`00:00
`00:30
`
`0 @mdme}
`wC3
`'
`
`TreatmentA
`
`{Without Remedialysils)
`>4
`
`
`
`
`
`s1
`
`Treatment. B
`
`{with dialysis)
`
`X (predese)
`
`Biaij‘sis
`
`
`
`
`
`
`
`
`
`01:00
`
`9130
`
`{33:90
`
`92:30
`
`02:45
`
`1333130
`
`3:30
`
`04:00
`
`06:00
`
`05:30
`
`06:30
`
`{33:00
`
`12:00
`
`24:90
`
`‘
`
`.... C)
`
`150
`
`163
`
`180
`
`219
`
`240
`
`359
`
`390
`
`y—n
`4 0
`
`480
`
`7'20
`
`1449
`
`1
`
`X
`
`r“:
`
`
`
`
`
`Adogegqgssoaism
`
`a$
`
`4
`
`mint. additional samples were drawn from the dialysis inlet and diaiysis outiet line as well as from the. diaiysis fluid.
`
`aim, an. additional sample was drawn from the dialysis fluid.
`
`Urine samples:
`Urine was collected for the determination of renal excretion of lacosamide and SPM 12809
`
`during the following collection period in Part 1 of the trial:
`' Predose (blank) (Day 1)
`- 0-4, 4-8, 8—12, 12—24, 24—36, and 36-48 hours postdose
`
`Sample Analysis: The concentrations of lacosamide and SPM 12809 were determined by means
`of a validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)
`method using Positive Electrospray Ionization (ESI) and Selected Reaction Monitoring (SRM) in
`plasma (Validation Report No.ba583-03) and urine (Validation Report No. 585—02). The LOQ
`for LCM in plasma was 0.01 ug/mL and in urine was 0.2 ug/mL. The LOQ for SPM 12809 in
`plasma was 0.01 ug/mL and in urine was 0.2 ug/mL. See tables below for summary of analytical
`assay data.
`
`ND,A ,—
`Lacosamide Film—Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`“(4)
`
`163
`
`

`

`?a:ramete:rs of the aasayeti standard censentmfiens and the calibration unwes
`
`
`
`
`Reference
`P‘reeision we]
`.Aceeraey 1%}
`{Ieeffieient of
`Precision 9f
`cempounds
`certainties]- “a"
`31999 ‘b’
`
`
`
`
`
`
`era's—megs
`
`3PM mane
`
`9.999?
`
`
`
`?a.rameiers of the assayed standard eeaeentmtiem and the caiiln‘ntiau (mares
`
`
`
`
`
`
`Reference
`Freeman {%3 Accuracy iii/5:}
`'Ceefficient of
`Precision of
`
`cempnunfis
`.
`ceweiatien ‘1"
`slope '13"
`
`
`
`SPM 92?
`{3.3 — 3-7
`33.3 — 13.3-3
`
`8PM mes:- - 934-1318
`
`
`
`3.199;?34
`0.99928
`
`
`
`13.5%
`1.1%
`
`
`
`Pharmacokinetic Results:
`
`Part 1: Normal to Severe Renal Impairment
`
`Lacosamide:
`
`. Plasma concentration-time profiles for lacosamide in subjects with different degree of remal
`function are shown in Figure 1.
`Linear sco§9
`
`Samllogarfihmlc scale
`
`“A O
`
`‘1
`3.5
`
`
`
`
`
`59M927PLASMA!)CGNCEN‘IRATIONSEgg/ML}
`
`5’
`
`SPM927pusmconczmmnoxsfag/ML;
`
`0.01
`
`O
`
`~rv~mw~m~ww~~v~mvm
`.
`"vs-"-e—«rWIrMM-awwwmmwm .
`'
`‘
`‘
`'
`A“
`6 12 18 24 30 35 42 48 54 60 66 "1’2 78 84 9096
`5 12 18 2430 36 42 48 5460 56 72 78 84 9095
`Thus after administration In]
`Time at“! admlnx‘flloalon [hf
`Group 1: chr >m BOmL/min (healthy car-cram) W
`Group 2: SOmL/min > CLGr >54. scmh/mln (mild roam: Imacthmant)
`“‘“"”°“V°‘””'“”"””¢’”‘”
`Group 25: somL/mtn > (31.45” >=§ SGML/min (madman). tuna! lmpoirmnnt)
`--*-—w,——-—--a----——n-———
`Graup 4: Car << ~30n1L/m1n. no? raquiring dlefiysls (savers rsnat Impairment)
`—“_“——"—’—_°—+—
`Note: Values below LOG (=161ug/mL} were replace-d by zero in calculations of mean and :35) if at. least 223
`'-
`of the data were above LOG.
`
`.
`0
`
`Figure 1. Mean plasma concentrations of lacosamide after single oral administration of
`100mg lacosamide in healthy subjects and subjects with mild to severe renal impairment.
`
`NDA K‘”
`Lacosamide Film-Coated Tablets
`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
`
`'0‘",
`
`Y
`b(4)
`
`164
`
`
`
`
`
`AgogSicilssod$98
`
`

`

`Table 4. Pharmacokinetic parameters of lacosamide in healthy subjects compared with
`subjects with mild to severe renal impairment.
`
`il‘ammeter
`
`
`
`
`
`(unit)
`
`Group I
`{N=3)
`
`Group 2»
`(37:3)
`
`
`
`
`Group 4
`{H}
`
`
`
`Geemetrie mean (CV %)
`
`4.7.01 {20.3}
`
`59.52. (11.5)
`
`34.75 {2.5.9}
`
`
`
`
`CV=coefficient of variation; PKS=Pharmacokinetic Set
`Group l=hea1thy subjects; Group 2=subjects with mild renal impairment; Group 3=subjects with moderate renal
`impairment; Group 4=subjects with severe renal impairment
`3 Median (range)
`bArithmetic mean d: standard deviation
`
`
`
`
`
`
`
`
`
`
`AUCMWM
`fllglnl*11*kg)
`
`m
`33.2.5 (15.4)
`
`49i6£24.6)
`
`51-95 (21.4}
`
`Cm“
`E:E.
`
`2.69 (35.0)
`
`2.95 (28?)
`
`202 (22.2)
`
`243 (15.7)
`
`3.132. (-23-3)
`
`210.314)
`
`(may
`
`we (0.5-2.0)
`
`omens-1.0)
`
`€er {Uh}
`
`2.13 {20.3)
`
`3.68 (17.5}
`
`
`mores—1-9)
`1.74 (19.0}
`
`1.00{B.5—1.5)
`
`1.34 (.263)
`
`CLR (Lat)
`
`(3.589? {37.9)
`
`0.3544(513)
`
`0.276%? (24.4)‘
`
`0-1428813)
`
`ESBGiTJE
`
`22.391329
`
`153313.10 ‘
`
`assays»
`
`13.22 {1316)
`
`13.1? (13;?)
`
`15.39 {13.9)
`
`13.39 {213)
`
`13.94 (3.1)
`
`13.92 (1.5)
`
`
`
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`
`° Summary statistics calculated for N=7 subjects only: no urine PK parameters were calculated for Subject 80306
`due to incomplete urine collection.
`
`The plot of relationship between individual values of AUC(O-ti) of lacosamide and the CLCr in
`healthy subjects (Group 1) and subjects with mild, moderate, and severe renal impairment
`(Groups 2-4) is shown in Figure 2 and Figure 3, respectively.
`
`APPEARS THIS WAY
`0N. ORIGINAL
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`I1:121:3135amide Film-Coated Tablets
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`50, 100, 150, 200, 250, 300 mg
`Original NDA Review
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`ib(4)
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`165
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