CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-372
`
`Pharmacology Review(s)
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE: July 23, 2003
`
`FROM: Supervisory Phannacologist
`Division of Gastrointestinal and Coagulation Drug Products, HFD-l 80
`
`SUBJECT: NDA 21,372 (Palonosetron}—Oral Carcinogenicity and Reproductive Toxicity
`Studies—Acceptability of”Studies in Support of NDA for 1.V. Injection
`
`TO: NDA 21,372
`
`The intended route of administration for palonosetron in humans is by intravenous injection.
`Generally, in toxicology studies, the drug is expected to be administered by the same route
`subject to practical considerations.
`In preclinical program, palonosetron was administered by
`oral gavage in mouse and rat carcinogenicity studies and reproductive toxicity studies in rats
`(Segment 1. Fertility and reproductive performance, Segment 1]. Teratology and Segment II].
`Prenatal and postnatal) and rabbits (Segment II. Teratology). These studies are acceptable for the
`following reasons. Palonosetron has been developed under two INDS, one for i.v. (IND
`,——
`(INH
`8 Dose selections for the carcinogenicity studies in mice and
`rats were based on maximum tolerated doses determined in 3-month oral toxicology studies. The
`Division and the CDER Executive CAC accepted them in 1994 and 1995.
`In the completed
`mouse carcinogenicity study, the systemic exposure to paolonosetron (plasma AUC) at the
`highest dose was about 150 to 289 times the human exposure (AUC =29.8 ng.hr/ml) at the
`recommended i.v. dose of 0.25 mg. In the rat carcinogenicity study, the systemic exposure at the
`high doses was 137 to 308 times the human exposure. Thus in both studies, the animals were
`exposed to sufficiently high doses. It is also impractical to administer the drug by iv. injection
`daily for two years. The agency always accepted alternate routes of administration in the
`carcinogenicity studies as long as the dose selections are reasonably high.
`
`,
`
`In the reproductive toxicity studies, doses above 60 mg/kg/day were too toxic and lethal.
`Sufficiently high doses were employed in these studies assuring high systemic exposures as
`judged by the available toxicokinetic information from the other studies.
`
`In conclusion, the oral carcingenicity and reproductive toxicity studies of palonosetron are
`acceptable in support of the NDA for palonosetron injection.
`
`

`

`/3/
`
`Date
`Jasti B. Choudary, B.V. Sc., PhD.
`Supervisory Pharmacologist, HFD-180
`
`Cc:
`NDA
`
`HF D-l 80
`
`HFD-l 8 l /CSO
`
`HFD-l SO/Dr. Leighton
`HFD—l 80/Dr. Choudary
`HFD-l 80/Dr. Justice
`HFD-l 80/Dr. Korvick
`
`

`

`--------------------------‘---.-.--.--...--------------n-------------------------.--'-------------------.—------——-
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Jasti Choudary
`7/23/03 12:28:25 PM
`PHARMACOLOGIST
`
`

`

`MEMORANDUM ,'
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE: July 10, 2003
`
`From: Yash M. Chopra
`Pharmacologist, HFD-IBO
`
`Subject: Safety limits for the impurities of
`
`‘\
`
`in Palonosetron
`
`To: NDA 21-372
`
`1. Two potential impurities in the final drug substance ofpalonosetron were identified by sponsor as
`———,
`. Sponsor has asked to set the upper limit
`of these impurities as ~ '6 in the final drug substance.
`
`2. The intended clinical dose ofpalonosetron injection is 5 ug/kg for nausea and vomiting induced by
`
`cancer chemotherapy. As per the sponsor request, the amount of each of the impurities administered in
`the suggested single clinical IV dose will be x.
`U V
`
`3. The Division had suggested to sponsor to limit the amount of each of the impurities to ——/o and not
`— ’0. Sponsor did not conduct any preclinical toxicity studies with the purified impurities under NDA
`21-372 and has now asked to set a limit of these impurities.
`
`4. The safety limits for these impurities is estimated by computing the amounts ofthese impurities
`present in the ‘no effect doses’ ofthe available intravenous toxicity studies in a rodent and non-rodent.
`The 26—week IV toxicity study in rats (PALO-99-08) and 40-week IV toxicity study in dogs (PALO-99-
`10) were considered.
`
`5. The ‘no effect doses’ in 26-week IV toxicity study in rats and 40-week IV toxicity study in dogs were
`7 and 3 mg/kg/day, respectively. The batch # P30893-P105 of palonosetron was used in 26-week IV rat
`and 40-week IV dog toxicity studies and, a sample from this batch of the compound was reported to
`contain If“ and ‘—‘ 6 of r
`—’
`_ respectively (according to the certificate of
`analysis attached with the study). The study #, doses used and % impurities, no effect dose and amounts
`of impurities computed from the data of the certificate of analysis are shown below in the table:
`
`

`

`NDA 21-372
`
`Page 2 of3
`
`Study Name
`
`.
`
`Study #
`
`Batch # Doses Used
`
`
`
`
`
`% Impurities Present
`No Effect
`Computed Amount
`(mg/kg/dBY)
`Impurities Administered
`(Certificate Analysis)
`Dose
`
`
`
`
`(mg/kg/day)
`in 'No effect Dose’
`
` O,2,7&10
`
`r105
`
`99-12
`PALO-
`
`99-)0
`
`P105
`
`
`
`26-Weele Toxin
`Rats
`40-Weele Tox
`
`in Dogs
`
`
`
` 0, 1,3/10/6
`
`
`
`--P104
`
`
`in the ‘no effect dose’ of7 mg/kg/day in 26-week rat toxicity
`\_ .
`6. The amounts of]
`ug/kg/day, respectively. As a rule ofthumb, one-tenth ofthese
`’—
`study were computed to be
`doses were considered safe for humans. Thus the amounts of
`\
`ug/kg/day
`——
`——
`in a clinical dose may be safe.
`In 40-week dog toxicity study, ‘no effect dose’ was 3 mg/kg/day
`and, the amounts of .
`~—
`administered were computed to be
`—— ug/kg/day,
`
`respectively. . As a rule of thumb, one-fifth of these doses were considered safe for humans. Thus the
`amounts of
`'—
`ug/kg/day of
`in a clinical dose may be safe.
`
`7. The amounts of the impurities present in the clinical iv dose of 0.25 mg (5 ug/kg/day) palnosetron
`could be “-
`ng/kg/day of.
`’N
`These are small fractions of safe doses of
`these compounds identified in these studies and support the proposed limit of the impurities.
`
`RECOMMENDATIONS:
`
`None
`
`COMMENTS:
`
`/
`
`Yash M. Chopra, M.D.,Ph.D.,
`Pharmacologist
`
`Date
`
`I‘S/
`
`Date
`Jasti B. Choudary, B.V.Sc, Ph.D.
`Supervisory Phannacologist,l-1FD- l 80
`
`

`

`ThisIs a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Yash Chopra-
`7/10/03 05:28:23 PM
`PHARMACOLOGIST
`
`Jasti Choudary
`7/11/03 07:51:45 AM
`PHARMACOLOGIST
`
`.
`
`

`

`MEMORANDUM I
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATEzluly 10, 2003
`
`FROM: Supervisory Pharmacologist
`Division of Gastrointestinal and Coagulation DrugTroducts, HFD-l 80
`
`SUBJECT: NDA 21,372 (Palonosetron)—Sponsor’s Proposed Labeling—Changes In Preclinical
`Portions of Labeling.
`
`TO:
`
`NDA 21,372
`
`The following portions of the sponsor’s proposed labeling should be replaced or changed as
`indicated. They relate to (I) Carcinogenesis, Mutagenesis, Impairment of Fertility, (2)
`Pregnancy. Pregnancy Category, (3) Nursing Mothers and (4) OVERDOSAGE. They are
`identified by the line numbers in the sponsor’s draft labeling.
`
`(I) Carcinogenesis, Mutagenesis, Impairment of Fenility---Lines 170 to 203.
`
`“In a IO4-week carcinogenicity study in CD—1 mice, animals were treated with oral doses of
`palonosetron at IO, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic.
`The highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about
`150 to 289 times the human exposure (AUC= 29.8 ng.h/ml) at the recommended intravenous
`close of - rng. In a IO4-week carcinogenicity study in Sprague-Dawley rats, male and female
`rats were treated with oral doses ofIS, 30 and 60 mg/kgday and 15, 45 and 90 mg/kg/day,
`respectively. The highest doses produced a systemic exposure to palonosetron(Plasma AUC) of
`I37 and 308 times the human exposure at the recommended dose. Treatment with palonosetron
`produced increased incidences of adrenal benign pheochromocytoma and combined benign and
`malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenoma and
`combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it
`produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell
`adenoma and combined adenoma and carcinoma.
`
`Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell
`(CHO/HGPRT) forward mutation test, the ex vivo hepatocyte unscheduled DNA synthesis
`(UDS) test or the mouse micronucleus test. It was, however, positive for clastogenic effects in
`the Chinese hamster ovarian (CHO) cell chromosomal aberration test.
`-
`
`

`

`Palonosetron at oral doses up to 60 mg/kg/day (about 1894 times the recommended human
`intravenous dose based on body surface area) was found to have no effect on fertility and
`reproductive performance of male and female rats”.
`
`(2) Pregnancy. Teratogenic Effects: Category B---LinesZO4 to 21 l.
`
`“Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the
`recommended human intravenous dose based on body surface area) and rabbits at oral doses up
`to 60 mg/kyday (3789 times the recommended human intravenous dose based on body surface
`area) and have revealed no evidence ofimpaired fertility or harm top the fetus due to
`palonosetron. There are, however, no adequate and well~controlled studies in pregnant women.
`Because animal reproduction studies are not always predictive of human response, palonosetron
`should be used during pregnancy only if clearly needed.”
`
`(3) Nursing Mothers---Lines 21510 218.
`
`'
`
`It is not known whether palonosetron is excreted in human milk. Because many drugs are
`excreted in human milk and because ofthe potential for serious adverse reactions in nursing
`infants and because of the potential for tumon'genicity shown for palonosetron in the rat
`carcinogenicity study, a decision should be made whether to discontinue nursing or to
`discontinue the drug, taking into account the importance ofthe drug to the mother.”
`
`(4) OVERDOSAGE—LINES 269 to 277. The following should be added after line 277.
`
`mmr
`
`.
`[13/
`
`_
`
`j
`
`Date
`Jasti B. Choudary, B.V. Sc., PhD.
`Supervisory Pharmacologist, HFD-l 80
`
`Cc:
`
`NDA
`
`RFD-180
`HFD-l 8 l /CSO
`
`HFD-l 80/Dr. Choudary
`
`

`

`Jasti Choudai'y
`7/10/03 08:49:23 AM
`PHARMACOLOGIST
`
`

`

`NDA 21-372
`
`Page 1
`
`PHARMA COLOGY/TOXICOLOGYREVYEW 0F NDA 21-3 72
`
`Sponsor and/or agent: Helsinn HealthCare SA, Lugano (Switzerland)
`
`Authorized US Agent: Craig Lehmann, Pharm. D.,
`Austin, TX.
`
`Review number/Date of submission: OOO/September 26, 2002
`
`Information to sponsor: Yes ( ) No (X)
`
`Reviewer name: Yash M. Chopra, M.D., PhD.
`
`Division name: Division of Gastrointestinal & Coagulation Drug Products, HFD-l 80
`Date of Submission: September 26, 2002
`
`Date of HFD180 Receipt: September 30, 2002
`
`Review completion date:
`
`July 1 l, 2003
`
`Drug:
`
`Trade name: Not Established
`Generic name (list alphabetically): Palonosetron Hydrochloride
`Code name:08-PALO, RS-25259-197
`
`Chemical name: (3aS)-2-(§)-l-Azabicyclo[2,2,2]oct-3-yl]-2,3,3a,4,5,6-hexahydroxo-1—
`oxo-lfl-benz[de]isoquinoline hydrochloride.
`CAS registry number: 135729-62-3
`Mole files number: NA
`
`Manufacturer of the Drug:
`
`"\
`
`Contact Name:
`
`~
`
`Molecular formula/molecular weight: C19H24N20.HC1
`
`Structure:
`
`

`

`NDA 21-372
`
`Page 2
`
`
`
`Helsinn code: 08-PALO
`
`Palonosetron HCl
`
`(Syntex lab codez‘Rs-25259-197)
`-
`.
`. a . _
`INDs/NDAs/DMFS: Type 11 DMF DINDiflflnjection) & mm
`
`Drug class: Serotinin 5-l-IT3 Antagonist
`
`Indication: For the prevention of acute and delayed nausea and vomiting associated with initial
`and repeated courses of emetogenic chemotherapy.
`
`Clinical formulation: Each 5 ml vial ofPalonosetron Injection contains 0.25 mg palonosetron
`base as hydrochloride, 207.5 mg mannjtol, disodium edetate and citrate buffer in sterilized water
`for injection. The pH ofthe solution is 4.5 to 5.5.
`
`Route of administration: Intravenous
`
`Proposed Clinical Use: An intravenous dose of 0.25 mg is recommended as a single dose
`approximately 30 minutes before the chemotherapy for the prevention of acute and delayed
`nausea and vomiting associated with initial and repeat courses of emetogenic cancer
`chemotherapy including the highly emetogenic chemotherapy.
`
`Disclaimer: Tabular and graphical information is from sponsor’s submission unless stated
`otherwise.
`
`None
`
`

`

`NDA 21-372
`
`Page 3
`
`1. Recommendations
`
`Executive Summary
`
`A. Recommendation on Approvability: From preclinical standpoint, approval of the
`application is recommended.
`
`B. Recommendation for Nonclinical Studies: None
`.
`
`C. Recommendations on Labeling:
`The suggested changes indicated in the revised text ofthe label should be adopted.
`
`II.
`
`Summary of Nonclinical Findings
`
`A. Pharmacological Activity:
`Palonosetron a 5-HT3 receptor antagonist (pki = 10.4 rat cortex) binds selectively with
`high affinity with cloned 5-HT3 receptor sites of 293E] cells and NGlO8 cells. It was
`seen to show a small effect on 5-HT4 receptors in rat esophageal muscularis‘mucosa and
`very little affinity for dopamine, histamine and acetylcholine and other 5-HT receptor
`sites.
`It blocked cisplatin—induced emesis in ferrets and dogs at intravenous doses of 0.01
`and 0.1 mg/kg, respectively without affecting the intestinal motility. At equivalent doses,
`palonosetron and ondansetron antagonized cisplatin induced emesis in ferrets.
`Palonosetron was efective in inhibiting cisplatin induced emesis in dogs, when
`administered up to 7 hr before cisplatin. The duration of effects for palonosetron effect
`was 6 hr prior to challenge. The inhibition of Bezold-Jarisch reflex by oral and
`intravenous routes of administration was more pronounced (ID50= 0.04 ug/kg, iv; 3.2
`ug/kg i.d.) than ondansetron and granisetron. It was found in brain after its systemic
`administration and exerted a mild CNS activity from intraperitoneal dose of3 ug/kg in
`mice.
`It exerted no effects on respiratory functions and only a transient decrease in
`diastolic blood pressure with minimal effects on myocardium conduction and dog EKG
`parameters. The metabolite M9 (N-oxide of the compound) identified in animals and
`human, from 0.001 to 0.1 mg/kg, IV did not affect the blood pressure, heart rate, and
`ECG in conscious dogs but exerted a weak anti-emetic effect at 0.1 mg/kg, iv. on
`chemotherapy induced emesis. Palonosetron affected the fast sodium ion channels and
`potassium channels at a high concentration of 10 nyml in in vitro rabbit purkinje fibre
`preparation. The minimum concentration (10 ng/ml) producing this effect is much higher
`than the 0.9 ng/ml Cmax attained at the recommended i.v. dose of 0.25 mg/day. Based
`on its anti-emetic effects for prolonged duration, the sponsor is seeking permisssion for
`its use in the control of immediate and delayed phases of chemotherapy induced
`vomiting. Sponsor did not conduct any preclinical study to demonstrate the efficacy of
`palonosetron onthe delayed phase of emesis.
`
`Intravenously administered palonosetron in rats, attained plasma peak concentration after
`5 min of administration with rapid systemic clearance and volume of distribution of 17.2
`l/kg. The systrnic clearance in dog was larger and its the terminal halflife was greater
`
`

`

`NDA 21-372
`
`Page 4
`
`than rat. The compound was disrtn'buted in bladder, ileum, lungs, adrenals, large and
`small
`intestines. Eight metabolites in the plasma of rat and 9 in the dog were detected
`and none of these conjugated before teir excretion. Metabolite 2, 3, 4, l and 5 (in order
`of rank) Were isolated in rats and, metbolite 6 was the major metabolite in rats. The
`excretion was in feces up to 82% in first 24 hr (the excretion in urine complete in 8 hr
`and in feces by 24 hr). The compound was transformed in M6 (33.6%), M3 (4.7%) and
`parent compound (4.43%) in the dog. The chemical identification ofthe metabolites has
`been undertaken and completed by sponsor. The structures of metabolites was provided
`in the submssion.
`In monkeys, most of the administered compound by intravenous route
`was metabolized before excretion in urine. Metabolite M9 at intravenous doses of 0.001,
`0.01, and 0.1 mg/ kg had no effects on blood pressure, heart rate, and ECG in conscious
`dogs.
`In man, a dose of 0.25 mg (5 ug/kgfor 50 kg man), the proposed dose attains a
`plasma concentration of Cmax of:0.92 ng/ml and AUC(o.ing, of 29.8 ng.hr/ml, halflife of
`47.2 hr and clearance of 1.8] ml/min/kg.
`
`B. Brief Overview of Toxicology
`
`The acute tolerance of the intravenously administered compound was determined in rats,
`mice and dogs. A single iv dose of 30 mg/kg RS-25259-197 was lethal in mice and rats.
`Symptoms of toxicity were convulsions, inactivity, labored respiration, salivation,
`tremors and collapse. 1n dogs, an iv dose of 20 mg/kg was not lethal. The signs of
`toxicity were similar.
`
`The toxicity ofthe prolonged duration with the compound was studied in rats, mice and
`dogs by intravenous, subcutaneous and oral routes of administration. Palonosetron was
`well tolerated in rats up to an intravenous dose of3 mg/kg/day in 4 week iv toxicity
`study.
`In 28-day subcutaneous toxicity study in neonatal/ juvenile rats, subcutaneously
`administered palonosetron from 5 to 25 mg/kg/day produced treatment related but non-
`dose proportional plasma concentrations in both seXes and these were similar on day 1
`and 28. The target organs (or tissues) oftoxicity were injection sites, optic nerve
`neuropathy, spleen and kidneys. In the repeated study, the optic nerve neuropathy was not
`observed. A 26-week iv toxicity study in rats was done at the doses from 2, 7 and 14 (10)
`mg/kg/day and convulsions were seen in animals treated with 14 mg/kg/day close but not
`after the dose adjustment was made to 10 mg/kg/day. A non-proportional plasma
`concentrations, bleeding at the site of injection, convulsions, reduced activity and deaths
`were observed suggesting central nervous system and site of injection as target organs of
`toxicity. In 1-month iv toxicity study in beagle dogs, sporadic bleeding in thymus, lungs
`and hemorrhage urinary baldder were seen in animals of 10 mg/kg/day group. In 28-day
`iv toxicity study in juvenile dogs, palonosetron at 0, l, 3 and 6 mg/kg/day produced dose
`proportional plasma concentrations and no target organs of toxicity were identified. In a
`40-week i.v. toxicity study in dogs, 1, 3 and 5/ 10/6 mg/kg were administered . At 10
`mg/kg/day, animals had convulsions, ataxia, vomiting and diarrhea. Ataxia was seen
`even after the reduction of the dose. Central nervous system was the target organ of
`toxicity.
`
`

`

`NDA 21-372
`
`Page 5
`
`In the mouse
`The 104-week carcinogenicity studies were conducted in mouse and rats.
`study, oral gavage doses of 0, O, 10, 30 and 60 mg/kg/day palonosetron were
`administered in 5 groups of animals (56/sex/group). A dose proportional plasma
`concentration of the compound. No increase in tumors incidences were reported in
`palonosetron treated animals. The exposure levels in the males and females included in
`the high dose treatment group on study week 26 were 289.3 and 149.7 times the human
`exposure at the recommended clinical dose.
`
`In 104-week rat carcinogenicity study, oral gavage doses of 0, O, 15, 30 and 60
`mg/kg/day palonosetron in males and, 0, 0, 15, 45'and 90 mg/kg/day in females were
`administered in 5 groups of animals (65/sex/group). A non-dose proportional increase in
`the plasma concentrations were seen in rats. The plasma concentrations in females were
`more than males ofthe treatment groups during the study. On study week 26, the
`exposure ofthe compound in male and female animals was 136.9 and 308.2 times the
`plasma concentration (AUC values) achieved after the suggested clinical dose of5 ug/kg
`in man. Palonosetron produced a treatment related but non-dose proportional plasma
`concentrations in animals. Increased incidences of benign pheochromocytoma in male
`and female animals and, increased incidences of combined benign and malignant
`pheochromocytoma, pancreatic islet cell adenoma and benign adenoma of pars distalis in
`high dose males were seen during the study. The higher incidences hepatocellular
`adenoma and thyroid C-cell adenoma were seen in high dose treatment group females.
`
`The mutagenicity of the compound was determined in Ames assay, chromosomal
`aberration test in CHO cells, in vivo mouse micronucleus test, mammalian gene mutation
`assay and ex-vivo unscheduled DNA synthesis in Fisher 344 rats.
`11 was clastogenic in a
`chromosomal aberration assay in CHO cells with and without S—9 mix.
`
`C. Non-Clinical Safety Issues Relevant to Clinical Use: None
`
`\C
`
`a
`
`111.
`
`Administrative
`
`B. Supervisor signature:
`
`A. Reviewer signature:_\—___ \
`6’3.
`' Concurrence -
`.
`\
`\
`Egg
`
`Non-Concurrence -
`
`(See mem ttached)
`
`C. C.:
`
`Original NDA
`HFD—l 80
`HFD-l 81/CSO
`
`HFD-l 80/Dr.Chopra
`HPD-180/Dr.Choudary
`HPD-345/Dr. Viswanathan
`
`

`

`PRECLTNICAL PHARMACOLOGY AND TOHCOLOGY STUDIES:
`
`
`Type of Study
`.
`-
`-
`‘
`
`
`PHARMACOLOG ————
`
`ABSORPTION DISTRIBUTION, METABOLISM AND EXCRETION
`—_
`
`
` C-16398-GTH-
`Binding ofRS-29259-197 to Plasma
`CL 6204
`
`
`
`27; Unlab
`Proteins
`
`
`PAl 5303—61 5
`
`A9204010
`
`
`_—
`Absor . fion/Pharmacokinetics —
`
`Pharmacokinetics ofR5252559-007
`
`AT 6303
`GTH-106
`.
`After a single Oral Dose of RS-25259-
`
`
`
`
`197 in Male Rats
`Unlab-l3977-66
`
`A9012010
`
`Pharmacokinetics of R5252559-007
`
`PA15303-5]
`
`A9201007
`and Its N-Oxide metabolite following
`
`
`once Daily Oral Dose MRS-25259-
`
`
`197 in Male Rats for 5 Da
`Phannacokinetics of R8252559-007
`
`
`After a single Oral Dose of RS—25259-
`
`197 administered to Dogs
`
`Plasma Pharmacokinetics of
`
`
`R5252559-007 and Its N-Oxide
`
`
`
`NDA 21-372
`
`Page 6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Metabolic Disposition of C-
`
`
`
`metabolite following once Daily Oral
`Dose ofRS-25259-l97 in Female
`Do-s for 5 da 5
`
`Distribution/Metabolism:
`
`
`Metabolic Disposition and Tissue
`
`
`Distribution of ”01132525594 97
`
`after single IV dose in Rats
`
`
`
` Metabolic Disposition and Tissue
`Distribution to Brain, Eye and
`
`
`Intestine after a Single Intravenous
`
`Dose following single Intravenous and
`
`oral doses of NC-R8252559-197 in
`
`Pi -
`ented Rats
`
`
`
`Metabolic Disposition following
`single Intravenous and oral doses of
`
`"011552559497 and Tissue
`Distribution afier a Single Intravenous
`Dose in Rats
`
`
`
`R8252559-l97 afier single POI'IV_
`
`Dose in cynolmolgus Monkeys
`
`AT6302
`
`AT 6304
`
`AT6301/
`AM1023
`
`
`
`
`
`
`
`AT 5975
`
`AT 6285
`
`AT 6264
`
`>
`
`,,
`
`DM 1078
`
`Study/Report
`#
`
`Name of Laboratory
`
`Drug Batch #
`
`
`
`
`
`
`Syntex Res Lab, Palo
`Alto
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1518SGTH-53
`Unlab.589l-74;
`A9012002
`
`15303—5],
`A9201007
`
`53; Unlab
`13977-86,
`A910210
`.
`C—
`16389SGTH-21
`
`(IV), Unlab:
`15303—615
`A9204010
`
`50
`
`53
`
`
`
`'
`53 (IV), 151188-
`GTH-l 06 (PO);
`Unlab: 13977-
`86, A9102010
`
`
`C-R525259 IV:
`
`
`#1748801'H-75;
`l7488GTH-72;
`Unlab:15303-l8;
`A9204029
`
`
`
`
`

`

`NDA 21—372
`Pa-e7
`TOXICOLOGY:
`-
`
`
`
`
`
`
`,
`_
`
`. —
`M1C€(CrlICD 1 )lCR BR VAF/Plus /8
`AT 5921
`Syntex Res, Palo Alto
`weeks)
`
`
`
`_—
`_—
`_—
`PA13977-140
`59
`PA13977—86
`
`
`
`Rat (Crl:SD)
`
`Rat (Crl SD)
`
`
`
`
`
`Do (Bea - le
`
` Dog (Beagle)
`
`Mice (Crl:CD-l)lCR BR VAF/Plus)
`
`71 l-R—9l _ PA13977-86
`
`5939
`
`71o-D-91
`AT 5922
`
`711-M-92
`
`PA13977-14O
`PA13977-86
`
`59
`
`_ 59
`PA13977-86 —
`PA13977-86
`PA13977-l40
`
`_-
`PA15303-6lS
`
`
`
`
`
`——__-
`_———_E-
`Dog (Beagle)
`5935-107/
`PA] 3977-86
`
`PAl3977-86
`
`-
`
`_6-
`SUBACUTEISUBCHRONlC/CHRONIC TOXICITY STUDIES:
`
`l—Month IV Study in Rats
`
`AT 5962
`
`Syntex Res., PaloAJto
`
`62
`
`
`
`
`
`PA13977-86
`PA13977-l40
`30893-105?
`
`
`
`
`
`
`PALO—99—12
`
`‘ "
`
`-
`
`4-Week SC Stud ' in Juvenile Rats
`
`4-Week SC Study in Juvenile Rats
`
`PALO-OZ—OS
`
`PAL0-99-08
`
`
`
`
`
`
`
`
`21000565 w
`
`30893-P105
`
`
`26-Week IV Toxicity Study in Rats
`
`
`PA15303—6lS
`l-Month Oral Gavae Stud in Rats
`AT 6329
`' "
`
`
`
`l-Month IV Study in Beagle Dogs
`AT 5963
`13977-86,
`PA] 3977-140
`
`
`
`
`
`
`
`
`
`
`
`l—Month Oral Gavage Toxicity Study
`in Beagle Dos
`
`4—Week 1v toxicity in Juvenile Dogs
`
`3-Month Oral (capsules) Study in
`Beale Do_s
`
`40—Week 1v Toxicity Study in Dogs
`
`Carcinogenicity Studies:
`
`
`
`AT 6328
`
`
`
`
`
`PALO-99-22
`
`
` AT 6787
`PA1530353ML
`
`
`PA16505-69S
`
`
`
`
`30893-P105
`
`
`
`PA] 5303-61 s
`
`88
`
`30893-P105
`
`PALO-99-10
`
`3-Month Oral Dose Ranging Study in
`Mice
`2-Year Mouse Carcinogenicity
`
`Syntex Discovery
`# 719-M-94-25
`59-97; AT675] Research, Palo Alto
`PALO-99-l 8
`"
`'
`‘ - '
`
`Three Months Oral Dose Ranging
`Stud ' in Rat with RS-25259-007
`
`# AT 6665
`
`\
`Syntex, Palo Alto, CA
`
`
`
`
`
`_
`
`13977-86,
`PA13977-l40
`30893-P104
`
`30893-P106
`
`
`
`
`
`
`
`
`115
`
`

`

`
`
`AT6756
`
`
`AT6755
`
`
`
`Segment 11]. Pre- and Post- Natal
`PALQ-99-13
`
`
`_
`Develo nment in Rats
`
`
`
`MUTAGENICITY:
`
`
`
`
`
`W
`W '
`
`
`
`Segmemnreramto, Stud'in Rats.
`Segment 1]. Teratology Study in
`Rabbits.
`
`\
`
`Assa ' in CHO-Kl BH4 cells
`Chromosomal Aberration Assay in
`
`A 0401
`
`
`
`cells (ATTC CCL 61
`In Vivo Mouse Micronucleus Assay
`
`
`
`
`
`
`
`Mama‘*a“m”°“‘“cp““ -__“
`
`
`
`
`13977-140
`\
`
`
`
`Unscheduled DNA Synthesis ex VIVO
`
`PALO-99-38
`l
`in Fisher 344 Rats
`
`
`
`
`SPECIAL TESTS:
` 13977-
`
`NDA 21-372
`Pa-e 8
`
`2—Year Rat Carcinogenicity
`
`
`
`
`PALO—98-O3
`
`
`
`122
`
`
`
`Segment 1. Male Fertility Toxicity
`
`AT 6700
`
`,,
`
`PA 16505-695
`
`142
`
`Segment 1. Female Fertility &
`Embryonic Development Toxicity
`
`AT6750
`
`PA17555-40ML
`
`144
`
`
`
`30893-P104
`30893—P106
`REPRODUCTIVE TOXlCOLOGY:
`
`Segment 1 Male Fertility Toxicity
`AT 6267
`PA 15303-51
`Syntex Res, Palo Alto
`
`
`
`Stud 'in Rats
`_- --
`
`--
`
`
`
`
`
`
`PA l7555-40ML [m
`PA l7555-40ML
`150
`
`30893-P105
`
`PA 15303-18
`
`157
`
`13977-86 & PA
`
`159
`
`30893-P105
`
`Syntex, Palo Alto
`
`
`Acute Vein Irritation Study in White
`
`Rabbits:
`86/PAl 3977-
`
`
`140; 25259-197—
`
`
`”99'“
`
`
`
`\
`30893-P106;
`-
`30/15-D6144
`
`__
`1737331/21
`
`
`Syntex Res, Palo
`13977-86/13977-
`In Vitro Compatibility Test in Human
`
`
`Whole Blood & slasma
`Alto
`140
`
`
`
`
`
`IRS 25259-197, injectable). The reviews of
`Most of these studies were reviewed in INDl
`these studies were acceptable and are included in this review. The new pharmacology and
`toxicology studies submitted with the present application are also reviewed here. The new
`toxicity studies submitted were 28-day juvenile rat toxicity study, 6-month i.v. toxicity study in
`rats, lO4-week oral gavage carcinogenicity studies in the mouse and the rat, prenatal and
`postnatal toxicity study in rat, 40-week toxicity study in dogs, ex-vivo unscheduled DNA
`synthesis in rat liver cells.
`
`The following studies submitted with the application but were not reviewed here were:
`”\—
`v‘
`
`PK
`
`

`

`NDA 2l-372
`
`Page 9
`
`GOOD LABORATORY PRACTICE & QAU REGULATIONS: Sponsor submitted
`statements ofcompliance with GLP and QAU regulations with each of the submitted toxicity
`studies.
`'
`'
`
`PHARMACOLOGY:
`
`Palonosetron a 5-HT3 antagonist was seen to exert a minimal effect on 5-HT} receptors in rat
`esophageal muscularis mucosa and in guinea pig ileum preparations.
`It did not show any effect
`(agonist or antagonist) on hipocampal adenylate cyclase activity in guinea pigs up to a
`concentration of 100 uM. It (1 uM) showed a little agonistic effect and shifted substance P
`induced dose response (contraction) curve in guinea pig ileum to the right. It exerted antiemetic
`and anti-nauseating effects in animals treated with cancer chemotherapy and was claimed to be
`‘ useful in chemotherapy induced emesis. The following preclinical studies submitted with the
`present application are reviewed below.
`
`Mechanism of Action:
`
`The chemotherapy induced nausea and vomiting had been shown to be due to the release of
`serotonin from the enterochromaffin cells of small intestines and stimulate 5- HT; receptors
`located 'on vagal afferents. This causes simulation of 5-HT; receptors in nuclear tractus solitaris,
`amygdaloid complex and area postrema and chemoreceptor trigger zone. Palonosetron, a
`selective 5-HT3 receptors blocking agent was seen to block the 5-HT induced contractions in
`isolated of guinea pigs intestines, block rat cerebral cortex membrane 5-HT3 receptors (pKi =
`10.4).
`lts binding with 293131 cells and NGlOS cells expressing 5-HT; receptors, was 9.5 and
`23.2 times more than granisetron.
`lt blocked the 2-methyl-5-hydroxy-tryptamine induced
`bradycardia (von Bezold-Jarisch reflex) in anaesthetized rats, dogs and cats following
`intravenous, intraduodenal or dermal administration (lD50= 0.04 ug/kg, IV; 3.2 ug/kg, i.m.).
`Palonosetron from 0.0] mg/kg in ferrets and, 0.] mg/kg p.o. in dogs completely blocked cisplatin
`induced vomiting without an effect on the intestinal motility. It also was shown to bind with
`central 5-HT3 receptors sites in the brain stem nuclei, dorsal motor nucleus ofthe vagus, limbic
`areas including the hippocampal subfields, nuclear tractus solitaris, amygdaloid complex and
`area postrema.
`
`PHARMACODYNAMIC EFFECTS:
`
`A. In Vitro Receptor Binding and Activation studies:
`
`l.- Using radioligand binding techniques, the affinity of RS-25,259-97 at 29 different receptor
`types/subtypes were examined. RS-25,259-l97 exhibited the highest affinity (pKi) for 5-HT;
`receptors in rat cerebral cortex of 10.4102 (mean i S.E.M., n=4). Binding affinities less than 6
`were observed for the following receptors serotonin 5-HT1A 5-HT“, 5-HT”), 5-HT; and 5-HT;
`and their uptake sites; a-adrenoreceptors (1 IA, a ”3, a 2A, a 23; B-adrenoreceptors BI, [32;
`Dopamine D1, D2; angiotensin II subtypes l and 2; dihydropyridine-Ca2+ channel; saxitoxin
`binding site of Na+ channel; N-methyl-D-aspartate (NMDA) receptor channel; ('y-aminobutyn'c
`
`

`

`NDA 2l-372
`
`Page 10
`acid (GABA), picrotoxin, and benzodiazepine binding sites on GABA receptor/channel complex;
`neurokinin NK 1; opioid delta, kappa, and mu; and muscarinic M 1, M2 and M3 receptors.
`Binding affinities, with respective test systems for these latter receptors are provided in Table 1,
`below. These data suggest that RS-25,259-l97 acts as a potent and selective compound for the 5-
`HT3 receptor.
`
`

`

`NDA 21-372
`
`Page 1]
`
`TABLE 1. Binding Affinities for 35—25,259-197 at Various
`'Recegtors and Test Systems
`
`
`
`——J
`
`
`
`
`
`
`
`
`
`_—
`
`Rabbit spleen
`
`
`
`
`
`
`
`
`
`
`__ Rat submaxillary gland
`
`__ Rat striatum
`
`__ Rat striatum
`
`mm
`
`
`
`Bovine Cerebellum
`
`“1—2
`
`
`
`
`
`
`
`
`

`

`NDA 2l-372
`
`Page l2
`
`
`
`
`
`
`
`
`
`A/
`ox1n
`Rat whole brain
`I!I_- Rat submaxillary gland
`
`
`Delta opioid
`4.0 (0.4)
`Guinea pig brain
`(minus cerebellum)
`
`Rat cerebral cortex
`Rat cere bral cortex
`
`‘ Rat whole br
`
`'a
`
`A
`
`
`
`
`
`
`
`
`
`Kappa opioid
`
`4-2 (0-1)
`
`3.7 (0.2)
`
`
`
`' Values are pICSO
`(SEM) = Standard Error
`
`
`
`
`
`The effects of RS-25,259-l97 (100 um) on 5—HT4 receptor mediated increases in
`2.
`« adenylate cyclase activity was tested in guinea pig hippocampus. These studies showed that
`when tested either alone or in the presence of 0.4 uM 5-carboxyamido—tryptamine, a 5—HT”,
`antagonist (added to eliminate any involvement of 5-HTlA-like receptor), R825259-l 97 had no
`effect on adenylate cyclase activity. In addition, RS-25,259-l97 had no effect on serotonin (10
`uM) induced stimulation of adenylate cyclase activity in this preparation in the presence or
`absence ofthe 5-HT1A antagonist. Collectively, these studies suggest that RSZS,259-197 has no
`activity (stimulatory or inhibitory) at either the 5-HT“ or the 5-HT4 type receptors.
`
`Additional in vitro studies to examine the specificity'ofRS-25,259-l97 for 5-HT; type
`3.
`receptors were conducted. These studies showed that RS-25,259-l97 (1 uM) did not antagonize
`the 5-HT-induced contraction of dog saphenous vein, rabbit aorta or proximal guinea pig ileum,
`events which have been shown to be mediated by 5-HT}, 5-HT2, and 5-HT3, receptor subtypes,
`reSpectively, In contrast, R825,259-197 (] uM) produced potent and insurmountable antagonism
`of 5-HT3 mediated contraction in proximal segments-of guinea pig ileum. These data indicate
`that RS-25,259-197 acts as a selective and potent 5-HT; antagonist.
`
`

`

`NDA 21-372
`
`Page l3
`
`4. The potential for 5-HT3 type receptors antagonism of RS-29-259-l97, RS-l 7825-007,
`Metabolite M4 (5-S—hydroxypalonosetron) and ondansetron was assessed in increasing
`concentrations on isolated guinea pig ileum preparation containing 5-HT”; receptor antagonist
`(methysergide) and 5-HT; receptor desensitizing agent (5-methoxytryptamine). All ofthe
`compounds showed antagonistic activity on 5-HT3 receptors but RS-29-259-197 had the lowest
`ICso value followed by ondansetron. The metabolite RS-l7825-007 and Metabolite M4 showed
`low activities as shown in the following table of the sponsor (vol 12.381, p 007). Granisetron
`used as a standard preparation and its lC50 was 10'6 M.
`In conclusion, in vitro binding studies
`as well