13. Evaluations of The Pharmacokineti
`Chronic Renal Failure -P1595)
` .
`The aim of the study was:
`
`es ofModafinil and Its Metabolites in Severe
`
`a) To evaluate the effect of severe chronic renal failure on the pharmacokinetic
`profile of modafinfl, administered orally, and its main metabolite;
`b) To assess the safety and incidence of adverse efiects with modafinil in this
`patient group.
`
`-
`
`.
`
`,
`
`mm M: leg”,
`2.2 mm
`This was a non-randomised open label study conducted in 10 male subjects with severe
`chronic renal failure who were not receiving any type of dialysis. Subjects received a
`single 200mg dose of oral modafinil at 8 am after an overnight fast. Blood and urine
`samples were taken before dosing and at intervals over 96 hours to assess levels of
`modafinil and its main metabolite, modafinil acid. The pharmacoldnetie parameters
`Cmax, Tmax, AUCMM, AUQMO, Tbs, Alias“, and C1,; were assessed.
`
`’
`
`a 2.23
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`
`
`Oh (taken before closing), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 1; 15, 24, 36,
`48, 72 and 96h after dosing.
`
`The blood was placed in a lithium heparin tube, centrifuged at 2000g for 10 minutes
`and the plasma separated into a plain tube and stored at -18°C pending collection by
`
`The total volume collected in each interval was measured and a 20ml aliquor
`withdrawn and stored at -18‘C pending collection by the sponsor.
`Results (Attachment 13) and Conclusions:
`
`Following a single dose ofmodafinil, severe renal failure did not influence the PK
`ofmodafinil. A slight reduction in renal clearance (f,=3% in renal patients and 5% in
`healthy volunteers), and Cam (3.33 mg/l in renal patients and 4.01 mg/l in health
`volunteers) would not have any impact on the plasma concentration ofmodafinil.
`
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`23
`
`
`Chronic Renal Failure -P1595)
` .
`The aim of the study was:
`
`es ofModafinil and Its Metabolites in Severe
`
`a) To evaluate the effect of severe chronic renal failure on the pharmacokinetic
`profile of modafinfl, administered orally, and its main metabolite;
`b) To assess the safety and incidence of adverse efiects with modafinil in this
`patient group.
`
`-
`
`.
`
`,
`
`mm M: leg”,
`2.2 mm
`This was a non-randomised open label study conducted in 10 male subjects with severe
`chronic renal failure who were not receiving any type of dialysis. Subjects received a
`single 200mg dose of oral modafinil at 8 am after an overnight fast. Blood and urine
`samples were taken before dosing and at intervals over 96 hours to assess levels of
`modafinil and its main metabolite, modafinil acid. The pharmacoldnetie parameters
`Cmax, Tmax, AUCMM, AUQMO, Tbs, Alias“, and C1,; were assessed.
`
`’
`
`a 2.23
`
`
`
`Oh (taken before closing), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 1; 15, 24, 36,
`48, 72 and 96h after dosing.
`
`The blood was placed in a lithium heparin tube, centrifuged at 2000g for 10 minutes
`and the plasma separated into a plain tube and stored at -18°C pending collection by
`
`The total volume collected in each interval was measured and a 20ml aliquor
`withdrawn and stored at -18‘C pending collection by the sponsor.
`Results (Attachment 13) and Conclusions:
`
`Following a single dose ofmodafinil, severe renal failure did not influence the PK
`ofmodafinil. A slight reduction in renal clearance (f,=3% in renal patients and 5% in
`healthy volunteers), and Cam (3.33 mg/l in renal patients and 4.01 mg/l in health
`volunteers) would not have any impact on the plasma concentration ofmodafinil.
`
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`23
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`.‘4..- _.M*— ~~.-l;l._\ ,_
`
`(
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`to
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`prolonged t“2 (to >3 fold). Nevertheless, subjects with renal failure exhibited no adverse
`effect in this study, indicating that these subjects had a good tolerance ofmodafinil and
`modafinil acid.
`
`Comments:
`
`1. At single dose of200 mg, only 25% ofthe modafinil dose was excreted in urine as
`modafinil acid in the renal patients, compared to ~45% in healthy subjects. This
`
`accumulated longer and more in renal patients in this single dose study. Had the
`study been designed as multiple dose, the accumulation ofmodafinil acid would be
`even more, ifnot equal to, that in single dose in renal patients. Since modafinil is to
`be administered chronically, it is important to know the clinical outcome ofchronic
`accumulation of modafinil acid.
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`,,,‘r‘mzzi‘rll 3»:
`
`
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`
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`Mean; an Volume
`
`
`Haematocri;
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`
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`Mega Ceu Haemoglobin:-
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`Red Cell Count
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`2 (20%)
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`1 (10%)
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`l (10%)
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`l (10%)
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`t (10%)
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`1 (10%)
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`.
`s (50%)
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`b) Biochemistry
`
`Baseline to 24h post-dose trends in biochemical laboratory parameters that fell outside
`the normal range are summarised below:
`
`Baseline-.241: puma“ ~
`
`" "
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`*
`
`Normal
`~ Low
`
`Normal - Normal
`Normal
`- Rich
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`Using tasting reference range of3.4 - 5.2 mmolll
`
`: —»»~
`‘
`
`Although fasting glucose samples were not taken. the glucose levels given in Listing 9
`show that samples from 9 of the 10 subjects fell within the normal fasting glucose range
`(3.6 - 5.6 mmol/l). Glucose levels of 6.1 and 6.0 mmol/l were recorded at baseline and 24h
`post-dose, respectively, in 1 subject.
`'
`
`Urea and creatinine levels were markedly higher than the upper normal value in all
`subjects, reflecting their chronic renal failure. Bicarbonate levels were low in 50% of the
`subjects and fell from normal levels to below normal in 2 subjects.
`
`None of the changes in laboratory parameters were attributable to modafinil.
`
`c) Urinalysis : Na glucose was racer-dd 5,, .4“? {+44 wine was. murvSKa-pq new
`wgisnwt wit-*6. rum! Jungian.
`‘
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`Human thucokineties and Bioavailability-—- Sumnury orHuman Phannaeokindiee Ind Bioavailability Study Results
`Table 6.2-79.
`' Mean‘(:l:SD) Pharniacoldnetic Parameters ofModafiniI and
`' Modafinil Acid After a 200 mg Oral Dose ofModafinil in
`Chronic Renal Impaired Patients arid Healthy Subjects*
`
`Subjects with Chronic Renal
`
`
`
`
`
`'Failure
`
`,
`Modafinil
`
`
`
`Modalinil
`Acid
`
`5.36
`
`
`
`Healthy Subjects“
`‘
`'
`Modafinil
`.
`Modafinil
`Acid
`
`
`
`NDA 20-717 I
`vaigil" (modafinil)
`
`v
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`
`
`
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`
`
`‘
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`
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`“20‘“,-
`
`
`
`n=7
`n=6
`n=8
`n=10
`n=9
`
`A = Not Applicable.
`Data obtained from a previous study Lafon P1589 (MOD~022). fl'fi I 7/
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`Drug-Drug Interaction Study
`
`Isl. {Double-Blind Placebo-Controlled 3 Way Crossover Study to Investigate the
`Kinetics and Acute Tolerability ofModafinil and Clomipramine Alone and in
`Combmation in Healthy Male Volunteers (C1538a/107/PK/UK)
`Objectives:
`To study the kinetic interaction between modafinil and clomipramine.
`Introduction:
`
`Study Design and Sampling:
`The study was a single—center, 3-way double-blind crossover study involving 18
`healthy male volunteers. The protocol ofthe study was as following:
`
`Afier fasting, the subjects were dosed with the following treatment schedule:
`
`‘
`Treatment A: Clomipramine (l x 50 mg capsule) - Day 1
`Modafinil (2 x 100 mg tablets) once daily - Days 1 to 3
`
`Treatment B: Clomipramine (l x 50 mg capsule) - Day 1
`2 x placebo tablets once daily - Days I to 3
`
`Treatment C: l x placebo capsule . Day 1
`‘
`-
`Modafinil(2xlOOmgtablets)oncedaily-Dayslto3
`17... am as. WWW/pm w e we we“ '95
`.
`444/“f
`I mt;
`_
`There was a Wis—{33¢}: washourtiperiod between each treatment phase. For modafinil, blood
`samples were collected immediatelyprior to the Day I modafinil dose (time zerp) and at l, 2,
`3, 4, 6, 12, and 24 hours following administration ofthe Day I modafinil dose, and at 60,
`72, 84, 96 and, 108 hours afier dosing ofthe Day 3 modafinil dose using the Treatment
`$47430 W r91 errmlnc t: q?”
`_
`'
`Schedules A and .Elbe prepared plasma samples were stored m a -20°C freezer and frozen
`in dry ice during shipment, and were stored at ~80 to -90°C awaiting analysis
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`25
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`ska ”a..-‘._..__.__n_..--¢. H.
`
`(
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`Results (Attachment l4) and Conclusions:
`It appeared that co-administration ofclomipramine did not afiect the PK of
`modafinil or 'its metabolites in humans. Modafinil did not afi‘ect
`
`
`
`.4 _
`C
`
`.
`clomipramine is the
`metabolites, rather the parent drug. Secondly, the relatively low dose of
`clomipramine in the study (50 mg), besides single dosing, might “hide” the
`interaction that would be reached at high doses.
`2. The sampling time for clomipramine, 72 hrs, is too short to cover the elimination
`phase ofthe drug, which may result in wrong estimation ofAUCM, on clomipramine.
`3. The sampling time for desmethyl clomipramine, whose reported t1/2 is 96 hr, is too
`short in this study to draw meaningful conclusions on its t/12, AUCO-oo in this study.
`Therefore, the conclusions for desmethyl clomipramine can only based on Cmax and
`AUG“.
`4. Variation on plasma concentrations and AUC(H for both clomipramine and its active
`metabolites were big.
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`26
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`_lelmnm
`4
`i
`--
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`4.1-3
`00537100100
`TWent
`“2:212: BEE nun-
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`(mcdmL)
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`Concentrntlon
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`20
`3O
`4O
`50
`60
`7O
`80
`Time (hours pox! initial dose)
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`of
`Parameters
`Pharmacokinetic
`(asp)
`Table 6.2-53. Mean
`Clomipramine Following Administration ofClomipramine
`(50 mg) with Either Modat‘mil or Placebo in Healthy
`Subjects
`
`
`
`
`
`
`
`t
`median range.
`Treatment A: Clomipramine (50 mg, Day I) and Modafinil (200 mg, Days 1 to 3).
`Treatment B: Placebo and Clomipramine (50 mg, Day 1).
`
`1mm,”
`
`mm m
`
`663 (364)
`
`
`
`
`
`Table 6.2-54. Mean (iSD) Pharmacokinetic Parameters of Desmethyl
`Clomipramine Following Administration ofClo’mipramine
`(50 mg) with Either Modafinil or Placebo in Healthy
`Subjects
`.
`
`mm mm
`
`
`
`AUC°.(pg-hr/L)
`6190(12999)
`1128(1141)
`
`483 1018
`
`88 102
`
`
`
`
`
`
`
`
`
`II
`
`median range
`Treatment A: Clomipramine (50 mg. Day I) and Modafinil (200 mg, Days 1 to 3).
`Treatment 13: Placebo and Clomipramine (50 mg, Day 1).
`
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`Cephalon, Inc.
`_
`CONFIDENTIAL
`O:\PGCDHALDN\NDA\FINALWH‘EM6\623_VO7.WP6: 11 November 1996 8:0 pm
`
`Page 197
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`ITEMG 00299
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` Plasma
`ClomiprnmineConcentntian-fimcdataGigi")forTreatmentA
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`Medan! Study No. MEOZGI
`
`Cephnlon Study No. C1538a/lO7IPKIUK -.
`ITEM 8 18987
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`PlasmaClomipramlneConcentration-timedata(”91.")
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`II
`EEHIHIHIHHHfiHHHI
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`Medan! Study No. MEOZGI
`Cephulon Study No. C15383/107/PK/UK V
`ITEM 8 18988
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