‘ CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-3 68
`
`. PHARMACOLOGY REVIEW
`
`MonoSol 1019—0001
`
`I
`
`MonoSol V. ICOS
`IPR2017-00412
`
`MonoSol 1019-0001
`
`MonoSol v. ICOS
`IPR2017-00412
`
`

`

`GENERAL PHARMA COLOGYfl'0X1COLOGY COVER SHEET
`
`NDA No: 21-368
`Sequence No: 000
`Information to sponsor: Yes (x) No ()
`Sponsor: Lilly ICOS LLC, Eli Lilly & Company, Indianapolis, IN 46285
`Manufacturer for drug substance: Eli Lilly & C0,, Tippecanoe Laboratories, Lafayette, IN 47909
`
`Review No: 1
`Date/type of submission: June 28, MOI/Original
`
`Reviewer: Yangmee Shin, Ph.D.
`Division: Division of Reproductive and Urologic Drug Products, HFD-580
`Review completion date:
`
`Drug:
`
`Trade name: Ciahs
`
`Generic name: Tadalafil
`
`Code name: IC351 (LY450190)
`Chemical name: Pyrazino[l’,2:’ l ,6]pyrido[3,4-b]indole-l ,4-dione, 6-(1,3—benzodioxol--S-yl)-
`2,3,6, 7, 12, lZa-hexahydro-Z-methylg (6R-12aR)~
`
`CAS registry No: 171596-29-5
`Molecular formula: CHH19N3O4
`Structure:
`
`Mole file No:
`Molecular weight: 389.41
`
`
`
`Relevant INDs/NDAs/DMFs: IND 54,553 .
`
`
`
`Drug class: B-carboline phosphodiesterase (PDE) type 5 inhibitor
`Indication: Erectile Dysfunction (ED)
`
`Clinical formulation: Yellow, film-coated, almond-shaped tablets containing 20 mg of tadalafil and
`inactive ingredients of lactose monohydrate, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
`iron oxide, croscarmellose sodium, sodium lauryl sulfate, microcrystalline cellulose, talc, titanium
`dioxide, triacetin & magnesium stearate.
`
`Route of administration: Oral
`
`Proposed clinical use: Treatment of erectile dysfunction
`
`Disclaimer: Tabular and graphical information isfrom sponsor 's submission unless stated otherwise.
`
`i
`
`MonoSol 1019-0002
`
`MonoSol 1019-0002
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`

`

`Studies reviewed within this submission:
`
`’ “ '
`
`PHARMACOLOGY (#321422, #01 -0007-1 1, #OO-OOIO-I l, #00-0009—1 1)
`TOXICOKINETICS (#D01899, 277—.
`88780, #‘—’—~ 88779, ire—853016)
`TOXICOLOGY
`
`l-Year oral toxicity study in’beagle dogs (vol. 31, p l, #D01899)
`CARCINOGENICITY
`
`2-Year oral carcinogenicity study in CD-l mice (vol. 33, p l, k —‘ 88455)
`2-Year oral carcinogenicity study in 1-" Wistar rats (vol. 34, p 1, at; ——- 88203)
`REPRODUCTIVE TOXICOLOGY
`
`Segment ll & III reproductive study in CD rats (vol. 37/38, p 1, # — -353010.—-.-353016)
`
`. Studies 101 reviewed within this submission (Appendix I):
`
`IND 54,553 Review #1, May 26, I998
`PHARMACOLOGY (#97-001-14, #97002-14, #97-003-14, #2— 94-007)
`SAFETY PHARMACOLOGY (#20215, #520996, #21011, #S20222, #97-004-14)
`PHARMACOKDETKB
`'
`
`Absorption (#1121 147, #D2] 148, #BPW662, #BPW64l/BPW659)
`Metabolism (#BPW549/BPW564, #BPW641/BPW659)
`Distribution (#BPW618)
`Protein binding (#BPW507, #BPW495)
`TOXICOKINETICS (#R20861, #R2 1236, #D21148, #D20786, #D20863, #D21235)
`TOXICOLOGY
`
`Acute toxicity (#M20798, #M20799, #M20977, #M20978, #R20796, #R20797, #1220979, #R20980)
`Repeated toxicity
`1. Maximum repeatable daily oral dosage study in the L“ Wistar Rat (#R20791)
`2.
`l-Month oral toxicity study in -- Wistar Rats (#1120861)
`3. Study to determine the maximum repeatable daily oral dosage in the beagle dog (#D20786)
`, 4.
`l-Month oral toxicity study in the beagle dog (#D20863)
`5. 6-Month oral toxicity study in the beagle dog (#D21235)
`GENETIC TOXICOLOGY
`
`l. Microbial mutagenicity study (#U20206)
`2. Mouse lymphoma thymidine kinase mammalian cell mutation study (#V21 166)
`3.
`In vitro cytogenetic evaluation in cultured human lymphocytes (#V209l8)
`4. WHO nitrosation assay (#U21004)
`
`IND 54.553 Review #2
`TOXIC OLOGY
`
`1. 6~Month oral toxicity study in the beagle dog (#D21235)
`
`IND 5*" Review #1, May 27, 1999
`PHARMACOKINETICS
`
`Metabolism (#1999IV-RSL05, #006R00)
`Excretion (#BPW549/BPW564)
`TOXICOKINETICS (#88270)
`TOXICOLOGY
`
`l. 3-Month oral pilling toxicity study with a 13-week recovery period in the Beagle dog (#88270)
`GENETIC TOXICOLOGY
`
`1. Micronucleus assay in bone marrow of male .- A Wistar Rats (#R20937)
`
`
`._I‘ID_:-'— Review #2 Jul 26 1999
`SAFETY PHARMACOLOGY (#PG9927)
`TOXICOKINETICS (#M04298, #Rl8498, #M04398, #3 -- 353004, #' —— 853005)
`TOXICOLOGY
`
`l.
`
`1- & 3-Month oral gavage toxicityin’CD-l mice (#M04298)
`
`MonoSol 1019-0003
`
`MonoSol 1019-0003
`
`

`

`REPRODUCTIVE TOXICOLOGY
`l. Embryo/fetal development in CD-1 mice (#"‘ 353004)
`2. Embryo/fetal development in CD rats (#‘ _, ~353005)
`
`" "
`
`IND 54.553 Review #3, Aug 10, 1999
`PHARMACOLOGY (#98-0001~l 1, #98-0002-1 l, #98-0003-1 l)
`PHARMACOKJNETICS (#132R98, #R14998, #M04198, ADME#6, ADME#7)
`TOXICOKINETICS (#r" 88440, #21236)
`TOXICOLOGY
`
`1. 3-Month oral gavage toxicity in CD-l mice (#88437)
`2. 6-Month oral gavage toxicity in —-— Wistar rats (#21236)
`REPRODUCTIVE TOXICOLOGY
`
`1. Oral gavage fertility study in CD rats (#96364)
`JUSTIFICATION FOR 2-YEAR CARCINOGENICITY STUDY DOSE SELECTIONS IN RATS & MICE
`
`IND i r——' Rew‘ew #3, Sep 3, 1999
`PHARMACOLOGY (#PR9902)
`PHARMACOKINETICS (#B00199, #R18498)'
`TOXICOKINETICS (#R18498, }.~——88632)
`TOXICOLOGY
`
`1. 3-Month oral gavage in Fisher 344 rats (#R18498)
`2. 6-Month oral pilling toxicity study with a 3—month recovery period in the Beagle dog (‘r ,— 88632)
`SPECIAL TOXICOLOGY
`
`1.
`
`In vitro ocular irritation-agar diffusion cytolysis & aqueous pH in cultured rabbit comea cells (#990416ADC)
`
`
`m ——’- Review #4 Dec 27 I999
`PHARMACOLOGY (#PR9902)
`SPECIAL TOXICOLOGY
`
`1.
`2.
`
`In vivo eye irritation study in New Zealand White rabbits (#SL13 130.495)
`In vivo acute dermal toxicity in New Zealand White rabbits (#SLI3130.487)
`
`IND .’ Review #5, Aug 15, 2000
`PHARMACOLOGY (#1999lV-EIOO4, #PR9906, #99-0005-11)
`PHARMACOKINETICS
`
`Distribution (#003R00)
`Metabolism (#1999IV-SF038)
`Excretion (#078R99, #002R00)
`Repeat Dose in Monkeys (i —“ 88548)
`
`Introduction and drug history: IC351 is a potent, competitive and reversible inhibitor of cGMP
`specific PDE type .5 for an indication of ED under IND 54,553. It is also currently being investigated for
`-——- under IND 1 ~_ Major toxicities are irreversible seminiferous testicular atrophy and vasculitis in
`dogs. The original submission by lCOS Corporation was placed on clinical hold because of vasculitis
`findings in dogs and the high daily clinical dose up to 100 mg.
`
`MonoSol 1019-0004
`
`iii
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`MonoSol 1019-0004
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`

`

`EXECUTIVE SUMMARY "
`
`“m.
`
`1.
`
`Recommendations
`
`7
`
`,,
`
`A. Recommendation on Approvability: The preclinical studies conducted support the safety
`of the proposed dose of 20 mg of Cialis.
`
`II.
`
`B. Recommendation for Nonclinical Studies: The 2—year carcinogenicity studies in male rats,
`and male and female mice were conducted at doses below those recommended by the ICH
`guidelines (see Exectutive CAC minutes in appendex 1]) based on the AUC exposures for the 20
`mg human dose. The Committee recommended an additional alternative mouse carcinogenicity
`assay be conducted for Phase IV commitment unless the sponsor provided evidence for
`saturation of absorption by measuring either total radioactivity or metabolites.
`
`C. Recommendations on Labeling: Refer to the labeling comments.
`
`Summary of Nonclinical Findings
`A. Brief Overview of Nonclinical Findings: EffectiVe antihypertensive oral doses of
`IC351 were 1 mg/kg in the rat. Reduction in mean blood pressure occurred at doses from 20
`mg/kg without effects on heart/respiration rate in conscious dogs, but moderate tachycardia was
`seen in a dog (1/2) at 30 mg/kg and in both dogs at 100 mg/kg in another study. The
`cardiovascular effects were not observed in the repeated toxicity studies. IC351 potentiated atrial
`natriuretic factor (ANF)~induced diuresis and natn'uresis in rats at lower doses (0.1 mg/kg, iv.)
`than those required for decreasing blood pressure. Slight-to~moderate ptosis and depression of
`the pinnal reflex were observed in rats given 200 mg/kg. IC351 did not cause death up to 2,000
`mg/kg (p.o.) in mice and rats in acute studies. Like other PDES inhibitors, the major findings of
`IC351 treatment in repeated dose studies are arteritis and testicular degeneration/anophy
`observed in multiple species. IC351 was not genotoxic and the carcinogenicity studies were
`negative although hepatocellular adenomas/carcinomas were observed with increased frequency
`in high dose male mice and rats. Reproductive and developmental studies: in mice and rats
`displayed no adverse effects on fertility at doses up to 1,000 mg/kg. Mice: were used for a second
`rodent species of embryo/fetal development studies since plasma exposure for rabbits was
`minimal. A NOAEL for maternal toxicity was established at 1,000 mg/kg; in mice and 200 mg/kg
`in rats (based on reduced body weight gain). A NOAEL for F1 developmental toxicity in the rat
`could not be identified due to significantly reduced postnatal survival in all dose groups from the
`combined segment 11/11] study. Sponsor defined a NOAEL of 30 mg/kg from a subsequent study,
`which gives 9-fold exposure for the unbound parent drug (pregnant rat) to the human exposure at
`20 mg. IC351 is a mild ocular and dermal irritant in New Zealand White rabbits.
`
`B. Pharm acologic Activity: IC351 is a potent and selective inhibitor of PDES among the PDEs
`tested in vi’tro. PDES is a major cGMP-hydrolyzing enzyme in human cavemosal smooth muscle,
`and theinhibition of PDES by IC351 enhances relaxant effects of NO by stimulating cGMP
`levels. This leads to relaxation of penile resistance arteries and the smooth muscle to enhance the
`erectile response. IC351 strongly potentiated the inhibitory effects of sodium nitroprusside (SNP)
`on human platelet aggregation with complete inhibition at 0.25 M, and on increased cGMP
`levels in human cavemosal smooth muscle, suggesting that the PDES inhibition by IC351 may
`lead to large increases in cGMP levels once activated. IC351 retains relatively low selectivity for
`PDES vs. human PDEl 1A (abstract from Am. Coll. Clin. Pharmacol., VA, 2001), which was
`widely expressed in kidney, liver, pituitary/salivary glands and testis (PNAS 97: 3702, 2000).
`Thus, pharmacological characterization of IC351 on human PDEl 1A may provide additional
`information on the mechanism of IC351.
`
`.
`
`iv
`
`MonoSol 1019-0005
`
`MonoSol 1019-0005
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`

`

`C. Nonclinical Safety Issues Relevant to Clinical Use:
`1.
`Testicular degeneration/atrophy were observed with increased incidence in the 3-month
`toxicity study and the carconogenicity study in mice and in the 3-, 6- and 12-month toxicity
`studies in dogs with no/low safety margin at a NOAEL compared to the proposed human dose of
`20 mg. The findings are likely to be irreversible since the incidence was observed during the
`recovery in the 3- and 6-month dog studies. In men, there were no clinically significant effects on
`semen parameters up to 6 months with a clinical dose of 20 mg (#H6D—MC-LVCZ).
`
`Vasculitis findings should be interpreted cautiously since the relevance to humans and the
`2.
`pathogenic mechanism of drug-related vascular lesions in animals are poorly understood, and the
`specific biomarkers are not identified. IC351 treatment increased the incidence of vasculitis in
`mice, rats and dogs but the effects varied considerably between studies. In a 13-week study in
`mice, there was hemorrhage in mesenteric lymph nodes in the high dose group (400 mg/kg,
`approximately 9 times the maximum human exposure of unbound drug). In another 3-month
`study, there was minimal vasculitis in the high dose group receiving 800 mg/kg (7 times the
`maximum human exposure; exposure estimates varied between and within studies). In Wistar rats,
`vasculitis occurred in a number of tissues with slight/minimal severity. In general, the incidence
`was only slightly higher in treated groups than in controls. These effects were seen at exposures
`anywhere from 2X (mesenteric phlebitis) to 33X the maximum human exposure. In dogs, findings
`of arteritis occurred in l and 6 month studies. Effects included perivascular inflammation in the '
`lungs, increased incidence of coronary arterial lesions and marked disseminated arteritis. These
`findings occurred in the absence of elevated heart rate and resulted in the drug being placed on
`clinical hold. The study pathologist, \ *— concluded "the high incidence of arteritis that has
`been associated with high doses of IC351 in the 6-month dog study, and the predominance of
`arterial changes in the mid- and high-dose groups in the 1-month study are strongly suggestive of
`a treatment related change or treatment related exacerbation of the spontaneous polyarteritis". In
`general, drug effects were seen at exposures between 5 and 16 fold in the: 1-month study, and
`between 29 and 54 times in the 6-month study (as measured by mean AUC of unbound drug) the
`maximum human exposure. Due to the concerns about vasculitis, the Division requested a 12-
`month toxicology study in dogs. This study was essentially negative at exposures of 3-33 times
`the maximum human exposure but there was marked neun'openia/thrombocytopenia indicative of
`type III immunopathy in two dogs (exposures 14 and 18X human exposure). The high dose dog
`did have perivasculitis in the circumflex branch of the left coronary artery with clinical signs of
`fever, anorexia and lethargy. In humans, symptoms of hypersensitivity such as myalgia, infection
`and back pain were the most frequently reported adverse events associated with IC351. The
`sponsor concluded that neither back pain nor myalgia was associated with inflammatory or
`myopathic etiologies based on a clinical study, which measured erythrocyte sedimentation rate
`and serum creatinine kinase.
`
`In dogs, direct measurements of artErial diameter, vascular resistance or blood flow were not
`conducted to determine if exaggerated hemodynamic effects were associated with the vasculitis
`(clinical data indicate that combined treatment with antihypertensive drugs generally reduced the
`episode of myalgia and backpain). In the safety pharmacology studies, moderate tachycardia (40.
`60 bpm) was observed in dogs at doses 230 mg/kg (1/2 at 30 mg/kg & 2/2 at 100 mg/kg). The -
`effective antihypertensive dose in rats is 1 mg/kg, po. In conscious dogs, single oral doses of 20
`and 200 mg/kg produced slight reductions in mean blood pressure without effects on heart rate or
`respiration rate. In the 1-month study (D20863), the high dose produced a moderate decrease in
`heart rate with some vasculitis in the lung, spinal cord and thymus. In a 6-month study (D21235),
`there were no drug—related changes in ECG but there was increased incidence and severity of
`arteritis with clinical signs in the high dose dogs. It seems that IC351 can induce vascular changes
`in the absence of any significant effect on cardiac function.
`
`MonoSol 1019-0006
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`MonoSol 1019-0006
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`

`

`In dogs with drug blood levels below approximately 29 times the human exposure, vascular
`effects, if any, were minimal to slight. In one 28-day study, D20863, there were positive effects
`(perivascular inflammation in the lungs in 3/6 dogs vs. 0/6 in controls) at: approximately the same
`exposure as men taking 20 mg. In the lZ-month study, exposures at the high dose were up to 33
`times the human exposure to free drug with essentially negative effects. lit is not known if humans
`are more or less sensitive to this effect than animals.
`
`.
`
`Although the data are not particularly convincing that the finding in animals is relevant to
`humans, hypersensitivity is the major manifestation of clinical drug-induced vasculitis. There
`were two dogs with symptoms of marked thrombocytopenia (14 and 18X the human exposure)
`indicative of type III immunopathy in the 12-month dog study and symptoms of back pain and
`myalgia as the most frequent adverse effects in men. Thus, it would seem to be prudent to include.
`in the label some information on vasculitis in animals.
`
`III.
`
`Administrative
`
`A. Reviewer signature:
`
`B. Supervisor signature:
`
`Concurrence -
`
`Non-Concurrence -
`
`(see memo attached)
`
`C. Cc: NDA 21-368
`
`HFD-SBO/D. Spell-LeSane, M. Hirsch, A. Batra, G. Benson, M.-J. Ng, D. Hoberman,
`8. Roy, V. Jarugula, A. Parekh, M. Rhee, R. Agarwal, Y. Shin, A. Jordan
`HIFD-S lO/J. El-Hage, K. Davis-Bruno
`
`MonoSol 1019-0007
`
`MonoSol 1019-0007
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`

`

`TABLE OF CONTENTS - PHARJIA COL 06WT0X16bLOGY REVIEW
`
`I.
`
`PHARMACOLOGY: ...........7..........................................................................._............................. I
`
`II.
`
`SAFETY PHARMACOLOGY: ................................................................................................ 1
`
`III. PHARMACOIGI‘IETICSNOMCOIGNETICS: 2................................................................. 1
`
`IV. GENERAL TOXICOLOGY: .......................................................................................... 2
`
`v. GENETIC TOXICOLOGY: ...........................................................................................9
`
`VI. CARCINOGENIcm:.................................................................................................... 10
`
`REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY: ................................. 25
`VII.
`VIII. SPECIAL TOXICOLOGY STUDIES: ......................................................................... 29
`
`1X. DETAILED CONCLUSIONS AND RECOMMENDATIONS: ............................................. 30
`
`x. APPENDIX/ATTACHMENTS: ............................................................................................ 35
`
`MonOSOl 1019-0008
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`vii
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`MonoSol 1019-0008
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`

`

`Reviewer:
`
`______________—____________.__flD__N&
`
`PHARMACOLOGY/TOXICOLOGYREVIEW
`
`I. PHARMACOLOGY (see Reviews #1/3/4 for IND 54,553
`
`~——————-——————-«+
`
`Primary pharmacodynamics:
`Mechanism of action: IC351 inhibits PDES, a major cGMP-hydrolyzing enzyme in human
`cavemosal smooth muscle, and enhances relaxant effects of NC by stimulating cGMP levels. This leads
`to relaxation of penile resistance arteries and cavemosal trabecular smooth muscle (#00-0010-11). »
`Drug activity related to proposed indication: IC351 enhances the erectile response by smooth
`muscle relaxation and inflow of blood into the penile tissues.
`
`i Secondary pharmacodynamics: IC351 had no direct effect on human platelet aggregation but markedly
`potentiated the anti-aggregatory effect of soluble guanylyl cyclase activator sodium nitroprusside (SN?)
`in a dose-dependent manner (#97-002-14).
`
`Pharmacology summary: IC351 is a potent inhibitor of PDES among 10 PDEs (700- to 49,000-fold) in
`vitro (#00-0006-11). IC351 displays >l0,000-fold selectivity for PDES against PEDESA found in cardiac
`myocytes and 700-fold selectivity against PDE6 in photoreceptor. PDES was not present in human
`cardiac myocytes (#00-0009-11). The intermediate derivatives of IC351 (catechol and methylcatechol)
`and the methylcatechol glucuronide metabolite were 45- and 230-fold less potent than IC351 with some
`selectivity for PDES. The major circulating metabolite in human plasma and urine, methylcatechol
`glucuronide, displays 13,000-fold less potency than IC351 as a PDES inhibitor, but does not show
`selectivity. Sponsor stated that methylcatechol glucuronide would not have clinically significant effects
`on any of the human PDEs at concentrations achieved in human plasma following efficacious oral doses
`(11101410074 1).
`
`Pharmacology conclusions: IC351 strongly potentiated the inhibitory effects of SN? on human platelet
`aggregation with complete inhibition at 0.25 1.1M, and increased cGMP levels in the presence of SN? in
`human cavemosal smooth muscle, suggesting that the PDES inhibition by IC351 may lead to large
`increases in cGMP levels once activated.
`
`II. SAFETY PHARMACOLOGY (see Reviews #1 for IND 54,553 ‘ M
`
`
`
`Safety pharmacology summary: IC351 produced emesis/tachycardia at 230 mg/kg (po) in conscious
`dogs (1/2 at 30 mg/kg and 2/2 at 100 mg/kg) and ptosis/depression of the pinnal reflex at 200Img/kgin
`rats. Decrease1n mean arterial blood pressure was observed at 21 111ng (p.o.)1n
`hypertensive/nonnotensive rats and 220 mg/kg (p.o. )1n conscious dogs. IC351 at cumulative i.v. doses of
`0.1 to 3 mg/kg produced dose-dependent decreases in blood pressure in anesthetized dogs secondary to
`decreased vascular resistance. Administration of IC351 to conscious guinea pigs at an oral dose of 400
`mg/kg produced significant reduction in heart rate and progressive bradycardia, concurrent with
`deteriorating clinical signs and weight loss resulting in death (#821422). IC351 potentiated ANF-induced
`diuresis and natriuresis in rats at 0.1 mg/kg (i.v.). IC351 had affinity for the D2 receptor at 1 11M.
`
`Safety pharmacology conclusions: The effective antihypertensive oral doses of IC351 were 1 mg/kgin
`the rat and 20 mg/kgin conscious dogs.
`
`
`
`III. PHARMACOKINETICS (see Reviews #1/3/4 for IND 54,553
`
`PK parameters: PK of IC351 are linear with respect to time and dose in healthy subjects or in patients
`with ED. Exposure (AUC) increased proportionally over a dose range of 2.5- to 210 mg. Cm was
`
`MonoSol 1019-0009
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`MonoSol 1019-0009
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`

`

`Reviewer:
`
`__________________________IN_2_N&
`
`achieved at a median time of 2 hrs afier dosing. Steadystate plasma cohcentrations were attained by Day
`5 with doses of 10- or 20 mg/day with a tm of 17.5 hours.
`
`Absorption: Absorption of IC35 1 is generally rapid in rats and dogs with Tmax of 1 to 2 hours and 6
`hours with oral administration of 10 mg/kg [”C]-IC35 1, respectively. Repeated oral dosing caused a
`variable and prolonged Téu, suggesting the possibility of absorption in the lower intestinal tract. Oral
`bioavailability at 10 mg/kg was 34-53% in rats and 10-18% in dogs. Plasma half-life afier oral
`administration in rats and dogs could not be calculated due to the limited number of data points and a
`prolonged absorptive phase.
`
`Distribution: An oral dose of [”C]IC351 (10 mg/kg) to rats revealed the highest concentrations of
`radioactivity in the stomach, GI tract, thyroid and lung. By 168 hrs after dosing, radioactive drug-related
`material was not detected in any tissues except for the liver. Exposure to pregnant rats on gestation Day
`18 caused the highest concentrations of radioactivity in maternal adrenal gland, preputial gland and liver
`at 8 hours post-dose. Parent and/or metabolites of IC35] were detected in the matemal placenta, and
`fetal adrenal gland, blood, brain, eye, kidney, liver & myocardium with substantially low exposure at 8
`hours post-dose, indicating the placental transfer.
`
`Metabolism: IC351 is predominantly metabolized by CYP3A4 in human liver. Unchanged IC351
`accounted for 26% in human plasma, indicating an extensive metabolism. In human feces, the majority of
`the radioactivity was associated with metabolites after 24 hours. In human, dog and mouse liver slices,
`the major metabolite was the methylcatechol glucuronide. Catechol glucuronide was the most abundant
`metabolite in rat liver.
`
`Excretion: Major route of elimination of a radiolabled dose (100 mg) was the feces with 61% and urine
`with 36% in human by 13 days. Elimination of radioactivity in feces at a single dose of 10 mg/kg was
`98% in rats, 84% in male dogs and 63% in female dogs. Only 50.1% of administered IC351 is excreted
`in maternal milk over a 3 to 24 hour period, suggesting that maternal milk is not a major route of
`elimination for IC35] and metabolites.
`
`Protein binding: In vitro plasma protein binding to mouse, rat, dog and human was determined to be
`85%, 92%, 87% and 94%, respectively.
`
`PK/TK summary: Plasma concentrations generally increased sub-proportionally to the increased dose
`in mice, rats and dogs. Exposure was higher after 1 to 3 months in rats and dogs, suggesting
`accumulation in the plasma. The plasma exposure in pregnant rats following daily oral dosing fi'om
`gestation Days 6 through 12 was also less than proportional to dose over the range of 60 to 1000 mg/kg
`with Trm of 4 to 1.2 hours. The only gender difference was a higher exposure in female rats, and is not
`marked in humans.
`
`Summa
`
`of AUC 0.24.. in Subchronic- and Chronic Studies for Mice, Rats and Do - s
`
`W-_uration Dose, mg/kg
`Mouse
`CTBR88440
`
`3 Months Day_90
`
`AUCwmw ngb/mL
`13390
`
`
`
`
`
`
`
`(CD-l)
`
`
`
`M04398
`
`3 Months
`
`Day 90
`
`400
`
`
`26275
`19"01
`
`26860
`27152
`
`
`
`'
`
`CTBR88780
`
`6 Months
`Day 180
`
`Carcinoaemci
`
`
`800
`
`MonoSol 1019-0010
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`MonoSol 1019-0010
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`

`

`Reviewer:
`
`— _—- ‘ 31223“
`Rat
`R20861
`1 Month
`Day 27
`10
`13280‘
`(Wistar)
`60
`54120e
`400
`83910°
`
`60
`100
`400
`800
`10
`60
`400
`
`10
`60
`180
`
`10
`45
`200
`
`10
`60
`200
`
`10
`60
`200
`400
`
`10
`60
`400
`
`29427
`21221
`49951
`41649
`14900'
`29100e
`72200‘
`
`16070
`38604
`78863
`
`2565-14553
`11907-21669
`35629-74920
`
`NCZ-6882
`13370-25863
`13007-62645
`31384-91270
`
`4350-43200
`13100-1 19000
`683 00-1 79000
`
`5060-1 1100
`6750-7420
`209000230000
`
`2390-4160
`1 5300-33200
`13 1000— l 3 8000
`
`IND No.
`
`20962
`25010e
`743206
`159600e
`
`46354
`51802
`126171
`77182
`28200‘
`82900e
`190000e
`
`35899
`91 106
`152863
`
`~
`-
`-
`
`NC-6202
`1 1424-44885
`16983-5500]
`41786-129341
`
`4960-26900
`36600-98600
`44300-261000
`
`8792-68012
`39276-158317
`28936-109961
`-
`
`Rl8498-
`(Fisher)
`
`
`
`CTBR88779
`
`Day 90
`
`3 Months
`,
`
`_
`
`6 Months
`
`Day 168/169
`
`6 Months
`(carcinogenicity)
`
`Day 180
`
`Dog
`(beagle)
`
`D20863
`
`1 Month
`
`Day 28
`
`88270
`
`3 Months
`
`Day 91
`
`CTBR88632
`
`6 Months
`
`Day 176
`
`D21235
`
`6 Months
`
`Day 182/183
`
`
`
`D01899
`
`1 Year
`
`Day 364
`
`25
`8576-43136
`100
`12122-62109
`v
`400
`16900-77350
`Human ——— 7692
`'AUCmm), bAUCmswf-Aucmsm dAUCum. eAUCu-m.)
`
`PK/TK conclusions: Metabolism was the primary mechanism for clearance of 113351 fi'om the systemic
`circulation with similar routes of biotransformation in mice, rats, dogs and humans. The major route of
`excretion was via the feces in both rats and dogs, indicating incomplete oral absorption and biliary
`excretion of metabolites. Slight- to moderate increases in hepatic enzyme activity and/or CYP450 content
`were observed in mice, rats and dogs after oral doses of 2400 mg/kg, indicating 1C351 as a inducer of
`CYP450 isoenzymes.
`
`IV. TOXICOLOGY (see Reviews #1/2/3 for IND 54,553
`
`
`
`Study title: l-Year Oral Toxicity Study in Beagle Dogs
`
`Key study findings: Testicular degeneration/atrophy was observed with deceased sperm in the
`epididymides at all treatment groups with increased severity following 12 months. Neutropenia,
`thrombocytopenia and/or anemia were observed in the mid- and high dose females (US each
`group).
`
`Study no: D01899
`Conducting laboratory: Eli Lilly & Company, Greenfield, IN 46140
`Date of study initiation: June 19, 1999
`QA report: yes (x) no (
`)
`% purity: 100.1%
`Drug/lot #: 1C351 (LY450190)/991020
`Formulation/vehicle: Gelatin capsule/1%(w1v) carboxymethylcellulose sodium & 0.5% sodium lauryl sulfate in purified water
`
`Volume #, and page #: vol. 3]
`.
`GLP compliance: Yes
`
`3
`
`MonoSol 1019-0011
`
`MonoSol 1019-0011
`
`

`

`Reviewer:
`
`Dosing:
`
`1ND No.
`
`Species/strain: Beagle dog
`#lsex/group or time point (main study): 5/sex/group
`Satellite groups used for toxicokinetics or recovery: no recovery studied
`Weight: 9.0 to 12.9 kg for males & 7.3 to 9.9 kg for females
`
`Age: 14 to 15 months
`
`Doses in administered units: 0, 25, 100 & 400 mg/kg/day
`Route, form, volume, and infusion rate: Oral suspension of 0, 12.5, 50.0 & 200.0 mg/ml. in capsules
`Observations and times:
`
`lmflflflMflIIIIIIIIIIIII'Nmn
`More than once dail
`Twice dail
`--re-stu base/Once weekl
`
`rust-dose -hase
`
`M Pretreatment & terminal examination
`Scheduled necro n Da
`365 & 366
`Da -7/re-dose & 2 hrs est-dose on Da
`
`180 & 362
`
`
`
`Twice daily pre-st‘udy phase/Months l, 3, 6., 9 a 12 for fasted
`
`Months 5, 8, 10, ll & 12 for non-fasted
`
`0,1.2,4,8.12,16& 24 hrs on Days 0.33.177 & 364
`
`
`
`Results: Treatment was suspended for one 100- & one 400 mg/kg female dogs between Days 140 and
`166 & from Days 196 through the end of the study due to marked neutropenia (1,610/1,11. for 100 mg/kg
`& 3 lO/uL for 400 mg/kg compared to reference 3,300 to 11,600/uL) with moderate thrombocytopenia
`(90,000/uL for 100 mg/kg & 226,000/uL for 400 mg/kg compared to reference levels of 191,000 to
`442,000/uL), which was initially identified on Day 91. Severe neutropenia (170/uL), moderately
`decreased platelets (1] LOGO/111.), hyperglobulinemia, minimal anemia, minimal eosinopenia and IALP
`in the absence of clinical signs were present in the 100 mg/kg dog on Day 140. The other blood
`dyscrasias included minimal monocytopenia, lymphopenia & eosinopenia in both dogs, which the
`sponsor considered to be due to stress. Clinical signs of fever (105.4 °F), anorexia & lethargy followed by
`minimal neutropenia (2,930/uL), anemia, severe monocytosis & slight hyperglobulinemia compatible
`with inflammation occurred in the 400 mg/kg dog on Day 128. Abdominal radiographs taken on Days
`128 & 288 excluded an occult inflammatory focus or splenic enlargement. Antibiotic therapy was
`initiated on Day 128 due to signs of inflammation (Ibasophilia/Dohle bodies). After removal from
`antibiotics on Day 138, clinical signs returned to normal with severe neutropenia (ZOO/til.) & neutrophil
`alterations. The dog became febrile & developed neck pain/inappetence on Day 14] despite the
`reinstatement of antibiotic on Day 139. Additional aspirin & antibiotics were administered on Days 146
`through 154. Following drug removal (& antibiotic & supportive therapy in the 400 mg/kg) on Days 140
`(400 mg/kg) & 142 (100 mg/kg), dosing resumed on Days 161 (400 mg/kg) & 166 (100 mg/kg). Marked
`neutropenia (1,130/ttL for 100 mg/kg & l,210/p.L for 400 mg/kg) and/or minimal thrombocytopenia
`developed within 8 days in the 400 mg/kg or within 10 days in the 100 mg/kg dog. These dogs were
`clinically asymptomatic until Days 195 when the 400 mg/kg dog developed clinical signs of
`stiffiiess/neck pain/anorexia, neutrophilia (10,250/uL), monocytosis & hyperglobulinemia
`Discontinuation of 1C351 on Day 196 rerurrfed the neutrophil (Day 204 for 100 mg/kg & Dat 196 for 400
`mg/kg) and/or platelet counts (Day 208 for 100 mg/kg) within the reference interval & without clinical
`signs. Bone marrow aspirates and core biopsies from humerus taken from these 2 dogs on Day 196
`demonstrated no abnormalities but increased numbers of immature neutrophilic precursors and
`myeloid/megakaryocytic hyperplasia, which were less pronounced on Days 231 (100 mg/kg) or 285 (400
`mg/kg) and absent on Day 366. Sponsor considered the findings to be idiosyncratic and not a result of a
`direct compound—related effect on early neutrophi] precursors or on bone marrow. The high-dose female
`had a single focus of per-ivasculitis in the circumflex branch of the left coronary artery. The 100 rug/kg
`dog showed a pituitary neuroblastoma, which was considered to be spontaneous.
`
`Drug-related degeneration & atrophy of the seminiferous epithelium occurred in dogs at 225 mg/kg with
`decreases in testicular weight & gross fmdings of small/sofi testes. Degeneration. of the seminiferous
`
`4
`
`MonoSol 1019-0012
`
`MonoSol 1019-0012
`
`

`

`Reviewer:
`
`'
`
`l’ND No.
`
`epithelium was characterized by disassociation or vacuolation of seminiferous epithelium, mutinucleated
`cells, exfoliated germ cells, pyknotic sperrnatids, megalospermatids, attenuation or loss of cell layers,
`and/or increase in Leydig cells. Low numbers of tubules also had markedly enlarged cells of
`spermatogonia with abundant eosinophilic cytoplasm & round nuclei with rarefaction of the chromatin.
`Scattered tubules had individual cell necrosis of the mitotic spermatocytes and/or elongating sperrnatids.
`Atrophy of the seminiferous epithelium was characterized by seminiferous tubules lined by only Sertoli
`cells and/or spermatogonia. Degeneration and atrophy were more pronounced in the periphery of the
`affected testes. These testes were decreased overall in diameter with obliteration of the lumen or
`
`’
`
`attenuation of the epithelium with increased intraluminal space compared to controls Aspermia were
`also noted, which was considered secondary to decreased testicular sperm production.
`
`
`Dose,m
`
`E-idid
`ides wei-ht (_), absolute
`
`Testes, small
`
`
`Testicular seminifcrous epithelium
`
`Bilateral degeneration
`
`
`1 moderate
` 3 severe
`
`
`
`
`l marked
`
`1 minimal
`
`
`
`
`2 severe
`2 sli
`
`
`
`
`
`
`2 minimal
`
`
`
`Significantly different from control a! p50.05
`
`Bilateral atrophy
`
`
`Epididymis
`Bilateral asperrnia
`Bilateral multifocal e-ithelial vacuolation
`
`
`
`l minimal
`
`sli_ t
`
`2 2
`
`Table below summarizes the results for the rest of the animals except the 2 female dogs with marked
`, neutropenia. No drug-related arteritis lesions occurred in the present study, due perhaps to lower blood
`. drug levels or different dog colony .
`_,__..
`No drug-related mortality was observed.
`Abnormal feces were more fi'equently observed in all treated groups. There was dose-dependent decrease
`in mean body weight in females, which was observed by 6 weeks after study initiation, & maintained
`without additional changes. WBC parameters of reticulocytes, neutrophils and monocytes were decreased
`from mid dose. IC351 produced slight dose-dependent increases in CYP450 content in males with
`increased liver weight. Increased adrenal weight was observed with enlarged/mutifocal agonal
`hemorrhage a