`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 020717
`
`PHARMACOLOGY REVIEW! S!
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`M E M 0 R A N D U M
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`November 7, 1997
`
`'
`
`FROM:
`
`TO:
`
`Glenna G. Fitzgerald, Ph.D.
`Pharmacology Team Leader
`Division of Neuropharrnacological Drug Products
`
`NDA 20-717
`Provigil”, modafinil
`100 or 200 mg tablets
`Sponsor: Cephalon, Inc.
`
`SUBJECT: Overview of Pharmacology and Toxicology
`
`W P
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`rovigil is indicated to improve wakefulness in patients with excessive daytime
`sleepiness associated with narcolepsy. The pharmacology/toxicology portion of this
` .
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`NDA is marginally acceitable to suiiort an aiiroviili iilllM
`
`It
`
`The mechanism by which modafinil promotes wakefulness has not been determined.
`does not bind to the usual spectrum of receptors, nor does it appear to act as an
`adrenergic agonist or to affect norepinephn'ne release. Modafinil’s effects are
`pharrnacologically distinct from those of the CNS stimulants in that it promotes
`wakefulness without increased locomotor activity, aggressiveness or stereotypic
`behavior.
`In drug discrimination studies in rats and monkeys designed to examine its
`abuse potential, modafinil substituted for cocaine or d-amphetamine.
`It was not self-
`administered in drug-naive rats, however. The metabolic profile of modafinil is
`qualitatively similar across species, including humans. There are two major
`metabolites, the acid and the sulfone, neither of which possesses pharmacological
`activity. Modafinil induces its own metabolism through induction of hepatic enzymes.
`The effect is marked in the mouse, less in dog and rat, and occurs at doses of 400 mg
`( ‘
`or higher in humans.
`\—
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`The 78 week mouse and 104 week rat bioassays were taken to the CAC-EC on March
`11 . 1997 (report attached). Doses of 6, 30 and 60 mg/kg/day were used in both
`studies. No increase in tumors occurred in the drug treated groups.
`It was
`recommended that the rat study would be acceptable, although the doses were
`marginal. based on an increase in the severity of spontaneous chronic progressive
`nephrosis in male rats, which led to an increase in mortality in that group. The mouse
`study was considered to be inadequate, however. in that a maximally tolerated dose
`was not reached. The sponsor was informed that an alternative in vivo assay might be
`an acceptable replacement or that the bioassay could be repeated using higher doses.
`In either case, it would be necessary for them to present a rationale for their choice to
`the full CAC. This was done on October 31, 1997 and a draft of that report is attached.
`
`choice was essentially limited to the TG.AC mouse, the only model for non-genotoxic
`compounds for which there is at least some experience. Modafinil is clearly non-
`genotoxic in an extended battery of tests which include the standard assays for
`mutagenicity and clastogenicity (in vitro and in vivo) as well as unscheduled DNA
`synthesis and cell transformation assay. The problem is that the TG.AC is a dermal
`application model, with skin as the primary target (forestomach and marrow also
`respond), and modafinil is an oral drug which is rapidly metabolized by the liver to two
`major metabolites. There is essentially no experience with the oral route in the TG.AC
`model. To address the issue of systemic exposure after dermal application the sponsor
`conducted an acute dermal study using two doses, 60 mg/kg (the high dose in the
`bioassay) and 360 mg/kg, in the parent strain of the TG.AC mouse. An oral dose group
`receiving 360 mg/kg was included. Plasma measurements were made of parent,
`modafinil acid and modafinil sulfone. at 1 and 4 hours. to determine if dermal exposures
`of parent and metabolites would be comparable to oral exposures. Although levels of
`both parent and metabolites were lower after dermal than after oral administration,
`especially the sulfone. the dermal route achieved reasonable exposures of all three
`moieties. The CAC unanimously agreed that the addition of a TG/AC assay to the
`standard rat bioassay would allow for adequate evaluation of the carcinogenic potential
`of modafinil. There was general agreement that it would be pointless to repeat the
`mouse bioassay at higher doses because the high degree of induction in that species
`makes it impossible to achieve adequate exposure to parent drug. The sponsor must
`now conduct a one month study to determine the appropriate doses and endpoints for
`the definitive TG.AC assay. When that study is completed. and the final protocol is
`submitted, the results will be taken to the CAC for concurrence with the dosage
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`selection and other details of the protocol (determination of target site exposure. use of
`appropriate solvent, etc.)
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`3
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`B
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`Ilill°
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`The sponsor has labeled modafinil Category B; we have changed it to C for two
`reasons: 1) a threshold dose for teratogenicity was established in the rat and 2) the
`segment I and II studies were conducted at inadequate doses to fully characterize the
`potential effects, in addition to the fact that they were non-GLP studies.
`
`The reproductive toxicology studies for modafinil border on being unacceptable, with
`the exception of a peri- and post-natal study in rats which was conducted by Argus
`Laboratories in 1995 according to ICH guidelines. The fertili
`stud in rats
`teratology studies in rats and rabbits, conducted by“in
` .
`1984 and 1985 were not carried out in compliance with Good Laboratory Practices
`Regulations, specifically lacking periodic and documented monitoring by an
`independent Quality Assurance Unit.
`I learned from our Scientific Investigations staff
`that we have an MOU with the French as of November.1986 which defines the
`I
`inspection process and acceptability of studies, but would not cover these studies.
`was told that, in general, the quality of such studies has been low until the last 3 or 4
`years. Irrespective of how the studies were conducted, they are clearly inadequate in
`terms of doses used to characterize potential effects. The only redeeming feature is
`that the rat teratology study establishes a threshold dose of 200 mglkg (5 times the
`human dose on a body surface area basis) for teratogenic effects. Minimal fetal toxicity
`(resorptions, hydronephrosis, skeletal variations) was seen at that close, in the absence
`of maternal toxicity. However, the ICH guideline, “Detection of Toxicity to Reproduction
`for Medicinal Products” clearly states (pages A-4 and A-5) that some minimal toxicity is
`expected to be induced in high dose dams, and it defines what endpoints are
`appropriate. Without appropriately high doses the studies do not adequately evaluate
`the full spectrum of potential effects on fertility or on the fetus.
`
`The peri- and post-natal study referenced above is an adequate GLP study, but it has
`not yet been officially submitted to the Agency.
`In the process of reviewing the studies
`for this memo it came to my attention that the report for that study which was submitted
`to the NDA was labeled an interim report.
`It did not. therefore. mntain any of the data
`to evaluate either reproductive performance of the F, (pups) generation or to evaluate
`the effects of the drug on behavioral parameters of the F1 pups, assessment of Ieaming
`and memory being a critical component of such a study.
`I telephoned the Sponsor on
`November 4, 1997. and they conceded that the final report had not been submitted.
`I
`received a desk copy (without plasma level data, which will not be available until
`December) on November 6, 1997, and on the basis of that am able to determine that no
`adverse effects occurred in that study at doses up to 200 mglkg/day.
`It should be noted?
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`that minimal maternal toxicity was achieved in this study, at a dose that did not cause
`toxicity in the segment II study, qualifying it as an acceptable study for peri- and post-
`natal evaluation. (The reason for the discrepancy with respect to maternal toxicity is not
`clear, but it may be due to better solubility in the solvent that was used - ORA-Plus
`instead of CMC. Modafinil is relatively insoluble in most solvents). That study was not
`designed to examine fetuses for teratogenic effects.
`
`4
`
`CONCLUSIONS
`
`The sponsor will conduct, and submit during phase 4, a dermal TG.AC assay to replace
`the inadequate mouse bioassay. This appears to be the best resolution to the issue,
`and lack of that study prior to marketing does not represent a public health hazard.
`Modafinil is non-genotoxic, and was negative in a 2 year rat bioassay, indicating a low
`potential for carcinogenicity. The 18 month mouse study. even though conducted at
`doses that were too low, does provide some additional reassurance.
`
`The patient population for whom modafinil is indicated includes women of child-bearing
`potential. Vifith respect to the reproductive toxicity studies submitted, modafinil appears
`to have a very low potential for toxic effects on reproduction and on the developing
`fetus. However, it has been shown to have some effects, and the extent of those
`effects has not been fully explored because of the use of inadequate doses in the
`fertility and teratology studies. Additionally, those studies were non-GLP, further
`diminishing our ability to rely on them as being definitive.
`If it were not for the fact that a
`threshold dose for teratogenicity has been identified in the rat, I would say that we
`cannot rely on them at all and that this NDA would not be approvable. Because we do
`have that information, together with information from the one acceptable reproduction
`study which indicates that there are no effects on behavior and learning, there is some
`assurance that reproductive effects of this drug are minimal. However, the fertility
`(segment I) and teratology (segment II) studies must be repeated under GLP
`regulations and using doses high enough to cause some maternal toxicity. The
`Precautions section of labeling should include a statement which indicates that effects
`on fertility and the fetus have not been fully evaluated.
`
`RECOMMENDATIONS
`
`This NDA ma
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` .
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`approvable
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` .
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`lS recommen e abeling.
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`RECOMMENDED LABELING
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`CLINICAL PHARMACOLOGY
`DRAFT LABELING
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`PRECAUTIONS
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`General:
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`Reproductive Toxicology
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`and PREGNANCY).
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`CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
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`Carcinogenesis:
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`Mutagenesis:
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`Impairment of Fertility:
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`PREGNANCY
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`DRUG ABUSE AND DEPENDENCE ‘
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`Preclinical
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`DRAFT LABELING
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`OVERDOSAGE
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`/S/
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`Glenna G. Fitzgerald, Ph.D.
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`Attachments
`
`NDA 20-717
`
`c.c. Div. File
`
`Leber, Katz, Rappoport, Atrakchi, Fisher, Fitzgerald, Malandrucco
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`N:\FITZGERA\MODAF.MEM
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`NDA# 20-717
`Original Pharmacology Review
`
`
`
`NDA#
`Drug:
`Sponsor:
`
`Indication:
`Category:
`
`20-717
`Modafinil (Provigil)
`Cephalon, Inc.
`West Chester, PA 19380-4245
`Narcolepsy
`Unknown mechanism of action, has agonistic effects on centran
`adrenergic and dopamine receptors.
`Dec 27 1996
`Dec 30 1996
`Mar 31st 1997
`
`Sub Date:
`Rec Date:
`Rev Date:
`Reviewer:
`Glenna Fitzgerald, Ph.D.
`Team Leader:
`Related lNDNDA(s): l
` .
`
`Aisar H. Atrakchi. Ph.D.
`
`,5,
`/S/
`
`/S/
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`Table of Content
`
`EXECUTIVE SUMMARY: .............................................................. 1
`PHARMACOLOGY: ............................................................ 1
`TOXICOLOGY: ............................................................... 1
`CARCINOGENICITY: .......................................................... 3
`W ........................................................ 3
`‘ REPRODUCTIVE AND DEVELOPMENTAL STUDIES: ................................ 5
`GENETIC TOXICOLOGY: ....................................................... 6
`
`LABELING: ......................................................................... 7
`
`Pharmacology ...................................................................... 8
`Mechanism of Action: .......................................................... 8
`Receptor Binding: ............................................................. 9
`Other Effects: ............................................................... 10
`
`GI Effects: ......................................................................... 1 1
`
`Immunology: ....................................................................... 1 1
`
`Activity of Metabolites: ............................................................... 11
`
`Drug-Drug Interactions: .............................................................. 11
`
`CVS: ............................................................................. 1 1
`
`PK Studies ........................................................................ 12
`
`Single Dose: ................................................................ 12
`Mice: ................................................................ 12
`Rat: ................................................................. 12
`
`Dog: ................................................................ 13
`Rabbits: ............................................................. 14
`
`Repeate Dose: .............................................................. 14
`Mice ................................................................ 14
`
`Dog ................................................................. 15
`DISTRIBUTION AND ELIMINATION ............................................. 17
`Rat ................................................................. 17
`
`Dog ................................................................. 19
`METABOLISM ............................................................... 21
`
`PK of the Stereoisomers, d & I: ........................................................ 24
`
`Special PK Studies .................................................................. 25
`
`TOXICOLOGY: ..................................................................... 26
`ACUTE TOXICITY: ........................................................... 26
`SUBCHRONIC TOXICITY: ..................................................... 26
`Mouse: .............................................................. 26
`Rat ................................................................. 31
`
`Dog ................................................................. 34
`
`Summary of Subchronic Studies: ....................................................... 36
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`CHRONIC TOXICITY: ............................................................... 37
`Rat ................................................................. 37
`Dog ................................................................. 40
`
`Summary and Conclusions of Chronic Studies: ............................................ 42
`
`REPRODUCTIVE AND DEVELOPMENTAL STUDIES ...................................... 42
`Seg I rat fertility study ......................................................... 42
`Seg ll teratology study in rats ................................................... 43
`Seg II teratology study in rabbits ................................................. 44
`Seg Ill peri- and post-natal study in rat ............................................ 45
`Seg III peri- and post-natal study in rat with functional and behavioral evaluation ........... 46
`
`SUMMARY AND CONCLUSION(s) FOR THE REPRODUCTIVE STUDIES: ..................... 47
`
`Genetic Toxicology .................................................................. 48
`
`SUMMARY AND CONCLUSION(s) FOR THE GENETIC TOX STUDIES: ....................... 53
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`Appendix I Carcinogenicity Studies and CAC Recommendations and statistical Review ............ 54
`
`Appendix II Amendment on Abuse Potential .................................................
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`EXECUTIVE SUMMARY:
`
`WO
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`The pharmacology of modafinil has been studied in a number of species: mouse. rat. g.pig, rabbit,
`dog. monkey. and cat
`
`Its awakening
`The exact site of action of modafinil responsible for wakefulness is unknown.
`properties are attributed to multiple sites to include 5HT, DA. and GABA systems. with the
`requirement of an intact a1 adrenergic system. Modafinil's effects are pharmacologicaliy distinct
`from amphetamine, methylphenidate, and other psychomotor stimulants such as caffeine.
`It does
`not affect the release or uptake of catecholamines nor does it interact with adenosine receptors or
`blocks phosphodiestrase activity.
`
`In cocaine-trained monkeys, modafinil was a reinforcer for self-administration, in the rat, modafinil
`did not induce i.v. self-administration or re-inforcement of response. whereas, cocaine did.
`
`Modafinil did not interact with other drugs such as antidepressants (clomipramine,
`chlorpromazine), antipsychotics (haloperidol), others e.g. prazosin, or warfan'n.
`
`Findings from both receptor binding studies and functional studies. indicate that modafinil is
`unlikely to act via a direct binding to adrenergic receptors since it binds either weakly (IC50 328uM)
`or not at all (Ki >1000uM) nor does it act indirectly on the release of catecholamines via in vivo
`models.
`
`Modafinil has limited or no peripheral effects on the CVS. respiratory. or immunologic systems. GI
`. movement, biliary, or pancreatic secretions. urine flow or blood coagulation.
`
`The minimum effective dose range of modafinil's various pharmacology effects are as follows:
`Mouse
`4-3256'mg/kg i.p.
`Rat
`1 (BID for 5d)-128mg/kg i.p., and 512‘mg/kg p.o.
`Dog
`5&10“mglkg i.v.
`Monkey
`6-22.5mg/kg p.o.
`Cat
`5mglkg p.o.
`
`' the high dose represents stereotype behavior.
`“ in genetic doberrnans and narcoleptic English bulldog respectively.
`The above effective doses were for hyperactivity. locomotion. stereotypy, incr wakefulness, decr in
`barbital sleeping time, Porsolt's test, avoidance auditory. and other. Increased wakefulness in the
`rat. dog, and cat occurred at 30mg/kg i.p., 5mglkg iv. and 5mglkg p.o. respectively.
`
`The sulfone metabolite of modafinil was found to be devoid of pharmacological activity in the
`mouse between 8-512rng/kg i.p. doses. Similarly, the acid metabolite showed no activity in the
`mouse at 8-512mg/kg and rat at 4-256mglkg.
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`L0,,o values for acute tox studies were as follows:
`
`LD50(mg/kg)
`1600
`1250
`1400
`790
`
`Species/Route
`rat/p.o.
`mouse/pa.
`rat/Lo.
`mousefip.
`
`Multiples of Human Dose'
`187
`239
`118
`209
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`‘ 400mg/d or 6.7mg/kg/d for a 60kg person.
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`MLD (minimum lethal dose) in the dog was 300mg/kg p.o. which is 45x the max human dose of
`400mgld.
`
`The following dietary subchronic tox studies were done:
`Mouse 13wk (2 studies)
`Dose range tested (mg/kg) 25-180
`Rat
`4wk, 12wk, 13wk, and 26wk
`Dose range tested (mg/kg) 20-400
`Dog
`12wk
`Dose range tested (mg/kg)
`
`The following dietary chronic tox studies were done:
`Mouse 78wk car study
`Rat
`2yr car study with 52wk interim sacrifice
`Dog
`52wk
`
`Doses (mg/kg) 6. 30, 60
`Doses (mg/kg) 6, 30, 60
`Doses (mg/kg) 10, 20, 40
`
`The NOEL were:
`
`20mg/kg in 26wk
`100mg/kg in 4wk
`Rat
`Mouse 6mg/kg in the carcinogenicity study,
`Dog
`<20mg/kg
`
`6mg/kg in 52wk and mrcinog. studies
`
`‘ The 6mg/kg NOEL dose in the rat and mouse is equivalent to the maximum human dose of
`400mg/d on mg/kg basis.
`
`The tox findings in the rat and mouse subchronic studies were mild to moderate with no life-
`threateninig toxicity.
`
`In the rat subchronic studies. one or more of the following findings were observed: deer in mean
`wt, food intake, incr in water intake, mild changes in hematology parameters (macrocytic anemia
`in m&f rats dosed 400mg/kg), incr in liver. spleen, 8. kidney wt (absol and/or relative wt;
`sometimes dose-dependently), deer in thymus wt, decr serum creatinine, serum protein incr, incr
`hepatic CI in rats dosed 100&200mg/kg. [TK data were not done in any of these studies].
`
`in the mouse subchronic studies, CD-1 and OF-1 strains were tested; the OF-1 was the one used
`in the car study. One or more of the following findings were observed: decr in mean wt, wt gain
`hematology parameters (Hb, bilirub), incr in liver wt, and liver hypertrophy.
`
`TK data were not done in the original 3mo mouse study (study conducted prior to ear study),
`attempts were made to measure TK in the recently conducted 13wk tox study in CD—1 mice.
`However, due to several technical difficulties and values below quantitation limit of the analytical
`method, the sponsor conducted a 3rd dietary 13wk TK study in 00-1 and OF-1 strains where
`dosing via gavage was done on d1&90 of study to ensure detection of plasma levels. Plasma
`levels were measured between 0.5&24hr postdose on days 1. 30, and 90. No difference in TK
`data between sexes or strains. Mean 1hr plasma levels & exposure deer with time whereas Cl
`incr with time. Highest mean plasma level on d1 at 60mg/kg was 19uglml with AUCM of
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`47ug.hr/ml and CI of 21mein/kg, the corresponding values on d30 were Bug/ml. 15ug.hr/ml. and
`65ml/min/kg. These plasma levels and exposure are equal to or several folds lower than the
`clinical steady state levels following 400mg/d max recommended dose.
`
`0
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`Dogs treated for 13wk had stereotypy at doses aZOmg/kg with head movement. agitation, panting,
`and sometimes hypotension at 100/75mg/kg dose. Mean wt gain was sig decr in all drug grs
`without an effect on food intake. Irreversible corneal opacity was observed in 1 dog dosed
`50mg/kg and 3 out of 6 dogs dosed 100/75mg/kg. Some changes in hematology and clinical
`chem that reached statistical sig and considered drug related included incr in MCV. platelet. and
`WBC. incr in cholest, lipids, and ALP. There were no gross or histopath. There were organ wt
`changes but considered secondary to wt loss. A NOEL could not be determined in this study due
`to clinical signs and wt loss at 20mg/kg dose.
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`Mouse car study did not reach an MTD. this conclusion was reached by both the reviewer and the
`CAC-Exec members. The study was negative with regard to tumor findings. Other toxicities were
`mild and included dose-dependent incr in absol and rel wt of the liver, liver hypertrophy in HD
`mice. and inhibition of spermatogenesis in MD&HD. TK data could not be measured except on
`wk4 because they were below detection limit of the analytical method; at wk4 values ranged
`between 0.023-0.102ug/ml in 6mg/kg to 0.205-O.402ug/ml in 60mg/kg dose gr.
`
`0
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`0
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`it is the opinion of the reviewer that similar to the mouse car study, an MTD was not reached in
`the rat study. However, the CAC-Exec members considered the rat car study adequate and that
`HD reached an MTD based on incr in severity of chronic progressive nephrosis (CPN) in male
`rats that led to incr in mortality in this gr. Mean wt although deer in HDm during wk80 and mean
`wt gain decr in HDm&f during wks 52-80, the final mean wt and wt gain were comparable to the
`controls. The study was negative with regard to tumor findings. Other toxicities in addition to the
`above. was dose-dependent incr in periarteritis nodosa in testes but this is reported to occur
`parallel to CPN in rats. TK data were determined for the parent and acid metabolite (main
`metabolite in humans). As in the mouse car study, the analytical method was not validated.
`animals were non-fasted. and contamination of cont samples with the drug sub. Modafinil plasma
`levels ranged between 0-0.035ug/ml in 6mg/kg, 0.24—0.171ug/ml in 30mg/kg. and 0.044-
`0.180ug/ml in 60mg/kg dose gr. The acid metabolite conc ranged between O-0.035ug/ml in
`6mg/kg, 0.032-0.142ug/ml in 30mg/kg, and 0.059-0.296ug/ml in 60mg/kg dose gr. Plasma t,”
`was 1-3hr compared with the long half life in humans of 10-12hr. Plasma levels incr non-linearly
`with dose.
`
`The CAC-Exec recommended that if the sponsor considers the mouse oar study is adequate, they
`may come in and present their case to the CAC. Also they recommended an alternative in vivo
`assay to be conducted to replace the invalid mouse car study. The sponsor is to submit a
`protocol and present it to the CAC with justification for using that particular assay.
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`The PK and/or metabolism of modafinil were investigated in the rat, mouse. dog. and rabbits
`following single and/or repeate dosing.
`
`O
`
`Concentration-response relationship of modafinil and its acid metabolite was tested using
`spontaneous motor activity as the end point. Modafinil was injected i.p. at 8, 16. 32, 64, or
`128mg/kg to rats. The data showed no correlation between motor activity and mean plasma
`levels of modafinil but a positive correlation was observed between the individual plasma values
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`Plasma cone of the acid were generally higher than those of MDF:
`
`Dose (mg/kg)
`Time
`8
`16
`32
`64
`128
`
`
`0
`
`0.5
`
`0.810.34
`(110.5)
`
`0.11102
`(0.2102)
`
`1.1105
`(1.8108)
`
`0210.2
`(0.5102)
`
`2.3108
`(411.4)
`
`212.6
`(312)
`
`6.4136
`(711.5)
`
`211.3
`(412.6)
`
`913
`(1314.5)
`
`1114.6
`(1314.6)
`
`Values are means1s.d. in ug/ml;
`
`() are the acid conc.
`
`In another concentration-response study, modafinil conc was checked against EEG in rats
`injected i.p. at 128mg/kg for 14days. Values are means1s.d. in ug/ml;
`() are the range of values.
`These are 2hr values:
`
`Day
`
`MDF
`
`MDF-acid
`
`MDF-sulfone
`
`‘
`
`1
`
`7
`
`14
`
`28.4127
`(OZ-54.5)
`
`1019
`(0.07-18)
`
`1318
`(4-20)
`
`8110
`(1-20)
`
`1215
`(8-18)
`
`514.6
`(2-10)
`
`818
`(0-16)
`
`613
`(3-9)
`
`315.5
`(ND-10)
`
`Values measured at 4hr postdose were similar to the above (2hr).
`
`It is clear from these results that with time. cone of MDF and its metabolites decr when given the
`same dose. There was a great deal of interindividual variation in the data.
`
`Modafinil is well absorbed after single and repeate dosing in mouse, rat. and dog. Absolute oral
`bioavailability was calculated at 80->85% in the dog and rat. Plasma levels correlated somewhat
`with doses and the kinetics were dose-independant
`
`Elimination half lives were short in rodents (1-3 hr) and dog (2-5 hr) compared with human t“2 of
`10-15hr. There were minimal sex differences in PK parameters.
`
`‘ Modafinil in the rat, mouse. dog. and humans induces its own metabolism through induction of
`hepatic drug metabolizing enzymes. This was evident by increase in liver weight. decrease in
`drug plasma levels after repeate dosing, increased rate of antipyn'ne metabolism. and in vitro
`studies.
`
`Modafinil is distributed to various tissues such as the liver, kidneys. and endocrines; brain levels
`were low but constant and homogeneous throughout the brain regions.
`
`In humans. 6
`Modafinil is metabolized mainly to 2 major metabolites: the acid and sulfone.
`metabolites have been detected (not all identified) with the acid and sulfone being the main ones.
`
`Modafinil is excreted mainly via the urine and some in feces. The drug enters the enterohepatic
`circulation as it is secreted by the bile in the rat (18-32%).
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`Studies of the stereoisomers indicate small differences in disposition or elimination compared with
`the racemate (modafinil). The acid and sulfone metabolites were inactive phannacologlcally and
`some differences in intensity of responses were noted between the isomers and the racemate
`with the d-forrn being more readily and completely absorbed than the Ham.
`
`Due to high auto-induction of metabolism, detection and measurement of plasma levels and other
`PK parameters of the parent and metabolites was difficult and many times impossible after
`repeate dosing. This was evident in the inability to measure plasma levels in the 13wk mouse tox
`studies and rodent life-time bioassays.
`
`WWE
`6
`Modafinil effect on reproductive and/or developmental parameters was tested in the following
`studies:
`
`1.
`2.
`3.
`4.
`5.
`
`Seg l in rats/doses: 20, 50, 100mglkg/Non-GLP
`Seg II in rats/doses: 50, 100. 200mglkg/d/Non-GLP
`Seg II in rabbits/doses: 25. 50, and 100mglkg/Non-GLP
`Seg III in rats/doses: 20, 50, 100mglkg/GLP
`Seg III in rats/doses: 50. 100. 200mglkg/GLP
`
`The NOEL values are as follows:
`Study
`End-point
`NOEL (mg/kg)
`“——
`
`Seg l rat
`
`fertility
`
`Seg ll rat
`
`Seg ll rabbit
`
`Seg lll rat
`
`maternal tox
`teratogenicity
`embryotox
`
`maternal tax
`teratogenicity
`embryotox
`
`maternal tax
`teratogenicity
`embryotox
`
`100
`
`200
`200
`200
`
`50
`100
`100
`
`100
`100
`20
`
`Seg Ill rat
`
`maternal tax
`teratogenicity
`embryotox
`
`100
`200
`200
`
`Modafinil administered orally to rats upto 200mg/kg and to rabbits upto 100mglkg was not teratogenic (the
`200mg/kg dose is 30x the max anticipated human dose of 400mg/d on mg/kg basis). Fertility in male and
`female rats was not affected upto 100mglkg. Embryotox seen as incr resorptions. occurred at 100mglkg
`in F0&F1 rats.
`in absence of maternal toxicity. modatinil in a Seg ll rat study incr total no. of resorptions in
`f dosed 200mglkg. in addition, there was an incr in litter hydronephrosis and incomp ossification in fetuses
`from these females. These embryo-fetal toxicities may not be of real biological significance because the
`number of resorptions per female was not affected and the visceral and skeletal effects were relatively
`small. The NOEL for embryotoxicity in this study is therefore, 200mglkg. Rabbits dosed modafinil during
`organogenesis period. showed a small decr in mean wt gain and food intake at 100mglkg. The NOEL in
`rabbits was 50mg/kg for maternal tox and 100mglkg for embryotox and teratogenicity.
`In a pre- and post-
`natal Seg Ill rat study, modafinil was dosed during pregnancy and lactation. There was a dose-dependent
`incr in RI but stated by the sponsor to be within historical data for this rat strain. Though dose-
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`independent. number of live fetuses per female was deer in all 3 drug grs and the stillborn rate and
`number of stillboms were incr in females dosed 50&100mglkg. The only effect on growth was a delay in
`startle response in the 508.100mg/kg dosed groups. The maternal NOEL is 100mg/kg whereas. that for
`embryotoxicity is 20mg/kg.
`In a more recent Seg III study in rats, modafinil was not teratogenic upto
`200mg/kg but caused a 40% deer in wt gain in females in this gr during gestation period 7-10; no effect
`thereafter. This decr however, affected the cummulative wt dun'ng gestation periods 7-20&0-20. Mean wt
`was slightly but sig decr during lactation period. Accompanying the decr in wt was a 7-20% decr in food
`intake in the 100&200mg/kg dosed grs during gestation periods 7-10&7-20.
`In contrast to the previous
`Seg III study where the NOEL for embryotoxicity was 20mg/kg. in this repeate study, modafinil was not
`embryotoxic upto 200mg/kg; the maternal NOEL was 100mg/kg similar to that in the previous study.
`
`W O
`
`Modafinil was not mutagenic in the assays evaluated. The following tests were conducted: Ames
`test, human lymphocyte chromosome aberration. chinese hamster V79 lung fibroblasts gene
`mutation. and in vivo chinese hamster bone marrow chromosome aberration assay.
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`Carcinogenisis, Mutagenesis, impairment of Fertility:
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`Muta - enesis:
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`cairment of Fertiii
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