CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022406Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`
`Xarelto (rivaroxaban)
`
`Date: June 30, 2011
`To:
`File for NDA #22-406
`From: John K. Leighton, PhD, DABT
`
`Associate Director for Pharmacology/Toxicology
`
`Office of Oncology Drug Products
`
`The pharmacology/toxicology review of Dr Chopra was examined previously and no
`additional pharmacology/toxicology studies were deemed necessary to support the
`proposed indication, and no additional nonclinical studies are needed to support the
`current approval. A labeling review was previously deferred.
`
`The pharmacology/toxicology information in the labeling is acceptable and supported by
`the studies submitted for review. The pharmacologic classification “factor Xa inhibitor”
`was chosen as it is pharmacologically valid and the terminology is consistent with other
`drugs in the class. Currently, there is no need or scientific justification to distinguish in
`pharmacologic classification, whether an inhibitor is “direct” or “indirect” in relation to
`factor Xa inhibitors, regardless of the pharmacologic mechanism of action. This
`approach is consistent with the FDA guidance: Labeling for Human Prescription Drug
`and Biological Products — Determining Established Pharmacologic Class for Use in the
`Highlights of Prescribing Information.
`
`
`Reference ID: 2968268
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN K LEIGHTON
`06/30/2011
`
`Reference ID: 2968268
`
`

`

`MEMORANDUM
`
`
`Xarelto (rivaroxaban)
`
`Date: May 12, 2009
`To:
`File for NDA #22-406
`From: John K. Leighton, PhD, DABT
`
`Associate Director for Pharmacology
`
`Office of Oncology Drug Products
`
`
` I
`
` have examined pharmacology/toxicology supporting review provided by Drs. Chopra
`and Laniyonu. I concur with their conclusions that Xarelto may be approved. No
`additional pharmacology or toxicology studies are necessary for the proposed indication.
`A review of the labeling will be deferred.
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`John Leighton
`5/12/2009 06:20:25 AM
`PHARMACOLOGIST
`
`

`

` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`
`INTENDED CLINICAL USE:
`
`
`SPONSOR:
`
`
`CONTACT PERSON:
`
`
`DOCUMENTS REVIEWED:
`
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`
`022-406
`
`000
`
`
`
`
`
`
`
`BAY 59-7939 (JNJ-39039039; Xarelto®/Rivaroxaban
`
`Micronized) Tablets
`
`For the Prevention of Venous Thromboembolism
`(VTE) and pulmonary embolism
`
`
`
`Johnson & Johnson Pharmaceutical
`Research & Development L.L.C., Raritan, NJ.
`
`Shelly Chandler, Johnson & Johnson
`Pharmaceutical; Phone (908) 704-4579
`
`
`
`Electronic submission (eCTD)
`
`Division of Medical Imaging and Hematology
`Drug Products (DMIHP)
`Yash M. Chopra, M.D.; Ph.D.
`
`PHARM/TOX SUPERVISOR:
`
`Adebayo Laniyonu, Ph.D.
`
`DIVISION DIRECTOR:
`
`Rafel D. Rieves, M.D.
`
`PROJECT MANAGER:
`
`Diane Leaman, D. Pharm.
`
`
`
`

`

`NDA 22-406
`Page 2 of 151
`
`Executive Summary
`
`I.
`
`A.
`
`
`NDA 22-406 is recommended for approval from P/T perspective.
`
`B.
`
`Recommendations
`
`Recommendation on approvability
`
`Recommendation for nonclinical studies
`None
`Recommendations on labeling
`
`C.
`
` A
`
` separate labeling review will be written.
`
`Summary of nonclinical findings
`
`Brief overview of nonclinical findings
`
`
`II.
`
`A.
`
`Pharmacologic activity
`
`BAY 59-7939 (Xarleto) a selective and competitive oral Factor Xa and thrombin
`generation inhibitor (Ki of 0.5 ± 0.02 nM; IC50 of 2.1 nM) acts by preventing the
`activation of prothrombin to thrombin. Reduction of thrombus formation was
`demonstrated in arteriovenous shunt model in rats/rabbits and, injury induced
`venous thrombus formation in rats. BAY 59-7939 did not show effects on the
`cardiovascular function, ECG, respiration, acid/base balance, hematocrit and
`electrolytes in anesthetized beagle dogs up to oral dose of 30 mg/kg. It showed
`no effects on pentylenetetrazol convulsions or hexobarbital-induced anesthesia in
`rodents. It did not exert effect on gastrointestinal motility, urine excretion or on
`the respiratory system.
`
`
`Absorption, Distribution, Metabolism and Excretion (ADME):
`
`Orally administered BAY 59-7939 was absorbed and showed an absolute oral
`bioavailability of about 60% in both rats and dogs. In rats, the T1/2 of the drug
`was 1.2 to 2.3 hours after oral and 0.9 hr after IV dose. The T1/2 of tagged
`compound was prolonged by 18.8 and 42.1 hrs by the IV and oral routes,
`respectively suggesting the tagging of the radioactivity with metabolite/s. In
`dogs, intravenously administered compound achieved dose related concentration.
`An IV dose of 0.3 and 3 mg/kg attained AUC of 1.0 and 6.03 mg.h/ml with
`similar half life of 0.95 hours. The protein binding was more than 90% and is
`variable among species. The labeled [14C]BAY 59-7939 was heterogeneously
`distributed in different organs and tissues without any specific tissues affinity.
`The compound is oxidized to morpholino moiety (M1) by CYP3A4 and M-1 was
`its major metabolite. In rat/human hepatocyte in vitro preparations, M-1 was
`
`

`

`NDA 22-406
`Page 3 of 151
`
`formed and was the major plasma metabolite and was excreted in the urine, bile,
`and feces of rats. Fecal route was the major route of excretion in rats. After an
`oral dose, 66.9% of the radioactivity was excreted in feces and 24.7% in the urine
`by day 7. About 0.2% of the administered radioactivity remained as unaccounted
`in the rat.
`
`Single dose Toxicity Study:
`
`Acute single oral dose of 500 mg/kg in mice and rats did not produce any effect in
`the animals and lethal/sublethal doses were not estimated. A single intravenous 25
`mg/kg dose in dogs produced CNS related effect of reduced activity, abdominal
`positioning, labored breathing, narrowed palpebral and piloerection.
`
`Repeat dose Toxicity Studies:
`
`a. Mouse: In a 4-week toxicity study in rats at the oral gavage doses of 0, 12.5, 50
`and 200 mg/kg/day (6/sex/group) there were no treatment related effects seen in
`the animals. The target organs of toxicity and the highest tolerated dose were not
`identified. Similar plasma concentrations in male and female mice were seen.
`
`BAY 59-7939 at oral gavage doses of 50, 100 and 200 mg/kg/day (PEG-6000
`co-precipitate) for 13 weeks produced linear non-dose proportional plasma
`concentrations. There were higher incidences of fibrosis of the heart,
`mononuclear cell infiltration in kidneys, hyperplastic spindle cells in adrenal
`and increased cellularity of marginal zones of the spleen in males and, high
`incidences of Kupffer cell foci in the liver and mononuclear cell infiltration in
`the kidneys in females of high dose group. The liver, adrenal, kidneys and
`spleen were the target organs of toxicity in both sexes. A 100 mg/kg/day dose
`was the MTD in the study. The plasma exposure was 20 and 29.5 times the
`exposure produced by the clinical dose in humans. In another 13-week toxicity
`study, CD-1 mice were fed 1250, 2500 and 5000 ppm of BAY 59-7939 in
`dietary admixture (10% PEG-6000 coprecipitate). The mean drug administered
`in diet was 237, 476 and 1007 mg/kg/day in males, and 237, 476 and 1007
`mg/kg/day in females. A dose dependent increase in coagulation time and,
`increased liver enzymes activities and incidences of focal renal tubular
`hypertrophy in males, and focal necrosis of liver in females were noted. The
`kidney and liver were the target organs of toxicity in males and females and
`5000 ppm in diet appears to be the MTD. The exposure levels (AUC0-24h) at
`study MTD were 31.3 and 43.0 mg.h/L in males and females, i.e., about 7 and
`10 times the human exposures of the clinical dose of 60 mg/day (30 mg b.i.d).
`
`b. Rat:
`
`BAY 59-7939 at intravenous doses from 0.0657 to 0.657 mg/kg/day for 14 days
`in rats produced a dose proportional plasma concentration. Foamy
`macrophages in lung parenchyma, swelling/vacuolation of proximal convoluted
`
`

`

`NDA 22-406
`Page 4 of 151
`
`renal tubules and, extramedullary hematopoiesis of spleen was reported in high
`dose group and high dose of 0.1971 mg/kg/day (1.183 mg/m2) was a ‘maximal
`tolerable dose’. Target organs of toxicity were lungs, kidneys and spleen.
`
`In 4-week oral gavage toxicity study conducted at doses of 0, 12.5, 50 and 200
`mg/kg/day, a 12% decrease in body weight of high dose males and, treatment-
`related increase in several liver enzyme activities in treated animals were noted.
`There were insignificant decrease in CD45total cells, slight increase in IgA levels
`females and IgG levels in males. High incidences of bilateral retinal atrophy,
`focal inflammation of the pancreas unilateral diffuse dilatation of the testes were
`suggestive of eyes, pancreas and testes as the target organs of toxicity. A dose
`between 50 and 200 mg/kg/day was the highest tolerable dose and will provide
`the plasma exposure of 68 to 162 multiples of human plasma concentration.
`
`Sponsor submitted three 13-week oral gavage toxicity studies and in the first 3-
`month study with 4 weeks of recovery, oral doses of 12.5, 50 and 200 mg/kg/day
`produced treatment- related increase of ALT and, decrease of GLDH and LDH
`enzymes significantly in high dose treatment group. These changes were not of
`clinical importance. The increased incidences of pigment deposition in the
`pancreas, mesenteric lymph node hemorrhage and focal retinal atrophy in the eye
`were seen in only males. Females of high dose group showed higher incidences of
`epicarditis, lung congestion and thymic hemorrhage. The high dose of 200
`mg/kg/day was considered as an MTD and drug induced adverse effects were not
`completely resolved in the recovery period. In the 13-week dietary study, BAY
`59-7939 was administered at the doses of 75 to 300 mg/kg/kg in diet containing
`0.5% of BAY 59-7939. A non-dose proportional plasma concentration and minor
`change of hyper pigmentation in periductal pancreatic islets was seen in males of
`the high dose group. The target organs of toxicity were not identified. CAC-Ex
`committee concluded that the proposed MFD in diet was not identified in the
`study and the maximum amount of the active compound was 0.5% and not 5% as
`required by ACH Guidelines 51C.
`
`The third 13-week oral gavage toxicity study in Wistar rat conducted with the
`micronized form at 0, 60, 300 and 1500 mg/kg/day BAY 59-7939 doses showed
`that there was dose-dependent increase in the coagulation time in rats and no
`treatment related effects in any of the treated group animals. The plasma
`concentrations were erratic and non-dose related. The target organs of toxicity
`and MTD were not identified in the study.
`
`Six-month chronic study was performed at oral doses of 12.5 to 200 mg/kg/day
`and treatment related increase in the plasma concentration of animals was seen
`within 60 minutes of the dosing. No other relevant data could be obtained as the
`histopathology report of the study animals was not included.
`
`c. Dogs:
`
`
`

`

`NDA 22-406
`Page 5 of 151
`
`BAY 59-7939 at 5 to 50 mg/kg/day for 4 weeks produced a treatment but non-
`dose proportional peak plasma concentrations in 1.5 to 3 hr. Alveolar
`macrophages and hemosiderin deposits in lymph node were produced in greater
`intensity in animals of 50 mg/kg/day group. The NOEL was 5 mg/kg/day and the
`highest tolerable dose was 15 mg/kg/day in the study and the target organs of
`toxicity were lungs and lymph nodes.
`
`In 4-week oral toxicity study, vomits containing white colored fluid/foam and
`discolored (green/bright) feces were seen in 150 mg/kg/day group. On study week
`2, a dose related increase of 141.7%, 46.2% and 63.6% in males and 100%, 120%
`and 290% in females in reticulocytes at 15, 50 and 150 mg/kg/day groups.
`Treatment related subcutaneous hemorrhage was present in 1, 3, 1 and 3 males
`and, 0, 3, 3 and 3 females of the treated groups. The hemorrhage and hematomas
`were observed at the venous puncture sites for blood pressure measurement sites.
`Extramedullary hematopoiesis in spleen of treated males and females of the study
`indicated that the target organ of toxicity was the spleen. The highest tolerated
`dose was 50 mg/kg/day.
`
`13-Week subchronic oral gavage toxicity study in dogs was conducted at 15 to
`150 mg/kg doses. White fluid/foam vomiting, discolored (green/bright) feces and
`subcutaneous hemorrhage in tissues and, extramedullary hematopoiesis in the
`spleen were reported in high dose group animals. A dose of 150 mg/kg/day was
`identified as the highest tolerated dose. In 52-week toxicity study in dogs, oral
`gavage doses of 0, 5, 25 and 50 mg/kg/day produced a treatment but non-dose
`proportional increase in plasma concentrations from 1.75 to 2.25 hr of
`administration in males and, 1 to 3 hr in females. The study did not include
`histopathology evaluation. The target organs of toxicity and NOAEL could not
`be identified and the study was not full and complete.
`
`Carcinogenicity Studies:
`
`The 104-week mouse and rat carcinogenicity studies were not required for the
`short term indication.
`
`Reproduction Toxicology:
`
`In segment I. Fertility and reproductive performance study, BAY-59-7939 from the oral
`doses of 12.5 to 200 mg/kg/day in male and female rats during the fertility and reproductive
`performance period produced a reduction in number of dams (90.5%) with viable fetuses and
`a slight increase in post implantation loss and a dose related reduction in ovarian weight by
`8.8% in the dams of the high dose group. It was embryo- and feto- toxic NOAEL was 50
`mg/kg/day. Based on body surface area (mg/mm3), it provides 41 times greater plasma
`exposure than the proposed clinical dose exposure.
`
`BAY 59-7939 from 10 to 120 mg/kg/day doses during organogenesis period of day 6 to 17
`postcoitum produced dose related increase in rat plasma concentrations and was not
`
`

`

`NDA 22-406
`Page 6 of 151
`
`teratogenic in rats. Based on body surface exposure (mg/mm3), the highest dose provides 97
`times greater exposure than the proposed clinical dose. BAY 59-7939 in pregnant rabbits
`during organogenesis produced a linear increase in plasma within 0.5 to 2 h of administration
`and was not teratogenic. Systemic maternal NOEL and intrauterine development safe dose
`was 2.5 mg/kg/day in the study and provides 4 times greater exposure in the study animals.
`
`In prenatal and post- natal toxicity study in pregnant rats, BAY 59-7939
`Coprecipitate 10 % 100 at oral gavage doses of 2.5 to 40 mg/kg/day in pregnant
`female produced generalized tissue bleeding and still births. The dose related
`increase incidences of empty stomach, no detectable milk spots in stomach and
`intestines indicating delayed/abnormal sucking reflex in the pups born to 10 and 40
`mg/kg/day treated dams was reported. The other postnatal common adverse effects
`in pups were hypoactivity, pale skin, cold to touch surface. The NOAEL for dams
`(FO) and, pre- and postnatal development of the F1 generation was 10 mg/kg/day
`and based on body surface area it was 8 times the exposures of the proposed human
`dose.
`
`Mutagenicity:
`
`BAY 59-7939 was not mutagenic in Ames test, chromosome aberrations assay
`in V79 Chinese hamster lung cells and the mouse bone marrow micronucleus
`induction test by the intraperitoneal route.
`
`
`B.
`
`None.
`
`
`Nonclinical safety issues relevant to clinical use
`
`
`
`

`

`NDA 22-406
`Page 7 of 151
`
`
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`2.6.1 INTRODUCTION AND DRUG HISTORY
`
`NDA number: 22-406
`Review number: 001
`Sequence number/date/type of submission: 000/July 22, 2008/Original
`Information to sponsor: Yes ( ) No (X)
`Manufacturer for drug substance: Johnson & Johnson Pharmaceutical Research &
`
`Development L.L.C., Raritan, NJ.
`
`Reviewer name: Yash M. Chopra, M.D.; Ph.D.
`
`
`
`
`
`
`
`Division name: Division of Medical Imaging & Hematology Drug Products
`
`
`
`
`HFD #: 160
`Review completion date: May 11, 2009
`
`Drug:
`Trade name: Xarelto® Tablets
`
`Generic/Code name: Rivaroxaban micronized/BAY 59-7939/JNJ-9039039
`
`
`Chemical name: 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-
`1, 3-oxazolidin-5-yl) methyl)-2-thiophenecarboxamide. BAY 59-7939 is a pure S-
`enantiomer.
`
`CAS registry number: 496775-62-3.
`
`Molecular formula/molecular weight: C19H18ClN3O5S/435.89.
`
`
`
`Structure:
`
`Drug Class: Factor Xa Inhibitor/Antithrombotic Agent
`Indication: For the Prevention of Venous Thromboembolism (VTE) and
`pulmonary embolism.
`
`
`
`
`

`

`NDA 22-406
`Page 8 of 151
`
`Clinical formulation (and components): Each film-coated tablet contains
` BAY 59-7939. In addition to the active ingredient, each tablet
`contains the following inactive ingredients: microcrystalline cellulose,
`croscarmellose, lactose monohydrate, hypromellose, sodium lauryl sulfate,
`purified water, magnesium stearate,
` and titanium oxide.
`
`Relevant INDs/NDAs/DMFs: IND 64,892
`
`Intended clinical population: For the prevention of recurrent venous
`thromboembolic events (VTE) and pulmonary embolism in patients undergoing
`hip replacement surgery or knee replacement surgery.
`
`Route of administration: Oral
`Recommended Dose: The recommended dose of XARELTO™ is 10 mg (0.2
`mg/kg) taken orally once daily taken at least 6 to 10 hours after surgery once
`hemostasis has been established.
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer
`unless cited otherwise.
`
`Studies reviewed within this submission:
`
`
`PRECLINICAL STUDIES AND TESTING LABORATORIES
`
`Review Page#
`Drug Batch #
` Study #
` Type of Study
`13
` --
` --
`I. Pharmacology
`13
`
`
`1. Primary Pharmacology
`20
`
`
`2. Safety Pharmacology
`20
`
`
`a. Cardiovascular
`20
`
`
`b. Respiratory
`20
`
`
`c. CNS
`21
`
`
`d. Renal
`21
`
`
`e. GI
`22
`
`
`3. Drug Interaction
`II. ABSORPTION, DISTRIBUTION, METABILISM AND EXCRETION. 23
`1. PK of a single IV or PO dose
`PH-32007 V3
`-
`23
`unlabeled BAY 59-7939 to rats:
`
`2. PK of a single IV or PO
`dose unlabeled BAY 59-7939
`to fasted female dog
`3. Qualitative tissue distribution
`of the radioactivity in Wistar rats
`after IV or oral doses
`4. Protein Binding and
`Distribution into Blood Cells
`5. Metabolism & Excretion of
`[14C]BAY 59-7939 in Wistar
`rat Plasma, Urine, and Bile
`
`PH-33250/#31990/I
`6001555
`
`I300149/PH-32339
`
`PH-32966
`
`PH 3461600/1 3001444
`
`
`
`#507018
`
`25
`
`-
`
`-
`
`-
`
`26
`
`26
`
`27
`
`(b) (4)
`
`(b) (4)
`
`

`

`PH-34783
`
`Rat:
`#PH32076)
`Dog:
`33250
`
`#PH-488872
`
`-
`
`-
`
`-
`
`-
`
`-
`
`#010507.
`3010507.
`
`
`
`NDA 22-406
`Page 9 of 151
`
`after Oral, Intraduodenal and
`Intravenous Dose
`6. In Vitro Metabolism &
`Excretion of BAY-59-7939 in
`Liver Microsomes of Rhesus
`Monkey, Beagle Dog, New
`Zealand Rabbit, Wistar Rat,
`NMRI mouse and Man
`7. Excretion of Orally or
`Intravenously administered
`[3H]BAY 59-7939 in Rats and
`Dogs:
`
`8. Placental Transfer in Rats
`Following Single Dose
`Administration
`9. Identification of Human CYP
`Isoforms Involved in the In Vitro
`Metabolism of BAY 59-7939.
`
`III. TOXICOLOGY
`Acute Toxicity Studies:
`Oral:
`T 0070940
`a. Mouse
`T 1070941
`b. Rat
`
`IV:
`T 5070936
`Mouse
`SUBACUTE, SUBCHRONIC AND CHRONIC TOXICITY STUDIES:
`MOUSE (CD-1):
`4-Week Oral Gavage)
`Toxicity Study
`Thirteen (13)-Week Oral
`(gavage) Toxicity study of
`BAY 59-7939 in Mice
`
`Thirteen (13)-Week Oral
`(Dietary) Toxicity study of
`BAY 59-7939 in Mice
`Subchronic Oral Toxicity Study in
`CD-1 Mice (13 Weeks
`Administration by Gavage)
`RATS:
`Subacute 2-Week Intravenous
`Toxicity study in Wistar rats
`
`Four-Week Oral Toxicity
`Study with BAY 59-7939 in
`Rats
`Three (3)-Month Oral (Gavage)
`Toxicity study of BAY 59-7939
`in Rats with a 4-Week Recovery
`Period
`Thirteen (13)-Week Oral (Dietary)
`Toxicity study of BAY 59-7939 in
`
`T7072792/ PH-33755
`
`0850001
`
`#T8074494
`
`T1073975
`
`
`PEG 6000 co-precipitate
`10% 100; Batch no.
`031212-100
`
`040526-100.
`
`Study No.: T6075725
`
`
`
`
`#T2073138/PH-34189
`
`
`0850001
`
`T 7070622
`
`
`T7072116
`
`507 047
`
`J20020703
`
`T8074601/PH-34553
`
`BAY 59-7939 (031212-
`100), PEG 6000 co-
`
`31
`
`33
`
`
`33
`
`34
`
`35
`
`37
`37
`
`37
`
`39
`
`42
`
`46
`
`50
`
`
`54
`
`58
`
`63
`
`69
`
`

`

`NDA 22-406
`Page 10 of 151
`
`Rats
`
`Thirteen (13)-Week Oral Gavage
`Toxicity study of BAY 59-7939
`in Rats
`6-Month Chronic Toxicity
`Study in Rats
`
`T4075697
`
`DOGS
`Four-Week Oral Toxicity
`Study With BAY 59-7939 in
`Dogs
`Study Title: 13-Week Subchronic
`Oral Gavage Toxicity Study With
`BAY 59-7939 in Dogs
`52-Week Chronic Oral
`Gavage Toxicity Study in
`Dogs
`III. MUTAGENICITY:
`1.Ames Test in Salmonella
`Typhimurium and Escherichia
`Coli
`2. Study title: Salmonella
`Microsome Test Plate
`Incorporation and
`Reincubation Method
`3. Bacterial Reverse Mutation
`Assay of Anilino-morpholinone (a
`by product of BAY 59-7939 co-
`precipitate)
`4. In Vitro Chromosomal
`Aberration Test with Chinese
`Hamster V79 Cells
`5. In Vitro Chromosome
`Aberration Assay with BAY
`59-7939 in V79 Chinese
`Hamster Lung (CHL) Cells.
`(Study #PH31536/T
`6. In Vivo Micronucleus Test
`3070547)
`in the Mouse Bone Marrow.
`CARCINOGENICITY STUDIES:
`No study submitted
`
`REPRODUCTIVE TOXICITY:
`Study of Fertility and Early
`Embryonic Development in Rats
`after Oral Administration
`Study title: Developmental
`Toxicity Study in Rats after
`Oral Administration
`Study title: BAY 59-7939
`Developmental Toxicity Study in
`Rabbits
`after Oral Administration
`Study for Effects on Pre- and
`Postnatal Development in Rats
`Including Maternal Function after
`
`Study no: T0073127/PH-
`33611/TO0731 27
`
`
`#T 7070631
`
`#AT00861/PH-33056/T
`9072703 T 7070631
`
`T4073149/AT02684/#P
`H-34235
`
`
`T 1070545
`
`
`(Study #: AT01556 /T
`1070545/PH31770)
`
`
`T 1076143/PH-34344
`
`
`Study No.: T 0073244/
`AT02611/PH34198
`
`Study no: T
`2070546/PH31537
`
`
`#T2062789; T2062789/AT0
`33273
`
`#T3063590/PH-33582)
`
`
`# TO062930/PH-
`33380/AT01303)
`
`T9062957/PH34608
`
`precipitate 10% 100;
`Batch no. 040526-100
`#Bx01UNC
`
`Batch #030618
`
`
`507 046
`
`#200303 14, 9.4 %
`
`#030723-100, (a co-
`precipitate 9.2%; purity
`not defined)
`
`Batch No. 010621
`
`Batch No. 010621
`
`BXR387U (Sample BGQ
`0210-85 rein)
`
`Batch No. BX01SFS
`
`Batch No. 010621
`
`
`
`Batch No. 010621
`
`
`
`#J20020528; coprecipitate;
`batch #F033082
`
`# J20020528; Coprecipitate
`10%, 101
`
`#J20020430
`
` #030723-100 BAY 59-7939
`Coprecipitate 10 % 100
`
`
`76
`
`82
`
`
`
`87
`
`91
`
`96
`
`
`101
`
`102
`
`105
`
`106
`
`109
`
`113
`
`115
`
`116
`
`119
`
`124
`
`128
`
`

`

`NDA 22-406
`Page 11 of 151
`
`Oral Administration
`SPECIAL TOXICOLOGY:
`BAY 59-7939 Nanosuspension
`2% (w/v) (IFT 163
`Nanosuspension 2% (w/v)
`Subacute Toxicity Study in
`Wistar Rats (2 Weeks
`Administration by Intravenous
`Administration)
`Local Tolerability Study in
`Beagle Dogs After Paravasal,
`Intravenous and lntra-arterial
`Injections.
`3. In vitro 3T3 NRU (neutral red
`uptake) phototoxicity assay
`
`
`#T7076284/PH34646
`
`Nanosuspension 2%
`(w/v)/[IFT 163
`Nanosuspension 2% (w/v)];
`batch # - BXOlGFL
`
`#. T4073400/ AT01346/PH3
`
`
`
`#BXOlNB2
`
`#T9075016/AT02074/ PH-
`33880
`
`
`
`#BXOlNB2
`
`136
`
`141
`
`144
`
`

`

`NDA 22-406
`Page 12 of 151
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION AND DRUG ISTORY……………………………………………….7
`
`2.6
`
`2.6.1
`
`2.6.2
`
`2.6.2.1 PHARMACOLOGY………………………………………………..……………….…...13
`
`BRIEF SUMMARY
`
`
`
`
`
`
`
`
`
`
`2.6.2.2
`
`TABLE OF CONTENTS………………………………………………………………….8
`
`PHARMACOLOGY/TOXICOLOGY REVIEW……………………….………….......13
`
`
`
` PRIMARY PHARMACODYNAMICS…………………………..………….…….....13
`
`2.6.2.4
`
`SAFETY PHARMACOLOGY.....................................................................................20
`
`2.6.2.5
`
`PHARMACODYNAMIC DRUG INTERACTIONS .................................................22
`
`2.6.4
`
`PHARMACOKINETICS/TOXICOKINETICS .........................................................23
`
`2.6.4.1
`
`ABSORPTION ...............................................................................................................23
`
`2.6.4.2
`
`DISTRIBUTION............................................................................................................26
`
`2.6.4.3 METABOLISM..............................................................................................................27
`
`2.6.4.4
`
`EXCRETION .................................................................................................................33
`
`2.6.4.5
`
`DISCUSSION AND CONCLUSIONS .........................................................................37
`
`2.6.6
`
`TOXICOLOGY..............................................................................................................37
`
`2.6.6.1
`
`SINGLE-DOSE TOXICITY.........................................................................................37
`
`2.6.6.2
`
`REPEAT-DOSE TOXICITY........................................................................................39
`
`2.6.6.3 GENETIC TOXICOLOGY ........................................................................................101
`
`2.6.6.4
`
`CARCINOGENICITY ................................................................................................115
`
`2.6.6.5
`
`2.6.6.6
`
`REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ..........................116
`
`SPECIAL TOXICOLOGY…………………………………………………………...136
`
`2.6.6.7
`
`LABEL..........................................................................................................................145
`
`2.6.7
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS................................145
`
`APPENDIX/ATTACHMENTS ....................................................................................................151
`
`

`

`NDA 22-406
`Page 13 of 151
`
`2.6.2 PHARMACOLOGY & TOXICOLOGY REVIEW
`
`2.6.2.1 BRIEF SUMMARY
`
`Disclaimer: Some of the Tabular and Graphical information from the sponsor’s
`submissions are incorporated in the review.
`
`Introduction and drug history: BAY 59-7939 a new molecular entity, is an oral
`bioavailabe selective and competitive inhibitor of Factor Xa and will be used for
`the treatment and prevention of arterial and venous thromboembolism. Activation
`of Factor Xa plays a central role in the cascade of blood coagulation. Factor Xa
`directly converts prothrombin (Factor II) to thrombin (Factor IIA) and the
`catalytically active thrombin then activates platelets. The hydrolysis of fibrinogen
`to fibrin leads to clot formation and thromboembolism. The inhibition of Factor
`Xa by BAY 59-7939 blocks the generation of thrombin and prevents the
`formation of venous thromboembolism.
`
`PHARMACOLOGY:
`
`Mechanism of Action:
`BAY 59-7939 acts by preventing the activation of prothrombin to thrombin via
`the inhibition of activated factor X (FXa).
`
`Drug Activity Related to Proposed Indication (Primary Pharmacology)
`
`In Vitro Studies
`
`Inhibitory Effects of BAY 59-7939 in Enzyme Assays:
`The inhibitory effects of BAY 59-7939 on free Factor Xa and other serine
`proteases were determined using chromogenic substrates. BAY 59-7939 caused
`concentration-dependent inhibition of human FXa with a Ki of 0.4±0.02 nM. The
`Lineweaver-Burk analysis suggested it to be a competitive inhibitor of FXa. It did
`not cause inhibition of other serine proteases, such as thrombin, Factor X1,
`plasmin, urokinase or activated protein C at concentrations up to 69 µM. The only
`serine protease affected by BAY 59-7939 was trypsin which was inhibited by
`25% at 69 µM. BAY 59-3979 exhibited a ~10,000-fold lower affinity for trypsin
`as compared with FXa.
`
`The inhibitory effect of BAY 59-7939 on FXa was also shown by measuring the
`inhibition of prothrombin-bound FXa in a reconstituted prothrombinase complex
`and measuring the generation of thrombin. BAY 59-7939 inhibited thrombin
`generation with an IC50 value of 2.1±0.4 nM. The inhibitory effect of BAY 59-
`7939 on unbound and prothrombinase-bound human FXa is shown below taken
`from sponsor’s submission.
`
`
`

`

`NDA 22-406
`Page 14 of 151
`
`
`
`
`The inhibition of endogenous factor Xa activity in plasma was measured by
`converting FX to FXa by Russel’s Viper Venom. The IC50s for the BAY 59-7939
`inhibition of the human and rabbit FXa activity were similar (21±1 and 21±2 nM,
`respectively); in the rat plasma, a 15-fold higher concentration was needed to
`inhibit endogenous FXa (IC50 = 290±18 nM).
`
`Activity of compound BR-4276 (BAY 59-7939) in Enzyme Assay (PT#
`1027604).
`
`The effect of BAY 59-7939 on various in vitro enzyme biochemical assays was
`determined. Significant results are displayed in the following table.
`
`
`
`
`Anticoagulant Activity:
`
`Platelet aggregation:
`The effect of orally administered BAY 59-7939 was studied on platelet aggregation.
`Bay 59-7939 did not affect the human rich plasma platelet aggregation induced by
`collagen, U46619, ADP or thrombin receptor activated peptide (TRAP-6), at
`
`
`
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`NDA 22-406
`Page 15 of 151
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`concentrations up to 200 µM. There was some inhibition of gamma thrombin-
`mediated platelet aggregation by BAY 59-7939 with an IC50 of 81 µM.
`
`Radioligand Binding assays of compound BR-4093 (BAY 59-7939): (PT#
`1009442).
`
`The available data of the binding of BAY 59-7939 with various receptors was
`consolidated. IC50 values were determined by a non-linear, least squares
`
`regression analysis using Data Analysis Toolbox™
`. The historical values for the Kd of the ligand (obtained
`) were used.
`experimentally
`BAY 59-7939 was found not to produce a significance binding with the selected
`substrates. The binding data is presented in the following table.
`
`
`
`
`
`In vivo studies:
`
`Antithrombotic Activity in an Arteriovenous Shunt Model in Rats:
`The antithrombotic activity of BAY 59-7939 was investigated in an arterio-
`venous shunt rat model in which the right common carotid artery and the left
`jugular vein were connected to affect shunt. The extracorporeal circulation was
`opened for 15 minutes, and the formed thrombus was weighed. BAY 59-7939 was
`administered orally 90 min before damage. Enoxaparin, a reference standard, was
`administered subcutaneously 60 min before damage.
`Treatment with oral doses of BAY 59-7939 produced a dose-dependent decrease
`in thrombus weight with an ED50 value of 5.0 mg/kg (SC). The inhibition of
`thrombus formation was 41%, 51% and 73% by 3.0, 6.0 and 10 mg/kg BAY 59-
`7939 doses, respectively. At oral doses of 3-6 mg/kg in rats, the FXa activity and
`the concentration of TAT (antithrombin III/thrombin complex) were both reduced
`by 60-80% and the PT was prolonged by 2.4-3.7 fold; in contrast, the aPTT was
`prolonged by <1.5-fold. Thus Bay 59-7939 produced prolongation of PT and
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`NDA 22-406
`Page 16 of 151
`
`APTT, and anti-FXa activity and TAT in the arterio-venous shunt model in rats as
`shown in the table.
`
`
`
`Enoxaparin also affected these parameters and ED50 was 21 mg/kg for TAT
`inhibition in the test.
`
`Effect on Thrombus Formation in Injury-Induced Arterial and Venous
`Thrombosis in Rats:
`The antithrombotic activity of BAY 59-7939 was determined in rats with
`mechanically damaged carotid artery and the jugular vein. Thrombus
`development was induced by chilling the vessels, and after 4 hours the thrombi
`were removed and weighed. BAY 59-7939 was administered orally 90 minutes
`before damage, whereas enoxaparin (reference standar