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`Protein binding study
`
`Clinical phase:
`
`'
`
`Phase II
`
`1.
`2.
`3.
`
`- Studg‘realthy humans ofthe kinetics of
`MO -
`I IL after multi
`le doses;
`Study'ofvariability in the ‘ etics of MODAFINIL
`in healthy humans.
`fixovgo stud of the protein binding of
`
`Number ofsubjects:
`
`‘
`
`Inclusion criteria:
`
`
`
`
`
`Double-blind trial:
`- gne group of subjects given MODAFINIL daily for 15
`3Y8
`- one group of subjects given MODAFIN'IL only on days
`1. 8 and 15
`.
`18 sub‘iects in all, Le. 12 in the treated group and 6 in the
`contra group
`.
`Healthy male volunteers; 18 < age 535; cooperative,
`With nonotable medical or psychdlogical past history. with
`no combined or previous (7 days) treannent
`
`Two tablets of MODAFINIL (ref. 12156, a. 'cave ingredient
`5/1939). i.e. 200mg per dang.” , f’fllafw DI
`15days ;~:
`_
`P8167 to 0: waif was‘
`The control group was given MODAFINIL at the same
`daily dosage only on days 1. 8 and 15
`.
`1.
`Plasma concentrations of MODAFINIL and its
`metabolite.
`'
`
`Pharmacoldnetic parameters of MODAFINIL
`H9 mQ cg bin-c? was drawn lag—Ewe. Mnnls-l'fafi‘ém sf ”70W 97‘
`mat/4%
`
`Trial compound:
`
`Treatment duration:
`
`Reference treatment:
`
`-
`
`Endpoints:
`
` .
`
` .
`
` .
`
`
`
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`
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`warfarin binding in plasma was reduced fi-om 98% to 89%.
`
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`
`Kinetics ofmultiple dam ofMODAFINIL in man .22
`QWS/
`
`.......l
`
`
`
`sound/ricenoonrmn 3
`
`A ~ BINDING 0F MODAFINIL T0 ALBUMIN
`
` .
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`
`
`.-
`
`30
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`
`35
`
`55
`50
`‘5
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`Serum albumin concentrations (g.l-')
`
`60
`
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`Bound/FreeMODAFlNiL
`
`BINDING 0F MODAFINIL TO OROSOMUCOID
`8 ~
`
` .
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` 0.2 . I . 1.0
`
`1.2
`1.4
`1.6
`La
`' 2.0
`Serum concentrations of alphai-acid giycoprotein (9.1-1)
`
`Figure4
`
`Relationship between bindingofMODAFINILto serum and concentration >
`ofalbumin (A) or concentration oforosomucond (B?
`
`__
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`
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`
`Figure 1
`
`Plasma concentrations of MODAFIN‘IL on days 1, 8 and 15
`during multiple dose kinetics study
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`Kinetics ofmultiple doses ofMODAFINIL in man ~ 13
`A - KINETICS on D!
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`
`Figure 2
`
`3\
`
`24
`‘
`
`30
`
`. '
`
`3‘
`
`Plasma concentrations ofacid MODAFINIL on days 1, 8 and 15
`during multiple dose kinetics study ofMODAFINIL
`
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`
`

`

`NDA 20-7 1 7
`Provigil" (modatinil)
`
`‘
`(.~
`u »
`
`Human Phannacokinctics and Bioavailability-‘-Summary ofHuman Pharmaeokineties and flioavailability Study Results
`6.2.10
`Summary of Human Pharmacokinetics and Bioavailability Study
`Results: In Vitro/In Viva Metabolism Studies
`
`-
`
`. __
`
`6.2.10.1 DP-96-014 (B) —-In Vitro Study of Plasma ~Ifrotein Fixation
`
`6.2.10.1.1 Objectives
`
`The objective ofthis study was to determine binding ofmodafinil to plasma proteins
`
`in vitro.
`
`’
`
`(1';
`‘
`
`6.2.10.1.2 Procedures and Methods
`
`6.2.10.1.2.l
`
`Study Design
`
`Plasma protein binding of modafinil was evaluated by equilibrium dialysis for
`I hours at 37°C at a speed of-rpm. One-hundred-twenty “L ofmodafinil solution
` .
` .
`( 1% methyl alcohol in pH 7.4, 0.067M Sorensen phosphate buffer) was added to
`120 uL ofpooled plasma or purified protein. The final plasma concentrations of
`modafinil were 0.1 and 50.5 pM. The protein binding ofmodafinil in serum albumin
`and a-acid glycoprotein was studied at
`the modafinil concentration range of
`05-005 uM. The plasnf’protein binding ofmodafinil in the presence ofmodafinil
`acid (0.5-00 uM) as well as the binding of modafinil (0-1000 11M) to warfarin in the
`presence ofmodafinil acid (0-5000 uM) was also studied.
`
`At the end of dialysis, an aliquot specimen was taken from each compartment and
`counted by liquid scintillation. Non-specific binding ofmodafinil to dialysis tanks
`or to the dialysis membrane was less than 10%.
`
`For experiments involving competition with warfarin, binding of ["C]-warfarin at
`a concentration close to the therapeutic range (1.5 1.1M) was studied in the presence
`of increasing concentrations of modafinil (O—IOOO pM) or of its acid metabolite
`(0-5000 uM).
`
`Cephalon. lnc.
`CONFIDENTIAL
`O:\PC\CEPHALON\NDA\FINAL\FITEM6\628_VIS.WN: ll November I996 "Bl pm
`ITEM 6 00421
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`Page 319
`
`
`
`

`

`
`
`
`
`NDA 20—717
`
`.
`
`I
`
`‘
`vaigil"(modafinil)
`Human Phlnnacokinetie: andBioavaillbility—SummaryofHuman thmacokineticsandBioavailabilityStudyResults
`Table 6.2-81. Mean (iSD) Protein Binding of Modafinil in Plasma,
`Serum Albumin or a-acid Glycoprotein
`
`
`
`Percent of Bindin -
`61.] i i.5°/o-64.5 :h 3.6%
`Pooled Human Plasma
`
`
`
`9’ 55.3 :i: 0.3%-58.7 :e 0.5%
`0.5-300.5 uM
`Human Semm Albumin
`
`
`a-Acid Glycoprotein w 5.1 e o.7%-9.9 a 0.6%
`
`
`
`Plasma Protein in the
`0.5100 nM‘
`61.6 :2 0.2% (in the presence of
`
`Presence of Modafinil
`
`0.5 uM Modaflnil Acid)
`Acid
`60.5 i 0.5% (in the presence of
`
`
`
`100 nM Modafinil Acid)
`
`
`‘
`= Concentration ofModafinil Acid
`
`Concentration ofModafinil
`
`I
`
`'
`
`.
`
`98.5 :t 0.2% - 98.0 :t 0.3%
`98.4 i 0. l% ~ 98.] :i: 0. l°/o-89.2 i 0.3%
`
`0-1000 pM
`0-500 M ~ 5000 M
`
`likely binding site is albumin, and 58.7-55.3% of the modafinil binds to serum
`albumin. Only 6.1-9.9% ofmodafinil binds to a-acid glycoprotein. The binding
`characteristics of modafinil did not change whether
`the acid metabolite
`(modafinil acid) was present or not.
`
`Cephaion. Inc.
`Page32!
`CONFIDENTIAL
`O:\PC\CEPHM.ONWDA\FINAL\FITEM6\62LVIS.WN: 'BEST’PBSSI’B LE C0PY
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`
`
`
`

`

`(’
`
`
`
`Food Effect
`
`:7. Evaluation ofthe Effect ofFood on the Pharmacokinetic Profile ofModafinil and
`Its Metabohte in a Single Dose Cross-over Study in Healthy Volunteers (MOD-022);
`
`Study Design and Sampling:
`
`in compliance with the
`
`completed the trial
`12 healthy male volunteers
`‘
`protocol and the schedule. .
`(SR
`The effect of food intake on the pharmacokinetic profile of modafinil
`96267)
`and
`its two metabolites
`(acid metabolite.
`CRL 40467 and sulfone
`metabolite. CRL 41056) was assessed after oral administration of a single
`do e of 200 mg (2
`ab ets containing 100 mg of sa 96267). 7% aim; was gammy”;
`«(er aver—rt:
`(foam? greatnmrmfilw 5659" S'f‘WJ br-egkagr (Fed
`The study emp oye
`an open cross-over comparison design.
`'“fl’ “The £4.54"? 3,“?
`Each subject was
`to receive the 2 modes .of administration (fasting marine-5n” w‘m‘l
`,(
`,.
`.
`
`.
`
`(
`
`in the.protocol.
`the times provided for
`taken at
`Blood samples were all
`except for subject 7. period 1 (fasting group) for whom the sample H + 0.5h
`was performed at H + 0.63h. Real
`relative individual
`times are shown
`in
`
`for whom the
`in 6 volunteers
`except
`collected.
`samples were all
`Urine
`collected urine fractions were not complete. The
`time'intervals are shown
`below :
`.
`
`N‘M
`Subject Period
`Group
`Incomplete fraction
`MN
`1
`2
`Fasting
`72 - 96h
`1
`l
`Non-fasting
`72 - 96h.
`2
`Z
`Non‘fasting
`24 - son
`4
`l
`Non-fasting
`72 - 96h
`11
`2
`Fasting
`72 - 96h
`11
`l
`Non-fasting
`72 — 96h
`MN
`Results (Attachment 7) and Conclusions:
`
`(_ _
`
`mg/l) and a smaH increase in TIm (3.21 vs. 2.05 h) in non-fasting conditions, compared to
`the fasting conditions. But these changes did not affectthe overall PK ofthe drug.
`
`“"
`
`
`
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`

`P 1589
`
`
`Modafiml
`
`l‘ 135‘!
`
`: Pharmacokinetic parameters of SR 96267
`Mwlavé‘Mll '
`
`..............
`
`.Fasting
`
`AUC o-4sm- (mg.h/'l)
`
`'
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`Non-
`fasting
`
`Fasting
`
`Non-
`fasting
`
` .
`
` .
`
` .
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` .
`
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`
` .
`
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`"OHerasting
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`
`sponding values of the fed group.
`
`Table 6.2-76. Mean (iSD) Pharmacokinetic Parameters of Modafinil
`Acid After a Single Dose (200 mg) of Modafinil
`Administered Under Fed or Fasted Co
`nditions in Healthy
`Males
`
`
`
`
`
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`

`Study Design and Sampling:
`
`‘
`-
`1‘1 [am
`
`Mkjfl- VOWS
`
`My received a single dose of 200 mg of modafinil (2 tablets of 100 tug) at an interval of at
`least one week after fasting or immediately after a standard breakfast. The sequences of
`administration with or without food intake were randomized over 2 periods
`
`Thebloodsamplesweretakeno 0..5h 1h 1.5h. 2h. 2.5h 3h. 3.5h, 4h 5h, 6h 8
`h.10h. 12h 18h,24h 36h 48h 72hand96haftertheadministration, andtheurine
`was also collected to determine the pharmacokinetic parameters of modafmii. All the
`samples were analyzed1n our department with a nonstereospecific method of determination
`(see clinical report No. 578. 6. 042 of 3/27/92).
`
`The samples of 6 subjects among the 12 were used for this kinetic study of the enantiorners:
`subjects 2. 4 6. 7 8 and 10. Each subject was selected by default, as a function of the
`number of samples for which there was sufficient plasma volume remaining to permit a
`second determination and not by making sure that the number of individuals for each
`sequence was distributed equitably.
`
`PRODUCTS
`- CRL 40476 hydrochloride. ref. 5/2435.
`
`- CRL 40982. levorotary enantiomer. ref. 1/0054.
`- CRL 40983. dextrorotary enantiomer. ref. 1/0055.
`
`Results (Attachment 8) and Conclusions:
`There was no evidence ofany effect offood on the PK parameters of either
`enantiomers ofmodafinil. During the assay process, no stereo-conversion was found
`between the two enantiomers, because ofthe stability ofthe racemate and ofthe
`enantiomers demonstrated during the validation. The PK results from this study are
`comparable to those obtained111 study CEP-ZIOI.
`
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`
`-
`Figure 5 - Mean concentrations of the enantiomers of MODAFINIL after oral administration of 200 mg of
`MODAFINIL to six subjects aft
`erfastinget afternneal
`
`.
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`Table 6.2-77 Mean (tSD)PharmacokineticParameters d-Modafimi and
`[-ModafmiiinHealthyMaleSubjectsAfteraSingle200mg
`Oral Dose ofModafinil
`
`-—
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`CRL 40982 (I-Modlflnil)
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`(mg/L)
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`
`.
`
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`
`Urine alkalinization cnd kinetics of MODAFINIL
`
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`(hours)
`
`‘3 300
`E
`
`250
`
`l'
`
`200
`
`|SO
`
`IOO
`
`'8
`E
`
`.5—«
`U
`
`.2:
`3
`1'3
`E
`3.
`
`B - Acid modafinil
`
`I
`
`I
`—/Q
`‘3
`
`‘
`:
`A Volvic" mineral water
`
`V
`
`A
`
`Vichy" mineral water
`
`
`0
`6
`12
`la
`24
`30
`36
`42
`48
`Time (hourS)
`
`Jig-mega.- Cumulalcd urine elimination of MODAFINIL (A) and acid ,modafinil
`(B) expressed in 111 mean i saw) .u
`nder condi '
`‘
`rmal pI-I
` .
` .
`
`
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`9. Evaluation ofthe Effect ofAlkalized Urine on the Kinetics ofModafinil
` .
`MOD-023)
`
`Objectives:
`To evaluate the effect of urine alkalization on Modafinil PK.
`
`Introduction:
`At 400 mg ofmodafinil, urine excretion ofunchanged drug is low (~10%), and
`the principal form of elimination is modafinil acid. A concomitant prescription of a urine
`alkalization treatment may accelerate the elimination ofmodafinil by increasing urine
`elimination of acid modafinil (ionization ofthe molecule with a reduction in its tubular
`reabsorption) and by shifiing the balance between modafinil and its acid metabolite
`towards the production ofthe latter. This shift may reduce the concentration ofthe parent
`drug in plasma and therefore affect the therapeutic efficacy ofmodafinil.
`
`Study Design and Sampling:
`This open, controlled trial was performed as follows:
`
`Six volunteer subjects who had fasted for 12 hours received an oral dose of 400 mg of
`MODAFINIL (4 tablets dosed at 100 mg).
`This dosage was chosen as
`it
`corresponded to the limit dose at which kinetics have been evaluated. The subjects
`
`received this dose '
`er under normal conditions of pH (their drinking water was
`d) or under conditions of alkalinization (their drinking water
`
` .
`
`w..—
` .
`
`
`The protocol was designed to be carried out using a dosage of 600 mg MODAFINIL,
`but the Ethical Committee at the_ requested that this dose be
` .
`reduced to 400 mg.
`‘
`The drinking water sequences were drawn by lot as follows:
`
`1
`
`Subject
`DUIJLUN
`
` .
`
`hid
`
` .
`
`2ndid
`
`Each dosing was given at an interval of one week. Treatment sequences were drawn
`by lot.
`Blood and urine samples Were taken at regular intervals:
`- 10 ml of blood was taken on dry heparin before (control sample) and then
`0.5, 1, 1.5, 2. 2.5, 3, 4, 6, 8, 10, 12, 15, 18, 24, 2.8, 32 and 48 hours after dosing. The
`blood was centrifuged, and after separation, the plasma stored at -20°C until assay.
`'- wines were collected before (control urine samples) and during the periods
`0-4, 4-8, 8.12, 12-24 and 24—48 hours after administration, and stored at ~20°C unh‘l p
`
`assay.
`
`'
`
`(
`
`'-
`
`A
`
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`:1:SEM)
`
`UrinepHvalues(means
`
` .
`
` .
`
`~40 4 812162024283236404448
`
`Time (110qu
`
`55155561.- Urine pH values (mean i 513M) under_watcx or-
`_wam.
`-
`.
` .
`
` .
`
` .
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`. _-\.‘_ ..._..._:V_.. ’,‘.—___.£—.—.‘_.~‘ ‘__r_
`
`‘
`
`GHp b (D p: H Wn! p.- pbp N DI ff.4Ou n!:1D.
`
`H (Ddp Om 0 H. t!O55H2Ht"
`
`A ~ MODAFINIL
`
` .
`
` 0
`
`I
`
`12
`
`ll
`
`2‘
`
`30
`
`J!
`
`42
`
`48
`
`Time (hours)
`
`
`
`B - Acid modafinil
`
` .
`
`A
`A
`
`
`
`
`water
`water
`
`6
`
`12
`
`I!
`
`2‘
`
`30
`
`35
`
`£2
`
`48
`
`Time (hours)
`
`
`
`
`
`
`
`Meanconcentrations1SEM(mg.l'1)M93“concentrations1SEM(mg-H)
`
`. C — Sulfone modafinil
`
` D
`
`
`
` Meanconcentrations:1:SEM(ng‘I) 0.0
`
`
`
`9J.
`
`0.2
`
`if? T T\1
`
`Twater
`~ A
` .
`
`' A
`
`water
`
`o
`
`a
`
`12
`
`u
`
`24
`
`so
`
`:8
`
`42
`
`45
`
`Time (hours)
`.
`Egan-r1— Mean plasma concentrations of MODAFINIL (A), acid modafinil (B)
`and sulfonc modafinil (C)'m man after dosing with 400 mg of MODAFINIL under
`conditions of normal pI-I _walcr) or alkaline pH_
` .
` .
`water).
`
`~
`
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