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`The pharrnacokinetic parameters for MA are presented in the table below from the sponsor.
`
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`Indavtdu-l and non phat-necklaces:
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`1.00
`3-00
`3.4.31
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`fable m:
`
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`1n the dog 01:0: 0:11 OM: :
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`
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`11.27
`97.0
`
`
`
`
`
`
`
`
`From these data, MA formation appears to be a nonsaturable process as evidant by the linear relationship
`between CW, AUC. and dose. MDF clearance appears to be high (0.6L/hr/kg) and independent on close,
`V‘1 is about 2 l/kg and also independent on close.
`
`Rabbits:
`
`New Zealand white rabbits (5m) were injected single i.v. of 5mg/kg modafinil. Mean AUCM was
`6ug.hr/ml anf terminal t1/2 was 1.2hr. Systemic plasma Cl was 1thr/kg which is slow compared to
`hepatic plasma flow of 2Uhr/kg. Apparent V" was small 1.5leg. Modafinil acid elimination tm was similar
`to the parent with a mean of 1hr. Single oral doses of modafinil of 25. 50, 100mg/kg. were administered to
`4m New Zealand white rabbits. Mean cm were 2. 4. and 11ug/ml respectively and. the corresponding
`AUCM were 10. 30, 88ug.hrlml. Linear relationship was seen between plasma level and dose and
`exposure and dose. Terminal tm ranged between 3-4hr. Modafinil acid was max cone and exposure incr
`with increasing the dose from 25-50mg/kg. However. at 100mg/kg, the values of modafinil acid were lower
`than those at 50mglkg. This suggested that metabolism of modafinil to the acid maybe saturated at doses
`higher than 50mglkg.
`
`WM
`
`ice
`Mice (both sexes) were treated twice daily with oral doses of 64mg/kg MDF for 4 days following 4
`protocols. Group 1 given water for 5 days, group 2 dosed with water for 4 days and MDF on day 5 (day of
`investigation), group 3 dosed MDF for 4 days and water on day 5, and grouglidosed MDF for all 5 days
`(repeate dosing). On day 5 mice were treated 30min prior to testing motility in actimeters; test lasted
`
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`30min. After end of study, mice were killed, blood and liver collect
`concentrations of MDF and its metabolite, MA, were determined by
`groups are as follows:
`MDF
`
`MA
`
` .
`
`each mouse and
`Plasma concentration in the 4
`
`1512
`gr 2
`0.210.06
`gr 3
`911
`gr 4
`values are means1sem in ug/ml.
`
`2.7103
`00210.01
`310.3
`
`Results indicate that MDF plasma concentration after repeate dosing is lower than that after a single dose
`(gr 4 vs. gr 2). motor activity correlated best with plasma levels of MDF but not its acid metabolite. and
`MDF at high and repeated dosing induces its own metabolism as reflected by 20% increase in liver weight
`and decrease in MDF plasma level without change in MA concentration.
`
`The above experiment was repeated for 18 days (investigation was conducted on day 19). MDF and MA
`plasma levels are as follows:
`
`MDF
`
`MA
`
`1611
`gr 2
`0.3101
`gr 3
`7.2106
`gr 4
`values are means1sem in pg/ml.
`
`3102
`0.2101
`2.5104
`
`,
`( _
`
`.
`
`Results are similar to those following 4 days of treatment.
`It is concluded that MDF produced linear dose-response, it induced its own metabolism as
`indicated by the enlarged liver and decrease in MDF concentration after repeate dosing without
`changes in MA levels.
`
`Dog
`Six dogs were orally dosed 30mg/kg of MDF for 15 days. On days 1, 8. and 15 each dog received both a
`30mg/kg antipyrine (enzyme inducer) and 30mg/kg MDF. Blood samples were collected at specified
`times up to 24hr postdose and drug levels determined by_analysis.
` .
`
`Antipyrine kinetic parameters:
`
`Days:
`
`1
`
`8
`
`15
`
`tm." (hr)
`tm,lbs (hr)
`AUG“, (ug.hr/ml)
`Cm (uglml)
`Tm, (hr)
`
`*
`
`1.841032
`03610.14
`108.47113
`29.681211
`1.421027
`
`1.1102
`07310.05
`0.4101
`0.521009
`47.34144
`49.11242
`1 0111.7
`234411.43
`110.13 1.33102
`
`Administration of MDF increased total clearance of antipyrine with time (0.3 day1 to 0.7 Vhr/kg day15).
`decreased CM. AUG”. and t1”... and slightly caused an increase in t1“. but no effect on Tm. Most of
`the siginificant effects occurred between day 1 and 8 and no apparent differences were noted between
`days 8 and 15.
`
`( _
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`Tables below present the kinetic parameters for modafinil and modafinil acid:
`
`mu m:
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`MDF caused a significant decrease in C,,m and AUC without an effect on Tmor Cm... These results show
`that modafinil changed its own kinetics and that of antipyrine through enzyme induction.
`In comparison to
`MDF, the kinetics of MA were not changed by repeated dosing of modafinil (Table above).
`
`_
`
`(
`
`The effects of phenobarb as an enz inducer, on disposition of modafinil was tested using antipyrine as an
`
`enz inducer control. Five male beagle dogs recieved phenobarb orally between days 2-14 and each
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`recieved 30mg/kg p.o. modafinil and 30mg/kg p.o. antipyrine on days 1, 8, and 15. Max cone of modafinil
`were 9ug/ml d1. 5ug/ml d8, and 4ug/ml d15. the corresponding AUCM (d1 and AUC.H on d8&24) values
`were 72. 22. and 14ug.hr/ml respectively. Both max conc and exposure were lower on days 88.15 from
`those on d1. The AUC‘H for antipyrine. induction control. on d8 & 15 were 42&24ug.hrlml respectively.
`was concluded that phenobarb alters PK parameters of modafinil as it did for antipyrine.
`
`It
`
`DISTRIBUTION AND ELIMINATION
`Rat
`“C-labeled MDF was used in all distribution, metabolism, and excretion studies with specific activity of
`ZOOpCi/mg and 97-98% puritiy. Male and female Sprague—Dawley rats were administered 5mg/kg cold
`MDF iv and 50 and/or 100mglkg orally. Drugs prepared in 5% gum arabic oral suspension or in 1%
`ethanol solution. Follwoing single i.v. administration. MDF was rapidly distributed and radioactivity was
`detected within 3min after injection with t1,z of 2hr in males and 4hr in females. Cm, 2 (expressed as a
`value of F) in both sexes, and AUC in males was 5 and in females 8.
`It was concluded that there is no
`sex differences in plasma concentration. tm ls shorter In males vs. females, and elimination
`followed 2-compartment model.
`
`Following oral dosing. MDF was rapidly absorbed with radioactivity detected by 10min postdose. no sex
`differences except for slightly higher plasma levels in females than in males, t"2 in males was shorter, 5hr,
`than in females, 9hr. and absolute bioavailability in males was 89% and. 85% in females.
`
`-
`( 1
`
`.
`
`Following oral administration, MDF was widely distributed to tissues with high levels measured at 0.25hr
`postdose in liver, jejunum. kidney. and thyroid and by 24hr radioactivity was very much reduced in all
`tissues. At 96hr in male and female rats. radioactivity level was highest in fur, this was proposed by the
`sponsor to be caused by urine contamination. Results were similar in males and females except for
`higher radioactivity in ovaries than testes.
`It seems that the drug does not accumulate over time. Brain
`levels were small but constant mroughout the selected measurements.
`Following repeated oral administration of 100mglkg for 8 days. MDF seemed to accumulate (attached
`Table) and elimination was slower after repeate dose by a factor of about 2. than after single
`administration.
`
`It is concluded that after single oral dose of ‘3-modafinil to the rat, absorption was rapid and
` .
`plasma levels were the same In both sexes. Elimination t1,z however. was longer In females than in
`males (9 vs. 5hr respectively). Similar results recorded after i.v. with tm of 2 and 4hr in males and
`females respectively. Drug was distributed rapidly to many tissues and elimination was mainly by
`urine. Fecal elimination was higher after oral dosing (20-30%) than after i.v. (78%). Substantial
`biliary elimination was noted (17-32%) Indicating enterohepatic clrculing of the drug. Elimination
`following repeate dosing was slow indicating the drug's tendency to accumulate.
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`Modafinil is eliminated mainly by urine and some in feces. Following 50mg/kg i.g. dose. total elimination
`of radioactivity at 24hr postdose was 80% (54% in urine and 26% in feces) in males and 69% in females
`(59% in urine and 10% in feces). These values increased to 87 and 77% in males and females
`respectively by 96hr. Similar elimination percent noted after 5mglkg i.v. or 100mg/kg i.g. dose. The
`absolute bioavailability of radioactivity was 79 and 84% in males after 50 and 100mglkg and 89 and 92%
`in females at the same doses.
`
`Following gastric or i.v. administration. bile was collected over 24hr. Data showed that MDF entered the
`enterohepatic circulation. Biliary elimination was fast and higher in females than in males (23 and 11% at
`2 hr and 36 and 21% at 24hr respectively). Bioavailability fact
`calculated on the basis of biliary
` .
`elimination was 85%.
`In bile cannulated SD rats (3/sex/route)
`-modafinil was administered either i.v. at
`5mglkg or orally at 100mg/kg, sampling done over 24hr. Biliary excretion was generally higher in f than m.
`Two hours after oral dose. bile of m&f contained 8 & 17% of radioactive dose respectively. Cummulative
`amount of radioactivity in bile 24hr postdose was 18&33% of dose respectively. Total 24hr un'nary
`elimination accounted for 40% of dose in either sex. Amount of radioactivity excreted in 24hr bile after i.v.
`dose of 5mglkg was similar to theat after p.o. dosing with 218.36% in m&f respectively. Urinary elimination
`after iv. was higher than that after p.o. ranging between 50-60% of administered dose. Comparison of
`fecal and biliary elimination suggested enterohepatic recycling.
`
`Dog
`Tables below present PK parameters and tissue distribution of oral 30mg/kg cold dose of MDF and
`10uCi/kg in dogs. Elimination t1,2 was 3hr, Cm. Tm, and V, varied between animals. Distribution was
`rapid and high levels of radioactivity were detected in the 2hr samples.
`
`‘-
`
`(
`
`Distribution was similar to that in the rat, but higher levels were found in the dog brain (distribution was
`homogeneous throughout the different regions). By 24hr. radioactivity was significantly decreased in all
`tissues. Elimination seems to be slower in the dog than in the rat. About 72% of radioactivity was
`eliminated within 72hr by urine (65%) and feces (9% of administered dose).
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`Below is a summary table for elimination of modafinil in various species including humans.
`
`Tablas-12. Urinary/Fecal Excretion Patterns in Preclinical Species
`
`
`and Man
`
`Pmlol mum Dose mull [ma Urine or Few
`
`
`“HurleyEmsMum-IIIII
`
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`METABOLISM
`
`investigated in the rat. mouse, dog. and rabbit. The sponsor indicated t
`t because MDF is heat
` .
`sensitive. -could not be used for analysis. therefore. MDF labelled at
`- (in the acetamide chain) and
` .
`3H- (in the aromatic ring) were used. Synthesis and purity data were provided and are acceptable.
`
`Sprague-Dawley and NMRI male mice were injected i.p. with a mixture of cold MDF (100mglkg) and one
`of the two labeled MDF (100uCi/kg). Urine was collected over 24hr and acidic and non-acidic metabolites
`were extracted and quantified using— Fractions extracted from the non-acid medium
` .
`“gr-e similar regardless of the label administered (32 and 21% of total eliminated radioactivity for 3H- and
` ., .
`respectively). However. the fra ' ns for the acid metabolites differed depending on the label used
` .
`with 54% for the 3H- and 18% for the
`.label. The non-extractable
`rtion paralleled the 3H-label
` .
`accounting for 15% of total radioactivity but after administration of the
`label this fraction accounted for
`60% of total activity. These differences seem to suggest that metabolism depends on the isotope used.
`However. the sponsor indicated that since cold MDF was used simultaneously with the label, therefore.
`the label served only as the tracer and unlikely will account for the large differences observed. These
`differences suggest the metabolism of MDF involves formation of 2 molecules with cleavage perhaps at
`the sulfur atom. The proposed molecules are:WW
`mjoagetamige gr acetamige gr. fiflxjde defiyatjyes.
`
`Modafinil was extracted from the non-acid fraction (30% in rat and 50% in mouse) and no S-oxide
`derivatives were found.
`In the acid fraction the majority of radioactivity (50%) was identified as modafinil
`acid (MA) in both species. Using in vitro microsome preparation. modafinil sulfone derivative which
`corresponds to the S-oxide was identified. This metabolite was also identified in plasma from rats treated
`with high doses of modafinil.
`
`a
`( .
`
`4
`
`It is concluded that modafinil is the main compound in the non-acid fraction and MA is the main
`metabolite in the acid fraction. Modafinil acid is also identified and quantified in plasma from
`animal and human PK studies. Also found but not identified, are smaller compounds formed by
`cleavage at the sulfur atom. Modafinil sulfone identified in phenobarbitone-lnduced rat
`microsomes is also detected in in vivo studies in rats administered high doses of modafinil.
`
`Urinary and fecal metabolic profile of modafinil was studied in NMRI mice. SD & Long Evans rats. Dunkin-
`Hartley 9. Pigs. and New-Zealand rabbits following 100mglkg p.o dose and 5mglkg i.v.
`(4mlspecies/strain/route). The metabolic profile was qualitatively similar in all species with the major
`fraction of urinary activity represented small molecules resulted from cleavage of the 2-carbon “C-
`fragment of modafinil side chain.
`In the rat. this fraction represented >90% of urinary activity over 24hr
`period. Modafinil acid was the main product representing 11% in mice, 5% in rats. >40% in rabbits. and
`36% in g.pigs. Guinea pigs were the only species where the sulfone and sulfide were the main
`metabolites (27% sulfone). Modafinil and its metabolites were determined in CD-1 mice. SD rats. and
`beagle dogs following 30mglkg p.o. (30uCi/kg ofWafinil). In mice. LC/MS analysis of 24-hr urine
` .
`samples showed presence of modafinil. modafinil acid. and 3 glucuronides of ring hydroxylated products,
`each representing <10% of total radioactivity. Mean cone of modafinil. modafinil acid. and sulfone in the
`24-hr urine following single dose were 19. 18. and 4ug/ml respectively. and those following repeate dosing
`were 15. 16. and 3ug/ml respectively. Conc of modafinil or its metabolites could not be detected in
`plasma of mice 24hr postdose.
`In rats. the main urinary metabolite was the acid at 70% with small
`amounts of modafinil. modafinil acid sulfone and glucuronide conjugates of hydroxy modafinil each about
`4-10% of adninistered dose. Rat urine at 0-4, 4-12. and 12-24hr periods contained modafinil acid at 75.
`23. and 7ug/ml respectively. the sulfone levels were below quantitation limit. and modafinil level at 0-4hr
`was 9ug/ml and at 4-12hr was 2uglml. Following multiple dosing in the rat. modafinil urinary levels were 8.
`4ug/ml and. below quantitation limit at the 3 collection periods and the corresponding values for modafinil
`acid were 37. 33. and 12ug/ml respectively. Similar to the mouse. rat plasma levels of modafinil or its
`metabolites could not be detected at 4. 12. or 24hr after single or repeate dosing.
`In dogs. the acid
`
`metabolite was the main urinary metabolite at 46-69% of dose at 0-4hr. with modafinil at 6-13%. and one
`
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`glucuronide at 1-7%, and 11-31% of solvent front radioactivity. Modafinil mean urinary conc after single
`dose were 66. 53. and Bug/ml at 0-4, 4-12, and 12-24hr periods, and those for the sulfone were 4, 16, and
`9ug/ml respecetively. Following multiple dosing, modafinil urinary levels in the 3 periods were 50. 4, and
`0.7ug/ml respectively; those for the acid were 304. 90, and 19ug/ml respectively, and those for the sulfone
`were 13, 8. and 3ug/ml respectively. Mean modafinil plasma levels at 4, 12, and 24hr post single dose
`were 9.1ug/ml and below quantitation limit. the corresponding cone for the acid were 6 O.5ug/ml. and
`below quantitation limit, and those for the sulfone were 3 1ug/ml and below quantitation limit respectively
`Following repeate dosing, levels detected only after 4hr at 2. 3, and 2uglml for modafinil acid. and sulfone
`respectively.
`
`Spregue-Dawley (3m) and New-Zealand rabbits (3m), were orally dosed 100mglkg modafinil. GC—MS
`analysis of urinary samples identified benzhydrol, OH-benzhydrol. Dihydroxy-benzhydrol,
`hydroxyphenylmethane, and dihydroxydiphenylmethane. which are products of side-chain cleavage of
`modafinil.
`In a separate study in SD rats, there was no evidence of production of modafinil sulfide or acid
`sulfide in rat plasma 30min or 4hr post 128mglkg i.p. of modafinil.
`
`In vitro studies using rat. dog, and human hepatocytes were done. The racemate and each of the
`stereoisomers were tested. There was no chiral inversion of modafinil enantiomeis and the l-isomer
`seemed to be more extensively metabolized than the d-isomer which is opposite to that seen in in vivo.
`However, only 1% of modafinil was converted to the acid in this study. Six metabolites were found (most
`not identified) in human hepatocytes by_ The sulfone was 1-2% of total radioactivity, the acid 25%
` .
`of total radioactivity at the lowest conc but only 3% at the highest. all remaining radioactivity was
`unchanged modafinil (75-94%). The sponsor in this study concluded that there was no evidence for
`autoinduction of modafinil following pre-incubation with cold drug, nor for formation of glucuronide or
`sulfate conjugates. Another study investigated auto-induction in human hepatocytes using liver samples
`from 3 volunteers and standard inducers. Exposure to modafinil for 72hr incr activities of most CYPs
`about 1 .5-4x vs. the negative controls. These incr occurred at the highest cone of 1mM of modafinil.
`Using human microsomes, it was shown that CYP3A4 is the isozyme responsible for the formation of the
`sulfone and that formation of the acid does not seem to involve a cytochrome P450-mediated metabolism.
`
`Table 2.5-1]. Speci- Coup-rhea of Urinary ElInI-ndon of Individual
`Metabolite-
`Ann-eunu- lbs-l of Urinary lunac- Inab-
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`Ring-Hydruyhld Mod-Ilsa
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`Glue-RIM. Cell-pl: ct
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`Figure 1.5-1.
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`Met-hon: Pull-In of Medan-fl.
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`PK of the Stereoisomers, d & l:
`stereospecificity played a role in modafinil absorption and metabolism.
`MW
`1. MDF and its isomers were absorbed.
`2. MDF and its acid metabolite appeared in plasma,
`3. MDF plasma concentration was very high (30pg/ml) compared with 10pglml in dog dosed 30mgll<g and
`4pg/ml in rat orally dosed 256 mglkg.
`4. plasma concentration of l-isomer were higher (50-60 pg/ml). than those of MDF =25 pglml. Mereas
`those of the d-isomer were comparable to those of MDF. AUCOM after MDF was 36 and increased to
`64 mg.hrl| after the l-isomer.
`4.
`t1,2 of MDF was short 1.2 hr
`5. concentrations of d-isomer acid were higher than those of l-isomer and MDF acid whereas,
`concentration of l-isomer acid and MDF acid were comparable.
`
`{aim I!
`I:
`Compound
`MDF
`levo
`dextro
`
`I
`cm...
`1012.5
`1612.6
`1212.7
`
`I
`
`_
`.
`L...
`210.4
`2.5104
`210.4
`
`1m.
`311
`411
`310.6
`
`,
`CI...
`0510.2
`0.231005
`0510.1
`
`t,“
`310.1
`310.4
`310.4
`
`AUG“...
`52112
`1713
`126136
`
`C"...
`Compound
`611
`MDF acid
`210.1
`levo-acid
`1 916
`dextro-acid
`values are means1sem
`AUCM", in mg.hr/I, Cm, pglml, time in hr
`Cm... AUG”... as well as total clearance are significantly different between l-isomer and MDF. Value of
`AUCWh after l-isomer was double (147 mghrll) that of MDF or d-isomer (=72 mg/l.hr), but total clearance
`was lower in l-isomer than that of MDF or d-isomer. The acid metabolites were also significantly different
`specifically those of the d-isomer as noted above.
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`‘
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`( >-
`‘
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`Conclusion: The isomers exhibited different kinetics. The d-isomer seems to be more readily and
`completely absorbed than the l-isomer or MDF and the l-isomer is less readily metabolized to the
`acid than either the d-isomer or MDF. Cm, AUCM‘, and total clearance of MDF were similar to
`those of the d-isomer but different between the I-lsomer and MDF. Significant differences noted in
`Cm,“ and AUG,“ after the d-isomer or MDF but no differences after the l-isomer.
`
`Doses: 75. 150. 300. 600 mglkg orally in a cachet
`MDF-acid administration:
`- slow absorption (tw 2.4 hr) and dose-independent
`- no relationship between dose and clearance (2-4 mgll.hr) and was higher than that of MDF. Check
`- V.1 increased proportionally to dose
`- CM (7, 10. 13. 18 pg/ml). and AUC increased linearly with dose (33. 48, 102, 162mg.hrlml respectively).
`- tm ranged between 2-6hr.
`
`'
`l
`-
`l
`Male SD rats were fitted with a straight intraventricular catheter to allow multiple blood sampling. SKF
`525A (enzyme inhibitor) was administered i.p. at 75mglkg; the control group was administered
`physiological saline under the same conditions. Modafinil was administered i.p. at 64, 256, or 512mg/kg
`3hr post SKF.
`In the absence of SKF, the AUCMM." for MA was >2 fold of the parent drug and the
`increase was not proportional to dose. Following SKF. modafinil AUC was markedly increased over that
`without SKF but AUC for MA was lower than that for MDF (Tables below). The results indicate that
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`pretreatment with SKF 525A modify the kinetics of MDF and its metabolite as reflected by the increased
`concentrations. this increase was inversely proportional to the dose: the higher the dose the lower the
`increase.
`
`It is concluded that the drug is absorbed, the increase in AUC is not proportional to dose and the
`kinetics is not linear. The marked increase in AUC of MDF after pretreatment with SKF 525A is
`indicative of the enzyme inducing ability of the drug.
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`mn‘
`”2:5..1'unmuummum
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`The PK of modafinil acid (64 or 256mg/kg i.p.) was studied in rats with or without 75mg/kg SKF 525.
`There was no sig difference in plasma levels of modafinil acid in presence or absence of SKF. This
`indicated that metabolism of modafinil acid does not involve P450.
`
`Special PK Studies
`Exposure of bone nircmw to modafinil was studied to confirm exposure in the micronucleus in vivo
` .
`cytogenetic assay.
`-Modafinil at 0.5 and 5mglkg (100&1000uCi) was administered orally to OF-1 mice
`on consecutive days. Radioactivity in bone marrow was much higher than background 24hr after the 2
`doses of modafinil compared with the cont. Bone marrow exposure was relatively proportional to dose
`and there was no sex difference in exposure at either dose.
`
`Autoradiography of HC-modafinil was done in pregnant SD rats. Pregnant females were orally dosed
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`modafinil at 100mg/kg orally on gd17 and killed at 1, 8, 24. and 72 hr postdose. At 1hr, highest
`radioactivity was seen in liver. kidneys, blood vessel walls, heart, and Harderian gland. Lower radioactivity
`was detected in the brain and spinal cord. Some radiolabel was detected in all other tissues.
`Radioactivity was comparable in fetus and placenta to other maternal tissues. At 8hr radiolabel was decr
`but distribution pattern was the same. Levels
`re further decr by 24 and 72hr but remained detectable in
` .
`Harderian gland. brown fat. and fecal pellets.
`afinii was detectable in milk 1hr after dosing of
`100mg/kg to lactating female SD rats at 24ugEquiv/g and peak radioactivity in plasma occurred at 0.5hr
`postdose at 28ugEquiv/g. By 24hr postdose, radioactivity was nearly gone from plasma but milk conc
`were 29-75% of the peak value.
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`TOXICOLOGY:
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`ACUTE TOXICITY:
`LDso values in the rat/oral: 16401109 mglkg. mice/oral: 1370193 mglkg, dog/oral: a dose of 400 mg/kg
`caused 2/3 deaths 28 and 72 hr postdose.
`
`In general, clinical signs in mice and rats included: hyperkinesia, stereotypy. loss of balance. convulsions,
`ptosis. dyspnea. hypersensitivity to noise (rat). and exophthalmus (rat).
`ln the dog, symptoms included:
`weight loss. hyperactivity. stereotypy. mydriasis followed by miosis. localized opacification of cornea.
`reddening of face, eye lid. and conjunctiva. and tachycardia with tachypnea at high doses (>300 mglkg).
`
`Gross necropsy was normal in mice and rats dosed orally. Animals dosed by i.p. route showed MDF
`deposition on liver (mice) or pale discoloration of kidneys and deposition on liver in rats.
`In the dog, blood
`was noted in urinary tract of 2/3 200 mg/kg and 1/3 dogs dosed 400 mg/kg.
`
`-
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`SUBCHRONIC TOXICITY:
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`13-week oral dietary study in OF-1 mice (GLP)
`13-week oral dietary study in OF-1 and CD-1 mice (GLP)
`4-week oral study in rat (Non GLP)
`12-week oral study in rat with 4 wk recovery period (Non-GLP)
`13-week oral dietary study in rats (GLP)
`12-week oral study in dog (Non GLP)
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`-
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`Mouse:
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`"
`(.1
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`- 13-week mice/GLP/DS-93-005/1988: 0F1 male and female mice (70/sexldose) administered MDF in
`the diet at the following doses: 25. 75. 100. 150 mg/kg/d for 13 wk
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`-
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`No drug-related deaths.
`Non-dose dependent changes in:
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`tip decr 4.5% in fdosed 25mg/kg. 8% in fdosed
`100mg/kg. and 5% in fdosed 150mglkg.
`Biljmbm decr (except at 75mg/kg no change) in m dosed
`25mg/kg (19%), in males dosed 100mg/kg (16%). and
`m&f dosed 150mglkg 168.28% respectively).
`Bejigujggfle no. incr in fdosed z75mglkg.
`mm decr 23% in f8. 25% in m dosed
`1008.150mg/kg.
`Dose-dependent incr in HELM both sexes (m: 7. 15. 25. 39% of cont; 1‘. 8.22.27,35% of cont in
`25. 75. 100. and 150mglkg doses respectively).
`
`A NOEL could not be determined because of some finding noted in each dose gr. TK was not done in this
`study.
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`- 3mo oral dietary study in 00-1 mice/DS-95-002IHazleton VAIlnitiation date: Mar 14 1995/GLP.
`Species/Strain/ageMt at initiation: CD-1 mice/6wks old/24-2Qg m and 19-239 f.
`Doses‘lno. per dose: 0, 60. 120, and 180mglkg/d/10/sex/dose.
`Route/Duration: dietary admixture/amo.
`
`‘ doses were selected as multiples of the HD (60mg/kg/d) used previously in the 18mo carcinogenicity
`study.
`
`Parameters assessed: mortality and clinical signs (2x daily). B.wt & Food inatake (pre dose and weekly),
`Hematology 8. clinical chem (via orbital sinus; day 87 & 93 respectively, from fasted mice). organ wts.
`gross exam, and histopath (only lung. liver. kidneys. heart. and any gross lesions from all mice). A TK
`study (DS-95—OO3) was also conducted.
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`Results; [table below from sponsor]
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`Table I. Bubehronle touchy away to oat-blur: eh. m of mod-Hull In
`coo-1 moo (nus-002V : “seldom or Hoar: (g 8.0.) Value.
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`8
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`%
`leor Wt. mmmmm
`noun-too e flflmm
`WM-
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`mm_——
`-
`,
`mm
`*
`ma:-
`-
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`'Slnlluue—lly alum (9 $0.05) MmW value.
`"Uppor Ilmlt mot value : 35 UIL. Indoor-la. d Mulch-l vulva. W
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`menmmmvswwalsmdo-MW.
`lam-loo.
`
`Mortality and Clinical signs: no deaths in any gr. No sig drug related clinical signs.
`B.wt, Wt change, Food intake: no consistent or dose-dependent effect noted in mean wt in any gr.
`Overall mean wt change in all male drug grs was reduced 16% and only 4.10% in female grs. This wt loss
`was considered drug related. There was no drug effect on food intake. [see figures below from sponsor].
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`Hematology 8. Clinical Chemistry:
`-
`Slight but sig deer in Hot in HDm (5%)
`-
`slight non-sig incr in mean ALT in all male grs and MD&HDf. The individual values were 325%
`higher than the upper limit for the cont noted in 2-3 of 5mice/sex. However, these values (for HcT and
`ALT) were within the historical data provided by the sponsor. The mean AST values were close-
`dependently but not sig incr in MD&HDf (188.21% respectively).
`Organ wt:
`Mean absol wt of the liver (non-fasted mice) incr sig and dose-depedently in MD&HDm&f (19&41% in m
`and 29&41% in f respectively). Absol wt in fasted mice incr dose-dependently in all 3 male grs but
`reached significance only in HDm (18% incr over the cont; 1.5410079 vs. 1.310.129 respectively); in
`MD&HDf the wt incr dose-dependently without reaching sig level. Rel wt of the liver (to B.wt) in non-fasted
`mice sig incr dose-dependently in MD&HD both sexes (22-40% in MD&HDm; 27-40% in MD&HDf) and in
`LDf (10%).
`In fasted mice, the rel wt of the liver to B.wt was sig incr in all 3 male grs (16, 25%. and 33%
`respectively) and in MD&HDf at 16% but not in LDf. There was no sig change when liver wt was
`determined rel to brain wt in fasted mice and reached sig only in HDm&f and MDf of non-fasted mice. A
`non-sig but dose-dependent incr noted in the rel wt of the lung in all Smale grs/fasted (17. 20, 22% higher
`than the cont value, respectively) and the MD&HDf grs (8% higher than the cont for both grs).
`Gross exam: no drug related findings.
`Histopath: the changes in organ/tissue wts did not correlate with any histopath findings except for liver
`hypertrophy (centrilobular to midzonal) in MD&HD male and female mice that incr in severity with incr in
`dose. The hypertrophy correlated with the incr in absol and rel wt of the liver measured in fasted and non-
`fasted mice of these 2 higher doses.
`
`Summary and Conclusion:
`Dietary administration of modafinil to mice upto 60mglkg did not affect mortality. clinical signs, food intake,
`hematology (except for a sig 5% deer in HDm HcT), cliniwl chem, or gross morphology. The only drug-
`related effect was an incr in absol and rel wt of the liver in males and females of the MD&HD (with 10%
`incr in LDf). This change was accompanied by centrilobular and midzonal liver hypertrophy that was
`dose-dependent in the 2 higher doses. Additionally. there was a small non-sig incr in ALT in all male grs
`and MD&HDf and