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`Table I Clomipramine (CL) and desmethylclomipramine (DCL) concentrationsin a
`patient treated with modafinil.
`
`DCL '
`
`Ratio
`Concentrations (rug/ml.)
`CL
`CUDCL
`03/01/96
`02/05/96
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`_, 06/08/96
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`15. An Open, 3.x3 Latin Square, Randomized, Cross-over Study to Investigate the
`Pharmacoltmetics ofModafinil And Methylphenidate When Given Alone and in
`Combination in Healthy Male Volunteers (ClS38a/lO9/PK/UK)
`Objectives:
`To study the interaction ofModafinil and methylphenidate on their single dose
`pharmacokineu'cs.
`
`Introduction:
`
`approved drug for narcolepsy. Although it is unlikely that both methylphenidate and
`modafinil would be given at the same time, it is quite possible that patients on one
`treatment eculd be changed over to the other, which makes it necessary to study the
`interaction ofthese two agents.
`
`APPEARS THIS WAY ON ORIGINAL
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`This was an open 3 x 3 Latin square. randomized. cross-over study involving 21 healthy male
`volunteers. performed in 3 groups of 7 volunteers. Only non-smokers and/or err-smokers for at
`least 6 months were screened; similarly. volunteers were only allowed to be moderate alcohol
`drinkers (Le. a maximum of 21 units per week). The three treatment schedules were:
`
`Treatment A:
`
`‘ Methylphenidate (‘unmediate release) 4 x 10 mg and modafinil 2 x 100 mg.
`Both given concomitantly as a single dose on Day 1.
`-
`
`Treatment 8:
`
`Modafinil 2 x 100 mg as a single dose on Day 1.
`
`Treatment C:
`
`Methylphenidate (immediate release) 4 x 10 mg as a single dose on Day 1.
`
`Volunteers were randomized to one of the following sequence order of treatment schedules:
`(,0 5+5: 4 4 -mj 094"” M pure . 61141414441 WW.
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`Treatment A-fl‘reaunent Bahamnt C
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`Treatment B-)Treatment C—)Treatment A
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`Treatment C-eTteau-nent A—r‘l‘reaunent B
`
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`27
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`W 3102,}: samples (10 1111.) we collected into lithium heparin
`3W ' monovette tubes pre~dose (0 hr) and at the followihg times
`post-dose: 0.5. l, 1.5, 2. 3. 4. 6, 8. 12, and 18 hem: for d- and
`l-threo-methylphenidate analysis; and 0.5. l. 2, 3, 4, 6. 8 12 24 36
`
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` (HPLC)method’andd-andI-methyipherfidaxeia“Mate—methodwith
`
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`of either agent. However, me
`thylphenidate caused a small increase in t,m for Modafinil
`(from 1.9 hr to 2.9 hr), whi
`ch indicated that coadmim‘stration ofmethylphenidate and
`modafinil may cause a del
`ay in the oral absorption of modafim'l.
`
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`*1,
`(SD)modaflnllplasmaconcentration
`Intwenty-onehealthymalevolunteersfollowinga‘slngleoraldoseof
`~.
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`16. Evaluation ofa New ChemicalEntity,Modafinil as an InhibitorofHuman P450
`Enzymes (DM-96-051 (XT052396))
`V
`
`400 mg daily dose)
`3459-5112101: BMW W m “Wow
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`500m .1 W“ t ,‘ W“
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`Hexobatbital
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`1 uM
`CYP3A415
`Ketooonazole
`0.5 uM
`CYP4A9/11
`No competitive inhibitor is available forthis enzyme
`Results (Attachment l6) and Conclusions:
`
`‘
`
`.
`(_ .
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`
`
`
`in this regard. modalinil onid be expected to inhibit the metabolism of those drugs
`CYP2019.
`that are substrates for CYPZCtQ. which include omeprazole. lansoprazole. hexobarbital.
`mephobarbital. propranoloi. citalopram. diphenythydantoin (diiantin). imipramine. mebhenytoin.
`
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`30
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`5 Pages RedactedTrade Secret/Confidential Commercial
`
`BEST POSSIBLE COPY
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`
`Objectives:
`To investigate the effect ofmodafinil on major CYP enzymes in cultured human
`hepatocytes obtained from three donors.
`
`Methodology:
`Modafinil at concentrations of 10 uM, 100 uM and 1 mM were used in the
`incubation with human hepatocytes for 72 hours. Classic inducers of each examined
`CYP enzyme were used in the same batc
`h of cells as positive controls for modafinil. The
`rate ofmetabolism for each marker substrate ofthe enzyme was recorded to determine
`the enzyme activities.
`
`Results (Attachment l7) and Conclusions:
`The results showed that there were large variations ofCYP activity among three '
`liver microsomes, among the
`
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`NDA 20-717
`Provigil° (modafinil)
`Human Phannacokinetics and Bioavuilubility~
`
`Table 6.2-92. Drug Metabolizing Enzyme Activities in Hep
`Prepared from the Human Livers
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`Ccphalon. Inc.
`as: 357
`CONFIDENTIAL
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