CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202570Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`
`
`
`
`202570
`Application number:
`0000
`Supporting document/s:
`March 30, 2011
`Applicant’s letter date:
`March 30, 2011
`CDER stamp date:
`Xalkori® (Crizotinib)
`Product:
`ALK-positive non-small cell lung cancer
`Indication:
`Pfizer Inc
`Applicant:
`Division of Drug Oncology Products (HFD-150)
`Review Division:
`Brenda J. Gehrke, Ph.D.
`Reviewer:
`Acting Team Leader: Whitney S. Helms, Ph.D.
`Division Director:
`Robert Justice, M.D.
`Project Manager:
`CDR Diane Hanner
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202570 are owned by Pfizer Inc or are data for
`which Pfizer Inc has obtained a written right of reference. Any information or
`data necessary for approval of NDA 202570 that Pfizer Inc does not own or have
`a written right to reference constitutes one of the following: (1) published
`literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously
`approved application is for descriptive purposes only and is not relied upon for
`approval of 202570.
`
`
`Reference ID: 3005407
`
`

`

`Justification:
`
`
`No change was made to the pharmacologic
`class in the indication statement.
`
`The pregnancy category was changed
`to D, therefore, a Pregnancy section was
`added to Warnings and Precautions.
`
`
`
`
`
`
`The pregnancy category was changed
`to D, therefore, a Pregnancy section was
`added to Warnings and Precautions.
`
`Standard language and formatting for
`pregnancy category D outlined in the CFR
`were used to comply with PLR regulations.
`The phrase” based on its mechanism of action”
`was added to indicate that the statement is
`based on the mechanism of action and not
`human data.
`
`The sentence, “In nonclinical studies in rats
`crizotinib was embryotoxic and fetotoxic at
`exposures similar to and above those
`observed in humans at the recommended
`clinical dose of 250 mg twice daily” was added
`to briefly describe the animal data.
`
`Labeling Review for Xalkori ® (Crizotinib) capsules (NDA 202750):
`
`
`The Sponsor Proposes:
`
`Indications and Usage
`TRADENAME is a kinase inhibitor indicated for
`the treatment of:
`
`
`Warnings and Precautions
`
`
`
`
`
`Reference ID: 3005407
`
`We recommend:
`Highlights:
`Indications and Usage
`XALKORI is a kinase inhibitor indicated for the
`treatment of patients with locally advanced or
`metastatic non-small cell lung cancer (NSCLC)
`that is anaplastic lymphoma kinase (ALK)-
`positive as detected by an FDA-approved test.
`(1)
`
`Warnings and Precautions
`
` •
`
`fetal
` Pregnancy: XALKORI can cause
`harm when administered to a pregnant
`woman. (5.5, 8.1)
`5. Warnings and Precautions
`5.5 Pregnancy
`XALKORI can cause fetal harm when
`administered to a pregnant woman based on
`its mechanism of action. In nonclinical studies
`in rats crizotinib was embryotoxic and fetotoxic
`at exposures similar to and above those
`observed in humans at the recommended
`clinical dose of 250 mg twice daily. There are
`no adequate and well-controlled studies in
`pregnant women using XALKORI. If this drug
`is used during pregnancy, or if the patient
`becomes pregnant while taking this drug, the
`patient should be apprised of the potential
`hazard to a fetus. [see Use in Specific
`Populations (8.1)].
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The Sponsor Proposes:
`
`8.1 Pregnancy
`
`
`
`Reference ID: 3005407
`
`We recommend:
`8. Use in Specific Populations
`8.1 Pregnancy
`Pregnancy Category D [see “Warnings and
`Precautions” (5.5)]
`XALKORI can cause fetal harm when
`administered to a pregnant woman based on
`its mechanism of action. There are no
`adequate and well-controlled studies of
`XALKORI in pregnant women. In nonclinical
`studies in rats, crizotinib was embryotoxic and
`fetotoxic at exposures similar to and above
`those observed in humans at the
`recommended clinical dose of 250 mg twice
`daily. Crizotinib was administered to pregnant
`rats and rabbits during organogenesis to study
`the effects on embryo-fetal development.
`Postimplantation loss was increased at doses
`≥ 50 mg/kg/day (approximately 1.2 times the
`AUC at the recommended human dose) in
`rats. No teratogenic effects were observed in
`rats at doses up to the maternally toxic dose of
`200 mg/kg/day (approximately 5 times the
`AUC at the recommended human dose) or in
`rabbits at doses of up to 60 mg/kg/day
`(approximately 3 times the AUC at the
`recommended human dose), though fetal body
`weights were reduced at these doses.
`
`Women of childbearing potential should be
`advised to avoid becoming pregnant while
`receiving XALKORI. Women of childbearing
`potential who are receiving this drug, or
`partners of women of childbearing potential
`receiving this drug, should use adequate
`contraceptive methods during therapy and for
`
`Justification:
`
`
`The pregnancy category was changed
`to D. Pregnancy Category D was considered
`appropriate for this drug for the following
`reasons:
`• Positive findings of post-implantation loss
`and low fetal weight in animals at
`exposures similar to the clinical
`exposure—based on an ODAC discussion
`in which it was agreed that based on
`mechanism of action (targeting rapidly
`dividing cells and targets that are
`important in embryogenesis) that Category
`D was appropriate for many cancer drugs
`despite the lack of human data.
`• The importance of ALK in neural
`development which would not be reflected
`well in the embryo-fetal development
`studies—while embryo-fetal studies are
`the only reproductive toxicology studies
`required for a drug in this patient
`population, pregnancy categories are
`based on an assumption of the full battery
`of reproductive toxicology studies being
`performed
`
`
`Language from the Warnings section was
`repeated based on recommendations from the
`Maternal Health Team.
`
`Additional details of the animal studies
`conducted and results were added, including
`doses of crizotinib and the finding of
`postimplantation loss in rats, in order to
`communicate all relevant findings.
`
`(b) (4)
`
`(b) (4)
`
`

`

`The Sponsor Proposes:
`
`We recommend:
`at least 90 days after completing therapy. If
`this drug is used during pregnancy, or if the
`patient or their partner becomes pregnant
`while taking this drug, the patient should be
`apprised of the potential hazard to a fetus.
`
`8.2 Nursing Mothers
`
`8.3 Nursing Mothers
`It is not known whether XALKORI is excreted
`in human milk. Because many drugs are
`excreted in human milk and because of the
`potential for serious adverse reactions in
`nursing infants from XALKORI, a decision
`should be made whether to discontinue
`nursing or to discontinue the drug, taking into
`account the importance of the drug to the
`mother.
`
`8.3 Pediatric Use
`The safety and efficacy of TRADENAME in
`pediatric patients has not been established.
`Decreased bone formation in growing long
`bones was observed in immature rats at 150
`mg/kg/day following once daily dosing for 28
`days (approximately
`times
`
` AUC). Other toxicities of
`potential concern to pediatric patients have not
`been evaluated in juvenile animals.
`
`8.4 Pediatric Use
`The safety and efficacy of XALKORI in
`pediatric patients has not been established.
`Decreased bone formation in growing long
`bones was observed in immature rats at 150
`mg/kg/day following once daily dosing for 28
`days (approximately 10 times the AUC in adult
`patients at the recommended human dose).
`Other toxicities of potential concern to pediatric
`patients have not been evaluated in juvenile
`animals.
`
`Justification:
`
`
`The statement on adequate contraceptive
`methods was expanded to include partners of
`women of childbearing potential as an
`additional precaution to take into account the
`finding of a miscarriage in 1 of 2 reported
`pregnancies in partners of patients receiving
`crizotinib in clinical trials. While these reports
`were not considered definitive evidence, the
`team concluded that extra caution might be
`warranted.
`Standard language and formatting outlined in
`the CFR were used to comply with PLR
`regulations
`
`The cross-reference to section 13.1 was
`removed since it is not necessary.
`
`
`As the findings in bone were observed only in
`male rats, the comparison should be based on
`the AUC value for the male rats alone. Male
`rats had a higher exposure than females. This
`statement also clarifies that the AUC data used
`for the comparison was from adult patients.
`
`Reference ID: 3005407
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`The Sponsor Proposes:
`
`12.1 Mechanism of Action
`
`We recommend:
`12. Clinical Pharmacology
`12.1 Mechanism of Action
`Crizotinib is an inhibitor of receptor tyrosine
`kinases including ALK, Hepatocyte Growth
`Factor Receptor (HGFR, c-Met), and
`Recepteur d’Origine Nantais (RON).
`Translocations can affect the ALK gene
`resulting in the expression of oncogenic fusion
`proteins. The formation of ALK fusion proteins
`results in activation and dysregulation of the
`gene’s expression and signaling which can
`contribute to increased cell proliferation and
`survival in tumors expressing these proteins.
`Crizotinib demonstrated concentration-
`dependent inhibition of ALK and c-Met
`phosphorylation in cell-based assays using
`tumor cell lines and demonstrated antitumor
`activity in mice bearing tumor xenografts that
`expressed EML4- or NPM-ALK fusion proteins
`or c-Met.
`
`
`
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`Carcinogenicity studies with crizotinib have not
`
`13. Nonclinical Toxicology
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`Carcinogenicity studies with crizotinib have not
`
`Reference ID: 3005407
`
`Justification:
`
` was removed since
`The word
`crizotinib inhibits multiple tyrosine kinases, and
` was removed because it was
`considered unnecessary by the review team.
`
`The first two sentences were combined and
`Recepteur d’Origine Nantais (RON) was added
`to the list of kinases inhibited.
`
`The sentences on translocations of the ALK
`gene and the formation of fusion proteins were
`added to provide context for why testing is
`important and to explain the mechanism of
`crizotinib in the indicated patient population.
`
`“Crizotinib demonstrated concentration-
`dependent inhibition of ALK and c-Met
`phosphorylation in cell-based assays using
`tumor cell lines and demonstrated antitumor
`activity in mice bearing tumor xenografts that
`expressed EML4- or NPM-ALK fusion proteins
`or c-Met.” This sentence mentions both the in
`vitro and in vivo activity of crizotinib without
`unnecessary details that could have been used
`promotionally.
`
`“or c-Met” was added to the tumor xenograft
`findings statement to indicate that the drug
`was studied and had activity in c-Met xenograft
`models as well.
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`The Sponsor Proposes:
`.
`
`been
`
`We recommend:
`been conducted.
`
`Crizotinib was genotoxic in an in vitro
`micronucleus assay in Chinese Hamster Ovary
`cultures, in an in vitro human lymphocyte
`chromosome aberration assay, and in in vivo
`rat bone marrow micronucleus assays.
`Crizotinib was not mutagenic in vitro in the
`bacterial reverse mutation (Ames) assay.
`
`No specific studies with crizotinib have been
`conducted in animals to evaluate the effect on
`fertility; however, crizotinib is considered to
`have the potential to impair reproductive
`function and fertility in humans based on
`findings in repeat-dose toxicity studies in the
`rat. Findings observed in the male reproductive
`tract included testicular pachytene
`spermatocyte degeneration in rats given
`greater than or equal to 50 mg/kg/day for 28
`days (greater than 3 times the AUC at the
`recommended human dose). Findings
`observed in the female reproductive tract
`included single-cell necrosis of ovarian follicles
`of a rat given 500 mg/kg/day (approximately 10
`times the recommended human daily dose on
`a mg/m2 basis) for 3 days.
`
`17. Patient Counseling Information
`
`Reference ID: 3005407
`
`Justification:
`
`
`
`Crizotinib was positive in 3 assays
`investigating genotoxicity and should,
`therefore, be described as genotoxic. The
`positive findings were listed first.followed by
`the statement that crizotinib is not mutagenic..
`
`During the labeling revisions, the sponsor
`wanted to add additional information on the
`results of the studies in order to explain or
`minimize the findings. These changes were
`rejected in order to simply state that crizotinib
`is genotoxic.
`
`
`
` was changed to “(greater than
`3 times the AUC at the recommended human
`dose)”. The margin of 3 times was used
`instead of
` based on the AUC in males at
`the 50 mg/kg/day dose on study day 26.
`
`“(approximately 10 times the recommended
`human daily dose on a mg/m2 basis)” was
`added to compare the dose in rats to the
`human dose. The margin was based on the
`recommended human daily dose on a mg/m2
`basis because there were no PK data for the
`500 mg/kg/day dose.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`We recommend:
`17.6 Pregnancy and Nursing
`Patients of childbearing potential must be told
`to use adequate contraceptive methods during
`therapy and for at least 90 days after
`completing therapy.
`
`
`
`
` Patients should also be advised not
`to breastfeed while taking XALKORI.
`
`Justification:
`This section was added at the request of
`DMEPA to add discussion on avoiding
`pregnancy while on the product, based on the
`information in section 8.1. The last two
`sentences were proposed by the sponsor and
`were acceptable to the team.
`
`
`
`The Sponsor Proposes:
`
`
`
`
`
`
`Reference ID: 3005407
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BRENDA J GEHRKE
`08/24/2011
`
`WHITNEY S HELMS
`08/25/2011
`
`Reference ID: 3005407
`
`

`

`MEMORANDUM
`
`
`Crizotinib (Xalkori)
`
`Date: August 11, 2011
`To:
`File for NDA 202570
`From: John K. Leighton, PhD, DABT
`
`Associate Director for Pharmacology/Toxicology
`
`Office of Oncology Drug Products
`
`
` I
`
` have examined pharmacology/toxicology review and labeling provided by Dr. Gehrke
`and the supporting memorandum provided by Dr. Helms. I concur with their conclusions
`that Xalkori may be approved for the proposed indication and that no additional
`nonclinical studies are needed.
`
`Reference ID: 2999555
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`08/11/2011
`
`Reference ID: 2999555
`
`

`

`MEMORANDUM
`
`
`
`Date: August 10, 2011
`From: Whitney S. Helms, Ph.D.
`Acting Pharmacology Team Leader
`Division of Drug Oncology Products
`To: File for NDA #202,570
`Crizotinib (XALKORI)
`Re: Approvability of Pharmacology and Toxicology
`
`Non-clinical studies examining the pharmacology and toxicology of crizotinib provided to
`support NDA 202570 for the treatment of patients with ALK-positive non-small cell lung cancer
`were reviewed in detail by Brenda J. Gehrke, Ph.D. The submission included studies of orally
`administrated crizotinib in rats, dogs, mice, and rabbits that investigated the drug’s
`pharmacology, pharmacokinetics, safety pharmacology, general toxicology, genetic toxicity (in
`vivo and in vitro), and reproductive toxicity. The reviewed studies include only original research
`conducted by the sponsor.
`
`The pharmacology studies submitted to this NDA demonstrate that crizotinib is a kinase
`inhibitor. Like other approved kinase inhibitors crizotinib targets a several proteins at clinically
`relevant concentrations including c-Met/hepatocyte growth factor receptor (HGFR), anaplastic
`lymphoma kinase (ALK), and Recepteur d’Origine Nantais (RON). Though the drug has its
`strongest potency against c-Met, the clinical development of crizotinib has focused on patients
`with tumors expressing ALK gene translocation products. ALK has an important role during
`development, particularly in neural development, but has limited expression in normal cells.
`Translocations with the ALK gene have led to the expression of oncogenic fusion proteins
`resulting in dysregulated expression of, and increased signaling through this kinase. Crizotinib
`was able to inhibit the growth of tumors derived from various cell types expressing c-
`Met/HGFR, and either EML-ALK4 or NPM-ALK4 translocations both in vitro and in a series of
`xenograft experiments conducted in athymic mice. Treatment of these mice with the drug also
`led to decreased phosphorylation of a number of downstream targets in the tumors, decreases in
`proliferation markers, and increases in apoptotic markers, further demonstrating the
`pharmacologic activity of crizotinib.
`
`In a one-month rat toxicology study high dose males displayed a minimal to moderate decrease
`in bone primary spongiosa. This observation was made in a single study at an exposure
`approximately 10-fold higher than human exposure at the clinically recommended dose,
`however, it may have significance for a pediatric population. Major target organs for crizotinib
`toxicity observed in the 3 month toxicology studies conducted in rats and dogs included the liver,
`GI tract, and heart. Significant increases in liver enzymes (ALT, AST, and ALP) were observed
`at the high dose levels in both species. Increases in blood urea nitrogen and creatinine were also
`noted. These increases correlate with hepatic abnormalities noted clinically. High dose animals
`of both species also displayed increases in inflammatory cells including neutrophils, eosinophils,
`and monocytes that may correlate with clinical observations of increased pneuomonitis. In in
`vitro assays investigating hERG and calcium channel signaling, dedicated safety pharmacology
`
`Reference ID: 2998866
`
`

`

`studies examining the effects of crizotinib on cardiovascular function, and ECG examinations
`conducted during the 3-month general toxicology study in dogs there was evidence of the
`potential for cardiac toxicity. These findings correlate with clinical findings of QTc
`prolongation, bradycardia, and cardiac arrest observed occasionally in clinical trials.
`
`Visual disturbances were a frequently reported adverse event in clinical trials. A dedicated study
`was performed in rats to further examine the basis of these clinically observed visual events.
`This electroretinography study suggested that treatment with crizotinib leads to differences in
`light/dark adaptation in animals. In addition, high levels of crizotinib were detected in the eye
`and eye associated tissue in a distribution study. Detectable levels of crizotinib remained in the
`eye for at least 504 hours following a single dose of the drug.
`
`During the course of the review, 4 impurities were identified with proposed specifications above
`the ICH threshold of 0.15%. The sponsor conducted a 1 month daily dose toxicology study in
`rats to qualify these impurities. For two of the impurities, doses administered to animals in the
`batch of crizotinib used in the qualification study exceeded the single cycle clinical exposure;
`these impurities were considered qualified. The 2 other impurities neither met this criteria nor
`were qualified by any other animal study submitted to the NDA and the sponsor agreed to lower
`their specification levels to the ICH limit.
`
`Crizotinib was shown to be genotoxic in both in vitro and in vivo assays. The genotoxic activity
`of the drug appears to be clastogenic rather than mutagenic. Carcinogenicity studies were not
`conducted and were not required for approval in this patient population.
`
`Reproductive studies investigating the effects of crizotinib on fertility or on post-natal
`development were not submitted and were not required for approval in this patient population;
`however, findings in 1-month and 7-day studies in the rat suggest that crizotinib may have
`effects on human fertility. In embryo-fetal toxicity studies in rats and rabbits there was increased
`post-implantation loss and decreased fetal weight at doses resulting in exposures at or above the
`approximate human exposure at the recommended clinical dose. Pregnancy category D is
`recommended.
`
`Recommendations: I concur with the conclusion of Dr. Gehrke that the submitted
`pharmacology and toxicology data support the approval of NDA 202,570 for XALKORI. There
`are no outstanding nonclinical issues related to the approval of XALKORI for the proposed
`indication.
`
`Reference ID: 2998866
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WHITNEY S HELMS
`08/10/2011
`
`Reference ID: 2998866
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`202570
`Application number:
`0000
`Supporting document/s:
`January 4, 2011
`Applicant’s letter date:
`March 30, 2011
`CDER stamp date:
`Xalkori® (Crizotinib)
`Product:
`ALK-positive non-small cell lung cancer
`Indication:
`Pfizer Inc
`Applicant:
`Division of Drug Oncology Products (HFD-150)
`Review Division:
`Brenda J. Gehrke, Ph.D.
`Reviewer:
`Acting Team Leader: Whitney S. Helms, Ph.D.
`Division Director:
`Robert Justice, M.D.
`Project Manager:
`CDR Diane Hanner
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202570 are owned by Pfizer Inc or are data for which
`Pfizer Inc has obtained a written right of reference. Any information or data necessary
`for approval of NDA 202570 that Pfizer Inc does not own or have a written right to
`reference constitutes one of the following: (1) published literature, or (2) a prior FDA
`finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved
`labeling. Any data or information described or referenced below from reviews or
`publicly available summaries of a previously approved application is for descriptive
`purposes only and is not relied upon for approval of 202570.
`
`
`
`
`
`
`
`
`
`Reference ID: 2998833
`
`1
`
`

`

`NDA # 202570
`
`
`
`
`Reviewer: Brenda J. Gehrke, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 7
`1.1
`INTRODUCTION.................................................................................................... 7
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 7
`1.3 RECOMMENDATIONS.......................................................................................... 10
`2 DRUG INFORMATION .......................................................................................... 10
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS: IND 73544 ...................................... 11
`2.3 DRUG FORMULATION ......................................................................................... 11
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 13
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 13
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 13
`2.7 REGULATORY BACKGROUND .............................................................................. 13
`3 STUDIES SUBMITTED.......................................................................................... 14
`STUDIES REVIEWED........................................................................................... 14
`3.1
`3.2
`STUDIES NOT REVIEWED ................................................................................... 16
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 18
`4 PHARMACOLOGY................................................................................................ 18
`PRIMARY PHARMACOLOGY................................................................................. 18
`4.1
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 47
`4.3
`SAFETY PHARMACOLOGY................................................................................... 52
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 73
`5.1
`PK/ADME........................................................................................................ 73
`6 GENERAL TOXICOLOGY..................................................................................... 83
`SINGLE-DOSE TOXICITY..................................................................................... 83
`6.1
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 84
`7 GENETIC TOXICOLOGY .................................................................................... 107
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)..................... 107
`7.1
`7.2
`IN VITRO ASSAYS IN MAMMALIAN CELLS............................................................ 110
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)................ 117
`7.3
`8 CARCINOGENICITY ........................................................................................... 124
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 124
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 124
`9.1
`9.2
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 124
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 140
`10
`SPECIAL TOXICOLOGY STUDIES................................................................. 141
`
`11
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 152
`
`Reference ID: 2998833
`
`2
`
`

`

`NDA # 202570
`
`
`
`
`Reviewer: Brenda J. Gehrke, Ph.D.
`
`Table of Tables
`
`Table 1: Upstate 102 kinase panel screening data and kinase hit follow-up ................ 21
`Table 2: Pfizer kinase panel screening and kinase hit follow-up .................................. 21
`Table 3: Selectivity of PF-02341066 in cell-based kinase assays ................................ 22
`Table 4:Cellular potency of PF-02341066 vs. c-Met/HGFR phosphorylation ................ 23
`Table 5: Biochemical potency of crizotinib and its metabolites..................................... 37
`Table 6: Cellular potency of crizotinib........................................................................... 38
`Table 7: Comparison of cellular potency of crizotinib and its human metabolites ........ 39
`Table 8: Immunohistochemistry analysis for caspase3, Ki67, pERK, and pAKT in NCI-
`H3122 xenograft tumor samples ................................................................................... 44
`Table 9: Effects of PF-02341066 in binding assays ..................................................... 47
`Table 10: Effects of PF-02341066 in enzyme assays .................................................. 48
`Table 11: Antagonist effects of PF-02341066 on the 5-HT4e and 5-HT7 receptors..... 49
`Table 12: Effects of PF-02341066 on the 5-HT2B receptor ......................................... 50
`Table 13: % inhibition of Nav1.1 sodium currents ........................................................ 53
`Table 14: Mean total activity during the 30-minute session.......................................... 56
`Table 15: % inhibition of hERG potassium currents ..................................................... 58
`Table 16: % reduction in KCl-induced contraction........................................................ 60
`Table 17: % inhibition of L-type calcium current........................................................... 62
`Table 18: Effects on the APD50 of the cardiac action potential..................................... 64
`Table 19: Effects on the APD90 of the cardiac action potential..................................... 65
`Table 20: % inhibition of Nav1.5 sodium currents ........................................................ 66
`Table 21: Plasma samples ........................................................................................... 70
`Table 22: Unbound fraction (fu) of PF-02341066 in plasma from preclinical species and
`humans determined using equilibrium dialysis .............................................................. 74
`Table 23: Pharmacokinetic parameters for blood and tissues in male Long Evans rats
`following a single oral administration of [14C] PF-02341066......................................... 75
`Table 24: Concentrations of radioactivity in the right and left eyes at 336 and 504 hours
`after dosing ................................................................................................................... 76
`Table 25: Relative quantitation of PF-02341066 and metabolites in plasma of male and
`female rats .................................................................................................................... 77
`Table 26: Relative quantitation of PF-02341066 and metabolites in feces and bile of
`male and female rats..................................................................................................... 77
`Table 27: Relative quantitation of PF-02341066 and metabolites in plasma of male and
`female dogs................................................................................................................... 78
`Table 28: Relative quantitation of PF-02341066 and metabolites in feces of male and
`female dogs................................................................................................................... 79
`Table 29: Excretion of radioactivity in male and female rats after a single administration
`of [14C] PF-02341066 (10 mg/kg): Group 1 .................................................................. 80
`Table 30: Excretion of radioactivity in male and female rats after a single administration
`of [14C] PF-02341066 (10 mg/kg): Group 2 .................................................................. 80
`Table 31: Concentrations of radioactivity in blood and plasma of male and female rats
`after a single administration of [14C] PF-02341066 (10 mg/kg): Group 3 ..................... 81
`Table 32: Pharamacokinetic parameters for radioactivity in plasma of male and female
`rats after a single administration of [14C] PF-02341066 (10 mg/kg): Group 3 .............. 81
`
`Reference ID: 2998833
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`3
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`Reviewer: Brenda J. Gehrke, Ph.D.
`
`NDA # 202570
`
`Table 33: Excretion of radioactivity in male and female dogs after a single
`administration of [14C] PF-02341066 (10 mg/kg).......................................................... 82
`Table 34: Concentrations of radioactivity in blood and plasma of male and female dogs
`after a single administration of [14C] PF-02341066 (10 mg/kg) .................................... 83
`Table 35: Pharamacokinetic parameters for radioactivity in plasma of male and female
`dogs after a single administration of [14C] PF-02341066 (10 mg/kg) ........................... 83
`Table 36: Preliminary Mutagencity .............................................................................. 109
`Table 37: Definitive Mutagenicity ...........