`
`Comments:
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`The similarvalues ofCMMug-in patients with narcolepsy to that in healthy
`volunteers (CEP-ZlOlfindicate the similar elimination rate between these two
`populations.
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`PlasmaConcentration
`
`
`Protocal No. C1538af301/NA/US: Pharmgcokiuetic Report
`Report: DP-96-008
`’
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`(pg/ml.)
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`I: Protocol No. Clsasa/‘ao
`Report: DP-96-oos
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`Age Study
`11. Blood Kinetics Trial ofModafinil CRL40476) in the Elderly Subject Before and
`'
`‘
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`‘MOD-OZO)
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`depression; (3) with no underlying organic condition: hepatic (normal state ofthe liver
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`19
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`._ ..-....t,s.u_‘_..'r .._._.,
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`with cap-2101 (US study), and found that with the
`in MOD-018 and CEP-ZIOI are ~50°/o ofthose in CEP-ZIOI study (see the
`attachment). As a result, the cle
`'
`I
`
`point-to-point comparison, the reviewer demonstrated that the modafinil
`concentration between the elderly and the young are co
`3. The sponsor has conducted another PK study following single dose ofmodafinil on
`healthy and elderly male healthy volunteers (C1538a/103/PK/US). The results
`
`the elderly than in the young (by lO-20%). Correspondingly, the formation of
`y than that in the young subjects by the same
`enantiomers the same with as the young subjects,
`again, with the exception ofclearance which is lower (for both enantiomers) in the
`elderly subjects (by ~20%).
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`Figures 1 A andB belofi [p. 12% gov/themeanplasmaconcentrations ofMODAFJNILand
`its metabclite, acid MO
`respectively:
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`
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`C
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`—'-" ‘2
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`'3‘:
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`
`
`A — CONCENTRATIONS OF MODAFINIL -
`o-—-o women
`o-—-o men
`-
`V
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`I
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`~0
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`[1SEM{One-l")
`
`
`MeanConcentrations1SEMI m
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`MeanConcentrations
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`3.3
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`'
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`RI NF
`
`Plasma
`
`concentrations
`on D1
`
`and/or D7
`
`Physical and/or
`psychologicalfbehavioutal
`effects correlated with the
`pharmacologiml activity
`
`Clearly apparent
`
`
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`young Subjects, nevertheless
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`NDA 20-717
`Provigil° (modafinil) ‘
`Human Phannacokinetics and Bioavailability—
`
`6.2.1
`
`Summary ofHuman Phannaeokinelics and Bioavailability Study Results
`Summary of Human Pharmacokjnetics and Bioavailability Study
`Results: Single Dose
`
`6.2.1.1
`
`C1538a/103/PK/US -- Open
`
`6.2.l.1.2 Procedures and Methods
`
`6.2.1.1.2.l Study Design
`
`Single-center, Single-dose, Open-label, Parallel—group:
`
`
`
`Young males mean age of29.4 years (range 22-37 years)
`Young males mean weight of82.9 kg (range 64.1-98.2 kg)
`Young females mean age of26.] years (range l9-4O years)
`
`’ Young females mean weight of 64.3 kg (range 51.8—86.8 kg)
`Elderly males mean age of62.7 years (range 53-72 years)
`'
`Elderly malesmeanae'ebtwéelsieeEIWJ-9mkg)
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`‘4 -eg. '_ '- --
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`NDA 20-717
`.
`mvign' (modafinil)
`Human Pharmacokineties and Bionvailability -—
`
`5
`
`Table 6.2-
`
`.
`
`Summary ofHuman Pharmacokineties and Bionvnilability Study Results
`
`
`
`(0-72 hr) After a Single 200 mg Oral Dose ofModafinil in
`.
`Healthy Subjects
`
`
`
`
`
`lr
`I.
`
`l
`l.
`L
`
`
`
`The absorption ofmodafinil was rapid as indicated by ~
`half-life and mean absorption time. An apparent vol
`suggests extensive tissue binding. The plasma clearance of modafinil was
`~ 50-60 mL/min and renal clearance accounted for ~
`5% of the plasma clearance.
`
`one hour for both absorption
`
`
`
`
`
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`- ~ .......:... .2»...... .-. ....m.._...... .32--..
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`Sub. 1
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`Su
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`200 mg
`Time
`0-5
`1
`1.5
`2
`3
`4
`6
`8
`12
`24-
`144
`144.5
`145
`145.5
`146
`147
`148
`150
`152
`156
`168
`192
`
`
`
`Sub.4 Sub.
`
` .
`
` .
`
`CEP'Z'M
`00110167
`US Study on Young _ Study on Young
`Mean
`Sd. Mean
`Sd. Time (Fr)
`0.40
`0.52
`0.85
`0.71
`0.5
`2.43
`1.16
`1.64
`0.69
`1
`4.17
`0.71
`2.01
`0.55
`1.5
`4.68
`0.47
`2.22
`0.39
`2
`4.56
`0.60
`2.42
`0.24
`2.5
`4.16
`0.62
`2.33
`0.1
`3
`3.32
`0.32
`2.32
`0.17
`4
`2.70
`0.31
`2.21
`0.63
`6
`1.83
`0.19
`1.71
`0.41
`8
`0.91
`0.14
`0.57 0.22
`24
`1.73
`0.25
`2.51
`0.81
`4.41
`1.03
`5.62
`0.62
`6.17
`0.59
`5.99
`0.81
`5.71
`0.96
`4.52
`0.57
`4.04
`0.85
`2.92
`0.79
`1.48
`0.58
`0.58
`0.16
`
`"
`.
`
`,.‘
`
`
`
`300 mg Old/fem
`Mean (SD)
`Time
`Conc
`2
`5.9 (1.20)
`4
`6.14 (1.76)
`7 *
`3.94 (1.04)
`10 ‘
`3.78 (0.96)
`144
`4.16 (1.44)
`146
`8.3 (2.58)
`148
`8.06 (3.08)
`151
`6.6 (2.90)
`154
`5.91 (2.00)
`
`Old/male
`Conc
`5.3 (3.6)
`7.31 (3.38)
`7.32 (3.38)
`6.27 (2.60)
`4.88 (1.08)
`9.21 (2.31)
`9.25 (1.91)
`9.68 (2.77)
`7.78 (1.86)
`
`-mao~m& us (dew/cl)
` .
`Young
`Young
`Conc
`Com:
`3.33
`7.02
`3.50
`6.24
`2.94
`4.57
`2.25
`3.45
`1.30 Pred.
`2.59
`4.63
`9.25
`4.28
`8.57
`3.30
`6.60
`2.85
`5.70
`
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`a). '. l~ .-....—;_x..;.w..‘..‘.-_..
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`-....
`
`12. Pharmacokinetics ofMulti le Doses ofModafinil in Hum
`Chronic Hepatic Insufficiency
`MOD-021)
` .
`
`.
`
`ans with S
`
`were
`
`
`
`If
`
` Number ofsubjects:
`
`-
`9 subjects, i.e.: 6 men and 3 women
`Patients with severe he atic insufficiency; cooperative, no
`Inclusion criteria:
`
`
`
`combined or previous
`days) treatment
`V
`
`
` Trial compound:
`
`
`
`
`Treatment duration:
`
`Reference treatment:
`
`Endpoints:
`
` 1.
`
`' Plasma concentrationsBf MODAFleand its
`metabolite. _
`
`Pharmacoldnetic parameters of MODAFlN‘lL
`2.
`
`
`1. Modelling of kinetics.
`
`2.
`Parametnc test (Student’s "t' test for grouped data).
`
`Nine subjects received an oral dose of 200 mg of MODAFINH. in the form of two non-coated
`' 100 mg tablets (ref. 12156) for 8 days. This dose was given as one tablet in the morning and
`‘ one at noon. This dosage was selected since it corresponded to the Usual therapeutic
`schedule. On days D1 and D8, the total dose of 200 mg was given as a single amount in the
`morning and a series of blood samples obtained.
`
`Blood samples were drawn on days D1 and D8, when the drug Was given as a single dose of
`200 mg:
`
`- 10 ml of blood was drawn into a dry heparin tube before (control specimen) then at times
`0.5. 1. 1.5. 2. 2.5. 3. 4, 6. 8. 10 and 12 hours after administration on D1, with additional
`points at 24 and 36 h on 08. Blood was centrifuged and, after separation, plasma frozen at
`-20°C until assay.
`'
`
`
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`21
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`Results (Attachment 12) and Conclusions:
`
`The elimination ofMODAFINILis essentiallyhepatic (only 10%of.the dose administered
`being foundintact in urine).
`‘
`1.
`in patientswith hepatic insufficien
`ol‘MODAFINIL
`cy (severe Cirrhosis), the kinetics
`after multiple doses wane dln'erent
`as compared to those found in h
`eaithy individuals:
`- elimination half-lifewas more than doubled, increasingfrom 13.6h intreated
`healthy subjects to siniost27.7 h in hepatic insuh'icienCypatients '
`1
`'- thevolumeofdisn-Ibutionatstea
`statewasdecreased,falling'from811linh
`ealthy
`subjects to almost 60.5 i in hepatic
`_
`-
`thesechangesWerereflected
`stea
`stateplasmaconcentrationsotMOIiAFINIL
`gppxuxhnatgéytwiceas high obs,in ting-yheaithyindividual
`'
`'
`o
`cxency patients as compared With 3.73 ng‘ 111
`
`eiency patients
`
`‘ 7.90 ng
`
`
`
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`Kinetics ofMODAFINIL in hepatic insnflidcncy patients - 11
`
`Afr/3"“ n. XE-NT‘ A ”(1...
`
`A ‘KINETICS ON 01
`
`.-.... Hepatic insufficiency group
`0‘0 Treated healthy subjects group
`
`
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`1:
`
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`sem(ng'
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`Meanconcentrations4
`
`.7 9
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`2'“. Hepatic insufficiency group
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`
`
`
`Plasma concentrations orMODAFINILon days 1 and 8 during
`multiple dose kinetic study
`
`,
`
`g
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`J NDA 20-717
`,
`pmvigit‘ (modufinil)
`Human Phannacokinctics and Bionvailability -— Summary ofHuman Phnnnncokineties and Bioavailsbility Study Results
`"Table 6.2-78. Mean (:hMSE) Pharmacokinetic Parameters of
`Modaflnil and Modafinil Acid After'Oral Doses
`
`(200 mg/day) of Modafmil in Hepatic Dysfunctional
`Patients
`‘
`
`Hepatic
`Insufficiency Patients
`
`Hepatic
`Insufficiency
`
`,
`
`3:.#5IE:
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`33.35
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`14.17
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`16so
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`
`Data obtained from a multiple dos: kinetics study-MOD-Ol9)
` .
`Significantly different (p<005) from corresponding values of the healthy subjects.
`
`
`Cephalon. Inc.
`Page 299
`CONFIDENTIAL
`QWOCEPHALOMNDAWALW‘EMéWZS_VN.WP6; ll Naval-the: I996 9:03 pm
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