Reviewer: Fred Alavi, Ph.D.
`
`'
`
`NDA No. 22-350
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY
`
`Pharmacokinetics: Absorption After a Single Dose (Saxagliptin, Rot)
`Pharmacokinetics of Snagliptin and EMS-510849 in Sprague-Dawley Rats following Single Dose Intravenous or
`Oral Administration ofSnxagllptln
`5"”, Dmrll‘m‘ °" Tm“
`
`Snxngliptin
`Non-GLP
`
`Test Article:
`Study Type:
`Locntlon in Dossier:
`
`Study NoJDocument Control Number: MAPOOS-477118/930000866
`RatlSprague—Dawley
`Male / 2 per treatment
`Fasted overnight and fed 4 h afler
`dosing
`Water
`
`Species/Strain:
`Gender (M/F) I Number of Animals:
`Feeding conditionz-
`
`Vehicle/Formulntlon:
`
`Male / 2 per treatment
`Ftasted overnight and fed 4 h afier
`dosing
`Water
`
`Method ofAdmlnlstrntlon:
`Sample (Whole blood, plasma, serum etc.):
`Analytes:
`Assay:
`
`IV Bolus
`Plasma
`Soxagliptin and EMS-510849
`LC/MS/MS
`
`Oral gavage
`Plasma
`Saxngliptin and EMS-510849
`LC/MS/MS
`
`Snxagliptin Dose (mg/kg):
`Route:
`
`Parameter
`cmax (HS/11¢)
`AUC(0-infinity) (pgxh/mL)
`
`10
`u
`
`8
`m
`
`.
`
`Snxagliptin
`5.2
`1.6
`
`EMS—510849a
`0.2
`0.3
`
`Saxagliptin
`0.5
`0.9
`
`EMS—510849a
`0.2
`0.4
`
`>
`
`
`CLTp (mL/min/kg)
`l 15
`Vss (L/kg)
`5.2
`Tl/Z (h)
`2.1
`% dose excreted unchanged in urine
`33
`(0~10 h)
`Bioavailobility (%)
`Additional Information: ND = not determined.
`Saxagliptin was well, rapidly absorbed, and rapidly cleared in rats. Saxagliptin was excreted in urine as parent. The Vss value indicated extravascular
`
`distribution ofsnxagliptin.
`
`ND
`ND
`ND
`-
`
`-
`
`-
`
`-
`-
`-
`ND
`
`75
`
`-
`—
`-
`-
`
`-
`
`a The bioanalytical assay that was used to measure concentrations ofBMS-S 10849 in this study may not have been completely specific for EMS-510849. Other
`mono—hydroxylated metabolites with the same MRM transition as EMS-510849 in the LC/MS/MS (332 -—> 196) may have oo-eluted with EMS-510849 under
`the conditions employed in the assay. Therefore the reported concentration values for EMS-510849 may include EMS-510849 and other mono-hydroxylatod
`metabolites. The measurement ofssxaglipfin was not impacted in this method.
`
`46
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`SM! ”BMW“ m“ “fl”
`
`'
`
`Species/Strain:
`
`Pharmacokinetics: Absorption After a Single Dose (BMS—510849, Rat)
`Pharmacoldnetlcs of EMS—510849 in Sprague-Dawley Rats following Single Dose Intravenous, Subcutaneous,
`and Oral Administration of EMS-510849
`Test Article:
`BMS- 510849
`Study Type:
`Non-GLP
`Location in Dossier:
`Study NoJDoeument Control Number:
`TSU3725/930023244
`Rat/Harlan Sprague-Dawley
`
`Gender (M/F) [Number “Animals:
`Feeding condition:
`.
`Vehicle/Formulation:
`
`Male I 3 per dose
`Fasted overnight and fed 4 h afler
`dosing
`10 mM citrate buffer, pH
`4/soiution
`
`Male / 3 per dose
`Fasted overnight and fed 4 h after
`dosing
`10 mM citrate buffer, pH
`4/soiution
`
`Method of Administration:
`Sample (Whole blood, plasma, serum etc.):
`Analyte:
`Assay:
`
`1V Bolus
`Plasma
`EMS-510849
`LC/MSIMS
`75
`m
`
`Bill‘s-510849 Dose (mg/kg):
`Route:
`Parameter
`.
`
`Cmax (pg/mL)
`298 :1: 26.1
`84.5 :t 14.8
`136 i 19.2
`2.00, 6.30
`6.14, 5.91
`AUC(0-infinity) (ug*h/mL)
`52.9 i 7.38
`137 1: 42.3
`274 :1: 15.6
`9.74, 17.9
`29.5, 28.1
`
`Tmax (1'!)
`0.0333 1 0.00
`0.583 t 0.144
`0.583 t 0.144
`1.00, 1.00
`0.500, 1.00
`
` CLTp (Uh/kg) 1.4310186 - - - -
`
`
`
`
`
`
`Vss (leg)
`0.920 i 0.203
`-
`-
`-
`-
`
`TM 0‘)
`11.4 i 7.21
`-
`.
`.
`_
`-
`129
`Bioavailability (%)
`129
`2.30, 4.23
`3.49, 3.32
`Additional Information: EMS-510849 was poorly absorbed in rats following oral administration. However, the absorption was approximately complete
`following aubuuhmeoua administration.
`a individual animal values ofpliarmaeoldnetio parameters are listed instead of group mean :1: SD values; phannacokinetie parameters were only determined in 2
`of3 rats in the oral dosing groups because incomplete concentration versus time profiles were obtained from 1 rat/group.
`
`Male/ 3 P51" dosea
`Fasted overnight and fed 4
`h afier dosing
`05% Methoeel A4M
`(citrate bufl'ered,
`pH 4)/suspension
`Oral gavage
`Plasma
`BMS— 510849
`LC/MS/MS
`600
`1200
`
`Subcutaneous
`Plasma
`BMS- 510849
`LC/MS/MS
`
`150
`
`300
`
`a
`
`:2
`
`Study Description or Title:
`
`Pharmacokinetics: Absorption After a Single Dose (Saxagiiptin, Dog)
`Pharmacoldnetica of Saxngliptin 1n Beagle Dogs following a Single Dose Intravenous or Oral Administration of
`Saxagllptin
`
`Saxagliptln
`Non~GLP
`
`Test Article:
`Study Type:
`lactation in Dossier:
`4
`
`Study NoJDocument Control Number:
`MAP005-477i 13/930000866
`Species/Strain:
`Dog/Beagle
`Male / 2 per treatment
`Gender (M/F) / Number ol'Animals:
`Male / 2 per treatment
`Fastcd overnight and fed 4 h aficr
`Feeding condition:
`Footed ova-night and fed 4 h aficr
`dosing
`dosing
`Water
`Water
`Oral gavage
`[V infusion (10 min)
`Plasma
`Plasma
`Saxngliptin
`Snxagliptin
`LC/MSMS
`LC/MS/MS
`5.2
`5.9
`Suagliptin Dose (mg/kg):
`Route:
`l!
`:9.
`Parameter
`
`
`Cmax (Pg/mL)
`10.1
`2.7
`
`AUC(0-infinity) (ugxhlmL)
`10.7
`7.3
`
`Tmax (h)
`-
`1.2
`
`CL'i'p (mi/min/kg)
`9.3
`-
`
`Vaa (leg)
`1.3
`-
`
`T1/2 (h)
`3.0
`-
`Amount excreted unchanged in urine
`40
`ND
`
`(0-24 h, %)
`Bioavaiiability (°o)
`-
`76
`Additional infomation: ND = not delcrmined
`Saxagiiptin was Welland rapidly absorbed in dogs. Soxagliptin showed intermediate clearance, and was excreted in urine as parent.
`
`Vehicle/Femulation:
`Method “Administration:
`Sample (Whole blood, plasma, serum eta):
`Analyte:
`Assay:
`
`.
`
`.
`
`47
`
`

`

`Reviewer: Fred Alavi, PhD.
`
`NDA No. 22-350
`
`Pharmacokinetics: Absorption After a Single Dose (Saxagliptin, Monkey)
`SI“dy Description or Title:
`Phorrnaeokinetics of Saxagliptln in Cynomolgus Monkeys following Single Dose Intravenous or Oral
`Admrnrltratron of Saxaglrptrn
`Test Article:
`Saxagliptln
`Study Type:
`Non-GLP
`Location in Dossier:
`MAP005-477118/930000866
`Study No./'Docurnent Control Number:
`~————————___—_.—__—____—__—
`Monkey/Cynomoigus
`Species/Strain:
`
`Gender (M/F) I Number ofAnimals:
`Feeding condition:
`
`Vehicle/Formulation:
`Method “Administration:
`Sample (Whole blood, plasma, serum ate):
`Analyte:
`Assay:
`
`BMS477113 Dose (uglkg):
`
`Male / 2 per treatment“
`Fasted overnight and [ed 4 l1 alter
`dosing
`Water
`IV infusion (10 min)
`Plasma
`Saxugiiptin
`LC/MS/MS
`3.4
`
`Male / 2 per treatment
`Fasted overnight and fed 4 h afier
`dosing
`Water
`Oral gavage
`Plasma
`Saxagliptin
`LC/MS/MS
`3.4
`
`Route:
`Parameter
`
`E
`
`19
`
`1,0
`5.4
`Cmax (uglmL)
`AUC(0-infinily) (tlgxl’I/mL)
`3.9
`2.0
`
`Tmax (h)
`—
`1.0
`
`CLTp (mIJminlkg)
`-
`14.5
`~
`
`Vss (L/kg)
`1.8
`-
`
`T1/2 (h)
`4.4
`-
`
`% dose excreted unchanged in urine
`60
`ND
`(0-24 h)
`
`
`
`-Bioavsilability (%) 51
`Additional information: ND = not determined Saxagiiptin was rapidly absorbed in monkeys. The oral bioavailability was approximately 51%
`Saxagligtin showed moderate to high clearance and was extensively eliminated in urine.
`a Phsrmseokinetio parameters were determined in only 1 of2 monkeys assigned to intravenous administration; the second monkey administered ssxogliptin
`intravenously was euthanized 4 hours after drug administration.
`
`Pharmacokinetics: Organ Distribution (Tissue: Plasma Concentration Ratios)
`
`Sill"! DfiffiP‘ififl 0" Title: Tissue Distribution of Radioactivity in Male Long-Evans Rats following Oral Administration of [14C]Snxagliptln
`
`[14C]Snagliptin
`Test Article:
`Study Type: Non-GLP
`location in Dossier:
`Study NoJDocnment Control NIL: DDBSM8/930007588
`Long-Evans Rats
`Species:
`Gender (M/F) / Number of Animals: Male / 24 (3 rats per time point)
`Feeding condition:
`Famed overnight and for 4 h after dosing, then fed ad libitum for the remainder ofthe study
`Vehicle/Formulation:
`0.011 M hydrochloric acid in water
`Method ofAdministration:
`Oral
`I
`
`Dose (mg/kg):
`Radionuclide:
`Specific Activity: ~
`Sampling time:
`Matrix
`
`-
`
`20 mg/kg (100 pCi/kg)
`14c
`5.84 pCi/mg
`0, 1, 4, 12, 24, 48, 96 and 168 h
`
`l h
`Mean 1 SD
`
`Tissue:Plasrna Concentration Ratios
`4 h
`Mean :l: SD
`
`12 h
`Mean :i; SD
`
`0.32 1 0.55
`0.08 1 0.07
`0.11 t 0.03
`Mime (ePidide‘)
`0.95 1 0.52
`0.30 :i: 0.36
`0.51 :t: 0.18
`“‘90“ (”ism“)
`—-—_—-———————._—.——_—_____—_____—
`Adipose (subcutaneous)
`0.30 :r; 0.08
`0.31 1 0.05
`0.00 1- 0.00
`
`48
`
`

`

`4.17 :l: 1.06
`0.91 $0.24
`0.34:1: 0.01
`Eyes
`1.27 :I: 0.26
`0.55 :l: 0.05
`0.51 :t 0.02
`Heart
`8.77 t 1.46
`245.17 t 205.25
`1.68:1: 0.81
`lle'um
`4.01 i 2.07
`61.23 i 27.13
`0.82:1: 0.17
`Intestine, Large
`
`25.21 1: 29.07
`8.05 :1: 1.96
`37.12 i: 7.41
`Jejunum
`5.32 i 0.54
`20.22 i 4.86
`4.50 1' 0.31
`Kidneys
`32.91 :I: 10.34
`74.05 i 9.79
`17.18 :1: 2.23
`Liver
`1.31 i: 0.08
`3.65 i 0.44
`0.91 :l: 0.07
`Lungs
`1.02 :t 0.14
`1.42 i 0.17
`0.95 :t 0.03
`Pancreas
`0.38 :1: 0.10
`0.18 i 0.31
`0.40 i: 0.04
`Skeletal Muscle (pectoral)
`0.38 :t 0.04
`1.20 i 0.15
`0.40 :1: 0.04
`Skeletal Muscle (thigh)
`0.73 :1: 0.08
`0.48 t 0.84
`0.55 :l: 0.02
`Skin, Nonpigmented
`1.11 :1: 0.41
`5.63 :t 5.45
`0.58 :1: 0.08
`Skin, Pigmented
`0.73 i 0.14
`2.63 :1: 0.38
`0.84 :t: 0.07
`Spleen
`1.14:“. 0.15
`1.12i 0.18
`2.30:1: 1.36
`Stomach
`Testes
`0.25 i 0.02
`0.66 :1: 0.07
`1.54: 0.41
`
`Thyroid
`1.53 i 0.20
`1.24 i 0.30
`1.23 i- 2.13
`Urinaw Bladder
`5.33 t 3.29
`41.97 i 53.88
`22.78 :1 17.26
`the 12 1: Lime
`Additional Information: Tissue:
`lasma ratios are onl
`re
`int since lasma levels ofradioactivit were not measurable afier 12 h.
`
`
`
`
`
`
`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350
`
`l4
`51““! Description 0" Title: Tissue Distribution of Radioactivity in Male Long-Emu: Rats following Oral Administration of [ CISaxngliptin
`
`Pharmacokinetics: Organ Distribution (Tissue: Plasma Concentration Ratios)
`
`114C]Snxaglipfin
`TestArtlcle:
`Study Type: Non-GLP
`Location in Dossier:
`
`Study NIL/Document Cnntml No.3 DDBSOS81930007588
`Matrix
`Tissuefl’lasmn Concentration Ratio:
`1 h
`4 h
`12 h
`Menu :1: SD
`Mean 1 SD
`Meant SD
`
`Adrenal Glands
`0.99 i 0.12
`0.913: 0.10
`2.18 5: 0.27
`Blood
`0.71 i 0.05
`0.88 :l: 0.04
`1.55 :l: 0.31
`Bone (femur)
`0.16 i 0.03
`0.13 t 0.12
`0.00 :l: 0.00
`Bone Marrow (femur)
`0.83 i 0.08
`0.85 :1: 0.04
`2.193: 0.12
`Brain
`0.041: 0.01
`0.68 i 1.07
`0.34 :t: 0.18
`Ceeum
`0.43 i 0.05
`36.51 1: 33.23
`95.79 1: 67.45
`Duodcnunl
`5.38 :1: 1.40'
`8.72 :l: 1.39
`3.81 i 0.21
`
`-
`
`_
`
`>
`
`V
`
`49
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`Pharmacokinetics: Organ Distribution (Mean Percentage of Radioactive Dose in Rat Tissues)
`
`Sm“? ”BMW” 0" Tm” Tissue Distribution ofRadioactivity In Male Long-Evans Rats following Oral Administration of [“anxngnpun
`Test Article:
`[14C]Soxagliptin
`Study Type: Non—GLP
`Location In Dossier:
`Stud! Nth/Document Control No: DDBS0381930007588
`
`Rat/Inng-Evans
`W24 (3 rats per time point)
`chd overnight and for 4 h after dosing, then fed ad Iibi‘tum for the remainder ofthe study
`0.011 M hydrochloric acid in water
`Oral
`20 mg /kg (100 uCi/kg)
`l4C
`5.84 pCi/mg
`0, 1 4, 12, 24, 48 96 and 168 1!
`
`Mean Percentage ofthe Radioactive Dose in Tissues and Gastrointutinal Tract Tissues
`4 h
`1 h
`
`Means»
`
`
`
`
`
`
`
`
`
`
`
`Species/Strain:
`Gender (M/F) I Number ofAnimals:
`Feeding condition:
`Vehicle/Formulation:
`Method ofAdministration:
`Dose (mg/kg):
`Radionuclide:
`Specific Activity:
`Sam [in time:
`
`
`Tissues/Organs
`
`
`Adiposeoubcummo ——n_|i_ii__
`_m_u_u_ii_m—In—
`—_——in_m_in_
`_——____
`———_m-iii—_
`I_——_m__m_
`_————__
`
`12h
`
`24» “-2:-
`Mean :i: S
`Mean :i: SD
`
`—m_—_-—m_
`_—m—m_n_n_u_
`——_ii_in_m-in_
`II_—__—E__
`mmc Large——_—__
`,
`_—__——ii_
`—————__
`—_—_——m_
`
`—_——IE_I§E-IT2_
`_—_E_li_
`mo:-
`IE—EE-
`E_E_
`
`.
`__—_E—
`
`m“_
`—__in—
`_—_I:_
`
`—_m__
`
`
`
`
`
`
`
`
`
`
`
`
`Abbreviations: SD = Standard Deviation; ND = Not detected. Concentrations of[,4C]saxagliptin-derivcd radioactivity were below the limit ofquantification
`
`50
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22—350
`
`Study Description or Title:
`
`Pharmacokinetics: Organ Distribution (Saxagliptin, Sprague—Dawley Rat)
`Tissue Distribution of Snagliptin and EMS-510849 ln Spmgue—Dawley Rats following Single Dose Intraarterlnl _
`Admlnlatration of Samgltptin
`
`Test Article: Samgliptln
`Study Type: Non-GLP
`Location In Dossier:
`
`Study NoJDot-umcnt Control NIL: 930009229
`Species/Strain:
`Rat/Spraguc Dawley
`Gender (M/F) / Number of Animals: Male/3 per dose
`Feeding condition:
`Fasted overnight and for duration of study
`Vehicle/Formulation:
`Propylene glycol:water (50:50)
`Method ofAdministration:
`Intr-aanerial Bolus
`
`_
`
`'
`
`Dose (mg/kg):
`Radionuclide:
`
`Specific Activity:
`Sampling time:
`
`0.1 or 2.5 mg/kg Saxagliptin
`None
`
`NA
`1 h
`
`Tissues/organs
`
`Saxagliptin
`Dose (mg/kg)
`
`EMS—5108493
`Saxagliptin
`Average Concentration
`Tlssued’lasma
`Average Concentration
`Tlssued’lasma
`
`(ng/g) 1: SD
`Rntlo 1: SD-
`(nglg) :1: SD
`Ratio :1: SD
`Plasma
`0.1
`4 :1: 2
`1
`I
`1.3 i 0.4
`1
`
`2.5
`97 i 23
`1
`48 t 18
`1
`
`Small Intestine
`0.1
`159 1:15
`46 1:18
`28 :l; 5
`H
`24 1:10
`
`i
`2.5
`942i193
`101:1
`23961348
`‘
`55121
`
`Large lntestine
`0.1
`71 i 13
`20 i 5
`BLQ
`NA
`
`Duodenum
`
`Kidney
`
`Spleen
`
`Heart
`
`Pancreas
`
`Brain
`
`,
`
`25
`0.1
`
`2.5
`
`0.1
`
`2-5
`
`0.1
`
`2.5
`
`0.1
`2.5
`
`0.1
`
`2.5
`
`0.1
`
`2.5
`
`2205i411
`501 22
`
`134t10
`
`1243 :t 76
`
`1373i282
`
`so 1 23
`
`3Bi50
`
`39 i 7
`224 :1: 34
`
`26 d: 5
`
`186 i 20
`
`1
`
`s i 1
`
`24i8
`1519
`
`1:0.3
`
`349 i 102
`
`14i1
`
`21: 3
`
`4i]
`
`11 j; 3
`2 :l: 0.3
`
`7 i 2
`
`2i 0.3
`
`0.1
`
`0.08 i 0.01
`
`113:1:20
`15:1
`
`329:106
`
`68 :l: 9
`
`4171110
`
`2
`
`131:9
`
`BLQ
`27:1: 8
`
`12
`
`32:1:5
`
`BLQ
`
`BLQ
`
`3i]
`14
`
`7:1
`
`53 i 9
`
`9:2
`
`1
`
`0.3i0.1
`
`NA
`0.6 :l: 0.1
`
`10
`
`0.71:0.2
`
`NA
`
`NA
`
`‘
`
`W 2
`
`0.11 0104
`7 i 4
`3 i]
`i
`291: 21
`.5
`——————_—_____________—_—~,_______
`
`Additional Information: Plasma and tissue homogenates were analyzed for saxagliptin and EMS-510849 using LC-MS/MS. SD = Standard Deviation; BLQ =
`below the lower limit of quantification; NA = not applicable. EMS-510849 lower limit of quantification: 8.6 ng/g (large intestine), 10.3 ng/g (heart), 2 nyg
`(brain), and 1.8 ng/g (muscle)
`___—____—_____—_—__________——___
`
`a The bioanalytical assay that was used to measure concentrations of EMS-510849 in this study may not have been completely specific for EMS-510849. Other
`mono—hydroxylated metabolites with the same MRM transition as EMS-510849 in the LC/MS/MS (332 —> 196) may have co-eluted with EMS-510849 under
`the conditions employed in the assay. Therefore the values for EMS-510849 concentration reported here may include EMS-510849 and other mono—
`hydroxylatcd metabolites. The measurement of saxagliptin was not impacted in this method.
`
`

`

`Reviewer: Fred Alavi, PhD.
`
`NDA No. 22-350
`
`Pharmacokinetics: Organ Distribution (EMS-510849, Sprague-Dawley Rat)
`
`510849
`Study Description or Tltle: Tissue Distribution ofBMS—510849 ln Sprague-Dawley Rats followmg Single Done Intraartenal Administration of EMS-
`Test Artlcle: BMS—510849
`Study Type: Non—GLP
`Localion in Dossier:
`
`Study NoJDacumcnt Control No.:
`
`930009229
`
`Rat/Sprague-Dawley
`Species/Strain:
`Gender (M/F) / Number of Animals: Male/3 per dose
`Feeding condition:
`Fasted overnight and for duration ofstudy
`Vehicle/Formulation:
`Propylene glycolzwater (50:50)
`Method ofAdministration:
`lnfl'anrterial Bolus
`Dose (mg/kg):
`0.1 or 2.5 mg/kg EMS-510849
`Radionuclide:
`None
`Specific Activity:
`NA
`Sampling time:
`1 h
`
`‘
`
`Tissues/organs
`
`Plasma
`
`Small Intestine
`
`Large Intestine
`
`'
`
`Duodenum
`
`Kidney
`
`Spleen
`
`Heart
`
`Pancreas
`
`Brain
`
`BMS-510849
`Dose (mg/kg)
`0.1
`2.5
`
`'
`
`BMS—510849
`Average Concentration (nglg) :3: SD
`5 i l
`103 :t: 18
`
`BMS—510849
`Thane:Plasma Ratlo 1 SD
`1
`1
`
`0.1
`
`2.5
`0.1
`
`2.5
`0.1
`
`2.5
`
`0.1
`2.5
`
`0.1
`2.5
`
`0.]
`
`2,5
`
`0.1
`2.5
`
`0.1
`
`2.5
`
`27 t 9
`
`1953 i 1029
`16 2t 12
`
`3191:81
`14
`
`229 :t 24
`
`1411 t 138
`3030 :l: 282
`
`491: 14
`139 i 39
`
`30 i 5
`
`146 i 25
`
`36 :l; 6
`488 t 42
`
`BLQ
`
`8.5 1 7.5
`
`.
`
`5 i 2
`
`20 :l: 14
`3 i 3
`
`3:05
`2.7
`
`2 :t 0.5
`
`271 :t: 39
`30 i: 8
`
`91:3
`It 0.2
`
`6 j: l
`
`11: 0.01
`
`7: 0.4
`5 i 0.6
`
`NA
`
`0.09 1 0.04
`
`‘
`
`Muscle
`0.1
`3.3
`0.7
`64.6 i 9.2 '2.5 0.6 :t 0.1M
`
`Additional Information: Plasma and tissue homogenates were analyzed for EMS-510849 using LC—MS/MS. SD = Standard Deviation; BLQ = below the lower
`limit of quantification; NA = not applicable. EMS-5 l0849 lower limit of quantification in mt brain homogenate: 2 ng/g.W
`
`
`
`
`
`52
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`Pharmacokinetics: Organ Distribution (Saxagliptin, Zucker Diabetic Fatty Rat)
`Tissue Distribution of Saxagliptin and EMS-510849 In Zucker Diabetic Fatty Rats following Single Dose Intraarterial
`Study Description or Title: Administration of Suagliptin
`
`Test Article: Samgliptin
`Study Type: Non-GLP
`Location in Dossier:
`
`
`Study NoJDocument Control No.:
`930009229
`Species/Strain:
`Rnt/Zucker Diabetic Fatty
`Gender (M/F) / Number of Animals: Male/3 per dose
`Feeding condition:
`Fasted overnight and for duration ofstudy
`Vehicle/Formulation:
`Propylene glycolzwater (50:50)
`Method of Administration:
`Intraarterisl Bolus
`
`Dose (mg/kg):
`Radionuclide:
`
`0.1 or 2.5 mg/kg Saxagliptin
`None
`
`Specific Activity:
`NA
`Sampling time:
`1 11
`
`
`Tissues/organs
`
`Saxagliptin
`Dose (mg/kg)
`
`
`Saxagliptin
`EMS—510849,
`Average Concentration
`Tlssue:l’lasma
`Average Concentration
`Tlssue:1’lasmn
`
`(11ng 1: SD
`Ratio :1: SD
`(mg/g) :1: SD
`Ratio 1 SD
`Plasma
`0.1
`14 i 11
`i
`0.7 t 0.03
`1
`2.5
`148 i 70
`l
`34 i 7
`1
`
`Small Intestine
`0.1
`164 i 2]
`17 :1: 9
`29: 10
`39:1: 15
`
`2.5
`759 t 392
`6 t 4
`943 :1: 47s
`28 i 15
`Large intestine
`0.1
`81 i 43
`10 i 8
`18
`. 24
`
`
`2.5
`15471 524
`13i8
`140:63
`4:3
`Duodenum
`0.1
`60:1: 13
`6:1:4
`193:8
`24i9
`2.5
`1791-. 74
`11:0.2
`2541119
`712
`——__—___—____._—___—__—_
`Kidney
`0.1
`923 $316
`87134
`20:02
`27:1
`
`8 i 2
`2711: 41
`21 :1: 11
`2662i 340
`2.5
`——~__—_—_____—__—____________
`
`Spleen
`
`NA
`BLQ
`16 i 12
`139 i 43
`0.1
`0.71: 0.3
`221:9
`9:1
`1300i 656
`2.5
`—————__—___._—______—__—__
`
`'
`
`Heart
`
`NA
`BLQ
`8 i 5
`26 i- 9
`0.1
`0.5:t0.l
`1715
`33:1
`236:108
`2-5
`-——._____—_—__________—_—
`Pancreas
`0.1
`115 i 70
`36 :t 30
`BLQ
`NA
`
`7.5
`940 i 671
`10 :1: 8
`BLQ
`‘
`NA
`
`
`Brain .
`0.1
`BLQ
`NA
`9b
`NA
`2.5
`10 :t: 1
`0.07 i 0.02
`0.8
`0.02
`
`
`Muscle
`
`0.1
`
`23 :t: 2
`
`2 :t: 1
`
`BLQ
`
`NA
`
`0.2 :i: 0.04
`5.6 :1: 2
`4 t 0.5
`500 $170
`2.5
`————__._—__—.—__._______—_________—
`
`Additional Information: Plasma and tissue homogenates were analyzed for saxagliptin and EMS-5] 0849 using LC—MS/MS. SD = Standard Deviation; BLQ =
`below the lower limit ofquantification; NA = not applicable. Saxagliptin lower limit of quantification: 0.77 ng/g (brain); EMS-510849 lower limit of
`——————__—.—.—_____—_______
`quantification: 22.3 rig/g (pancreas), 2.5 rig/g (heart), 1.8 ng/g (spleen), 0.8 ng/g (muscle), and 0.77 ng/g (brain).
`
`a The bioannlytiool assay that was used to memurc concentrations of EMS-510849 in this study may not have been completely specific for EMS-510849. Other
`mono-hydroxylated metabolites with the same MRM transition as EMS-510849 in the LC-MS/MS (332 ~—> 196) may have co-elutcd with EMS-510849 under
`the conditions employed in the assay. Therefore the values for EMS-510849 concentration reported here may include EMS-510849 and other mono—
`hydroxylated metabolites. The measurement ofsaxagliptin was not impacted in this method.
`b Represents mean value of 2 rats (Rat 1 = 16.6 ng/g, Rat 2 = 1.2 nyg, Rat 3 = BLQ)
`
`53
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`Pharmacokinetics: Organ Distribution (BMS-510849, Zucker Diabetic Fatty Rat)
`Tissue Distribution of BMS—510849 in Zucker Diabetic Fatty Rats following Single Dose Inmarterial Administration of
`Study Description or Title: BMS—510849
`
`Test Article: EMS-510849
`
`Study Type: Non-GLP
`Location in Dossier:
`
`Study Nix/Document Control No.:
`930009229
`
`Species/Strain:
`Rut/Zucker Diabetic Fatty
`Gender (M/F) / Number of Animals: Mule/3 per dose
`Feeding condition:
`' Fasted overnight and for duration ofstudy
`Vehicle/Foundation:
`Propylene glycol:water (50:50)
`Method of Administration:
`intmarterial Bolus
`
`Plasma
`
`0.1 or 2.5 mg/kg EMS-510849
`Dose (mykg):
`None
`Radionuclide:
`NA
`Specific Activity:
`1 h
`Sampling time:
`—-—-—-—-——————————————————-—————_—_—
`Tissues/organs
`HMS-510849.
`EMS—510849
`EMS-510849
`
`V Tianue:Pleamn Ratio 1: SD
`Average Concentration (ng/g) i SD
`Dose (mg/kg)
`1
`10 :1: 2
`0.1
`1
`346 t 52
`2.5
`—————-——___—_____________—_—_____
`Small Intestine
`0.1
`25 :i: 4
`3 :1: 0.1
`2.5
`920 :i: 165
`3 :i: 0.2
`————.__—____—______________
`Large intestine
`0.1
`17 i 3
`2 :i: 0.4
`2.5
`389 i 52
`1
`————————_.——__~.___——________—
`Duodenum
`0.1
`17 :t 9
`,
`1.6 :1: 0.6
`25
`407:119
`110.4
`_—————.—__—__—_—_____—__—____
`Kidney
`0.1
`940 i 106
`94 i 11
`2.5
`3019i429
`91:2
`——————________—_*______
`Spleen
`0.1
`7] i 7
`7 i l
`,
`2.5
`3171105
`11:0.2
`—————————___——____.__—__—_—___
`
`A
`
`:
`
`1i0.3
`1212
`0.1
`Heart
`
`
`2181102-5 121:0.lW
`0.1
`56 1 3
`Pancreas
`5
`
`5i!
`1553i365
`2-5
`——-————————_—.—.—__.________—______
`0.1
`0.79
`0.06
`Brain
`
`2.5
`
`
`
` 12 i 2
`
`0.04 i 0.01
`
`Muscle
`
`0.4 i 0.3
`4 i 2
`0.1
`0.53:0.1
`155 21:27
`2.5
`——-——————_____—_~_—_—___—_
`-—————-——————————_______________——
`Additional Information: SD = Standard Deviation. Plasma and tissue homogenates were analyzed for BMS-510849 using LC-MS/MS.
`
`54
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22—350
`
`Pharmacokinetics: Organ Distribution (Quantitative Whole Body Autoradiography in Male Sprague
`anley Rat)
`determined by quantitative whole body automdlography in male Spmgue Dawley rats
`Tissue distribution of radioactivi
`following oral administration on 4CISaxagliptln
`
`Titl :
`°
`
`it
`I
`5: a 1)
`" y “up °“ °'
`
`[“C]Saxagllptlu
`Test Article:
`Study Type: Non-GLP
`Location in Dossier:
`Study NoJDocument Comrol No.: 6108-566330022255
`
`
`
`Rat/Sprague Dawley
`Specie-c
`Gender (M/F) / Number of Animals: Male/8
`Feeding condition:
`Non-fasted
`Vehicle/Formulation:
`50 mM citrate buffer, pH 4.0/Solution (radiolabeled trifluoracetic acid salt combined with non-labeled free base
`monohydrate to give 1 mg/mL free base)
`Single dose oral gavage
`5 tug/kg free base equivalents (radioactive dose: 100 uCi/kg)
`
`Method ofAdministration:
`Dose (mg/kg):
`
`Radionuclide:
`Assay:
`
`[MC]
`Tissue distribution ofradioactivity was determined by quantitative whole body automdiogmphy (QWBA), and blood
`oonoenhations ofradioactivity were determined by liquid scintillation counting (LSC).
`
`.
`
`Sampling time:
`
`Blood and biological fluids were collated $0111 1 male rat/time point at pro-dose and l, 4, 8, 12, 24, 96, and 168 hours
`post-dose. The animal from which the pro-dose blood sample was collected was dosed with vehicle only. Carcasses were
`immediately frozen after blood and biological fluid collection for prepnrntion of samples for QWEA.
`
`Pharmcokinetle Parameters
`___________________________._-—————--————————-——
`Tissues/organs
`Cmax
`TI'I'IEIX
`AUC(0-infinlty)
`Terminal Tm
`
`(11)
`(ng cquivulents'h/g)
`(h)
`(ng equivalents/g)
`972
`1
`6970
`3.73
`Adrenal gland
`438
`1
`NC
`NC
`Blood
`
`4320
`68.9
`389
`1
`Blood (LSC)
`Bone
`NC
`NC
`NC
`NC
`Bone marrow
`636
`l
`2180
`1.9
`____________________________.____.————————————————-
`Cocum
`20500
`4
`157000
`3.62
`Cerebellum
`NC
`NC
`NC
`NC
`
`NC
`NC
`Cerebrospinal fluid
`NC
`NC
`Cerebrum
`'
`144
`1
`NC
`NC
`
`Diaphragm
`1650
`4
`NC
`NC
`_—____________—______—_._—_—————-————————
`Epididymia
`479
`1
`NC
`NC
`Esophagus
`800
`l
`4080
`3.68
`___________________—____._——___———————
`Exorbital lacrimal gland
`880
`1
`12500
`19.9
`
`Eye
`121
`1
`NC
`NC
`Eye (lens)
`121
`1
`NC
`NC
`Fat (abdominal)
`1 1‘7
`1
`1040
`5.77
`m (brown)
`348
`1
`NC
`NC
`Fat. (reproductive)
`107
`1
`NC
`NC
`Harderian gland
`727
`1
`2660
`2.08
`.
`lnuaorbital lacrimal gland
`765
`1
`NC
`NC
`__________________________________—————-———————-
`Kidney
`4790
`I
`120000
`26.3
`
`55
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350W
`
`Pharmacokinetics: Organ Distribution (Quantitative Whole Body Autoradiography in Male Sprague
`Dawley Rat)
`
`ti
`‘
`Stud D
`y ”cup on or
`
`:
`
`T‘tl
`I e
`
`detennlned by quantitative whole body autor-adingraphy in male Spragua Dawley rats
`Tissue distribution ofradiuactivi
`following oral administration of [ 4C]Staxagll|:ttln
`
`.
`
`[14C]Saxagllptin
`Text Article:
`Study Type: Non—GLP
`Location in Dossier:
`
`Study NIL/Document Control No.: 6108-566/930022255W
`Tissues/organs
`Cmax
`Tmax
`AUC(0-intinity)
`Terminal T1I2
`
`(In)
`(ng equivalents/g)
`(h)
`(ng equivalents‘h/g)
`4.87
`1.940
`12
`22500
`Large intestine
`10400
`1
`138000
`19.8
`Liver
`704
`l
`6740
`7.33
`Lung
`793
`l
`5660
`3.44
`Lymph nodes (mesenten'c)
`NC
`NC
`NC
`NC
`Medulla
`NC
`NC
`338
`1
`Muscle
`
`NC
`NC
`464
`I
`Myocardium
`329
`1
`1130
`1.91
`Nasal turbinates
`224
`1
`NC
`NC
`Olfactory lobe
`Pancreas
`576
`1
`4090
`5.59
`
`Pituitary gland
`525
`1
`NC
`NC
`Plasma
`483
`l
`3130
`22.2
`Preputial gland
`543
`1
`NC
`NC
`Prostate
`1020
`4
`9690
`5.57
`Renal cortex
`4680
`1
`72300
`18.1
`Renal medulla
`5510
`I
`141000
`33.6
`Renal medulla (high)
`6910
`1
`410000
`55.2
`Salivary gland
`742
`1
`2390
`1.74
`Seminal vesicle
`480
`12
`NC
`NC
`Skin
`363
`l
`3230
`6.62
`Small intestine
`5020
`1
`30400
`2.46
`Spinal cord
`NC
`NC
`NC
`NC
`Spleen
`770
`1
`7630
`10.5
`
`2.86
`1350
`l
`.
`6120
`Stomach
`5.16
`235
`1
`1870
`Testis
`515
`1
`2570
`3.05
`Thymus
`
`951
`1
`NC
`NC
`Thyroi
`NC
`NC
`NC
`NC
`Trachea
`.
`7430
`l
`108000
`3.19
`Urinary bladder
`Additional Information: Animal from which pre-dose sample was collected had no detectable radioactivity. NC = not calculable because sample below limit of
`quantitation (< 75.5 ng equivalents ["C]saxaglipitnlg) or radioactivity not detectable (sample shape not discernible fi-om background or surrounding tissue).
`The “C-saxagliptin-derivcd radioactivity was extensively distributed in tissues. The highest concentrations were found in GI contents and urine, which is
`consistent with the route of oral administration and the major elimination pathways of saxagliptin. Besides gastrointestinal tissues and urinary bladder, kidney and
`liver showed highest radioactivity. A differential distribution ofradioactivity was observed in the renal medulla. The radioactivity was quantifiable only in kidney
`and liver at 96 hours post-dose. The tissues showing lowest mdiouctivity included cerebellum, CSF, spinal cord, olfactory lobe, trachea, bone, eye and lens ofeye.
`At 168 hours, the final collection time point, the radioactivity was not quantifiable in any tissues. The exposure of total radioactivity in cerebellum, cerebrum and
`in («his tissue in male rats.
`cerebrospinal fluid were much lower than that in plasma, indicating limited distribution to the CNS system due to blood-brain barrier. Radioactivity was detected
`H—
`
`'
`
`56
`
`

`

`
`
`
`
`VReviewer: Fred Alavi PhD. NDA No. 22-350
`
`Pharmacokinetics: Organ Distribution (Quantitative Whole Body Autoradiography in Female Sprague
`Dawley Rat)
`
`rl ti
`St d 1)
`u y ”c P on or
`
`T tl :
`I e
`
`Tissue distribution ofradioactivity determined by quantitative whole body automdiography in female Sprague Dawley rats
`‘
`followlngoral administration of [14C]Sa.xagllptln
`
`[14C]Snxngliptin
`Text Article:
`Study Type: Non-CL?
`Location In Dossier:
`
`
`
`Study NoJDocumcnt Control No.: 6108-566I93002225S
`
`Rat/Sprague Dawley
`Species:
`Genda- (M/F) I Number of Animals: Non-pregnant female/8
`Feeding condition:
`Non-fasted
`Vehicle/Formulation:
`50 mM citrate buffer, pH 4.0/Solution (radiolabeled trilluoraeetio acid salt combined with non-labeled free base
`monohydrate to give 1 mglmL free base
`Single dose oral gavnge
`5 rug/kg free base equivalents (radioactive dose: 100 uCi/kg)
`
`Method ofAdministration:
`Dose (mg/kg):
`
`Radionuclide:
`Assay:
`
`[14C]
`Tissue distribution was determined by quantitative whole body autoradiography (W'BA). Blood concentrations of
`radioactivity were determined by liquid scintillation counting (LSC).
`Blood and biological fluids were collected from 1 non-pregnant rat/time point at pre—dose and l, 4, 8, 12, 24, 96, and 168
`Sampling time:
`hours post-dose. The aniinal from which the pro-dose blood sample was collected was closed with vehicle only. Carcasses
`were immediately frozen afier blood and biological fluid collection for the preparation ofsamples for WBA.
`Pharmacoklnefie Parameters
`
`Tissues/organs
`Crnax
`Tmax
`AUC(0-lnfinlty)
`Terminal T112
`
`(ng equivalents/g)
`(It)
`(ng equivalents‘h/g)
`(h)
`
`Adrenal gland
`887
`1
`6190
`4.34
`
`Blood
`33 l
`l
`l 380
`2.46
`
`Blood (LSC)
`398
`l
`2010
`7.57
`Bone
`NC
`NC
`NC
`NC
`
`Bone marrow
`833
`l
`3480
`2.47
`—____—__—_—_____—_—.___——.————_.—
`
`. Cecum
`5560
`12
`70100
`3.32
`
`Celebellum
`NC
`NC
`NC
`NC
`
`Ccmbrospinal fluid
`NC
`NC
`NC
`NC
`Cerebrum
`77.1
`4
`NC
`NC
`
`
`Diaphragm
`1070
`l
`3460
`1.75
`
`Esophagus
`858
`l
`2760
`1.74
`
`Exorbital lacrimal gland
`1430
`1
`11400
`5:47
`
`Eye
`NC
`NC
`NC
`.
`NC
`
`Eye (lens)
`NC
`NC
`NC
`NC
`
`Fat (abdominal)
`l 17
`4
`NC
`NC
`
`Fat (brown)
`400
`1
`NC
`NC
`
`NC
`NC
`Fat (reproductive)
`98.7
`4
`
`Harderian gland
`826
`l
`5280
`4.05
`
`Immorbital lacrimal gland
`878
`l
`8120
`4.80
`
`Kidney
`4760
`1
`126000
`32.8
`
`Large intestine 14.1 1170 12 ‘ 21200
`
`
`
`
`
`57
`
`

`

`
`
`Reviewer: Fred Alavi Ph.D. NDA No. 22-350M
`
`Pharmacokinetics: Organ Distribution (Quantitative Whole Body Autoradiography in Female Sprague
`Dawley Rat)
`
`Study Description or Title:
`
`4
`Tissue distribution of radioactivity determined by quantitative whole body autoradiography in female Sprague Dawley rats
`following oral administration of fl C]Saxagllptln
`
`[14C]Saxagliptin
`Test Article:
`Study Type: Non—GLP
`[mention in Dossier:
`
`Study NoJDocument Control No.:
`
`SIDS-566330022255
`
`Tissues/organs
`
`.
`
`Cmax
`(ng equivalents/g)
`
`Tmax
`(h)
`
`AUC(0-infinity)
`(ng equivalents‘lI/g)
`
`I
`i
`1
`4
`I
`1
`4
`NC
`1
`1
`1
`l
`
`'
`
`Terminal '1‘]/2
`(h)
`6.83
`39800
`6700
`Liver
`
`5690
`3.27
`' 898
`Lung
`NC
`NC
`780
`Lymph nodes (monomeric)
`NC
`NC
`75,8
`Medulla
`2020
`4.48
`288
`Muscle
`2260
`2.63
`513
`Myocardium
`NC
`NC
`195
`Nasal turbinates
`NC
`NC
`NC
`Olfactory lobe
`1810
`3.63
`312
`Ovary
`3820
`4.65
`527
`Pancreas
`3030
`2.58
`698
`Pituitary gland
`1790
`4.36
`451
`Plasma
`6490
`4.71
`885
`Preputial gland
`80500
`23.7
`4910
`Renal cortex
`93600
`17.1
`4300
`Renal medulla
`246000
`23.9
`7110
`Renal medulla (high)
`4950
`3.59
`887
`Salivary gland
`2730
`5.1 5
`343
`Skin
`NC
`NC
`4040
`Small intestine
`NC
`NC
`NC
`NC
`Spinal cord
`5570
`3.79
`I
`1020
`Spleen
`10300
`1.57
`1
`3290
`Stomach
`3820
`3.78
`1
`613
`Thymus
`NC
`NC
`1
`857
`Thyroid
`NC
`NC
`NC
`NC
`Tmchea
`14900
`1.85
`4
`3120
`Urinary bladder
`3460
`4.07
`l
`.
`624
`Uterus
`Additional Information: Animal from which pro-dose sample was collected had no detectable radioactivity. NC = not calculable because sample below limit of
`quantitation (< 75.5 ng equivalents [”C]Soxagliptin/g) or radioactivity not detectable (sample shape not discernible from background or surrounding tissue). The
`' C-saxagiiptin-derived radioactivity was extensively distributed in tissues. The highest concentrations were found in GI contents and urine, which is consistent
`with the route of oral administration and the major elimination pathways of saxagliptin. Besides gastrointestinal tissues and urinary bladder, kidney and liver
`showed highest radioactivity. A differential distribution ofradioactivity was observed in the renal medulla. The radioactivity was quantifiable only in kidney and
`liver at 96 hours post-dose. The tissues showing lowest radioactivity included cerebellum, CSF, spinal cord, olfactory lobe, trachea, bone, eye and lens of eye. At
`168 hours, the final collection time point, the radioactivity was not quantifiable in any tissues. The exposure of total radioactivity in cerebellum, cerebnrm and
`cerebros inal fluid were much lower than that in Iasma, indicatin limited distribution to the CNS a stern due to blood-brain barrier.
`
`
`
`'
`
`ugpa—H
`
`58
`
`

`

`Reviewer: Fred Alavi, Ph.D.
`
`NDA No. 22-350
`
`Pharmacokinetics: Protein Binding (BMs477118)
`Study Description or Title:
`Prellmtnary Protein Blndlng ofEMS-477118 In Mouse. Rat, Dog. Monkey. and Human Serum
`Test Artlcle:
`Study Typer
`Locatlon In Dossier:
`Study Nun/Document Control No.
`Test system nad method: Equlllhrlum diulysls amt LC-MSIMS
`
`Saxogllptln
`Non-6L?
`
`930025627
`
`
`Speclu
`Concentration Tested
`”/- Free
`(pg/ML)
`(mean 1: SD)
`Mouse
`25
`73.3 :t: It .5
`
`Rat
`5
`82 t 1.5
`
`
`Dog
`5
`109.0 i 303
`Monkey
`0.]
`79.6 :t: 25.5
`
`Human
`0.1
`107.91 34.2
`AddiLional Information: SD = Standard Deviation. The experiments were cam'ed out using equilibrium dialysis method in triplicate. The concentmtiona of
`anxagliptin were determined by LC-MSIMS aasay.
`'
`The retulu indicated that the m’ binding ot‘aaxggligtia is v51 low in mouse! ratI dogI monkgy and human scrim.
`Study Description or Title:
`Preliminary Protein Binding of EMS-510849 In Mouse, Rat, Dog, Monkey, and Human Serum
`Text Artlrle:
`3015510849
`Study Type:
`Non-GLI’
`lnratlnn In DolrIer:
`Study Nun/Document Control No.
`930025627
`
`
` Test cystcrn and method: Equlllhrlum dIalyula and m—MS/MS
`
`Species
`Concentration Tented
`% Free
`
` (ital-BL) (mm. 2 so)
`
`Mouse
`25
`109.71: 16.6
`
`Rat
`5
`104 i 8.4
`Dog
`5
`97.8 d: 10.5
`Monkey
`0.)
`89.4 :l: 3.0
`Human
`(H
`103.] d: 24
`- Additional Information: SD - Standard Deviation. The experiments wae carried out using equilibrium dialysis method in triplicate. The concentrations of
`BMS-Sl0349 were determined by LC'MS/MS away.
`The results indicated that the Edwin binding ofBMS-S [0849 is ve_ry low in momsI rag, dog, monkey and human serum.
`
`Study Description or Title:
`
`Pharmacokineh'cs: Study In Pregnant or Nursing Animals
`Latte»! excretlon ol‘mdloactlvlty In Iactatlng female Sprague Duwley nuts following oral mlmlnlrtratlon ol'
`"| C]BMS—477Il8
`
`("CJSaxagllpttn
`Tu: Article:
`Study Type: Non-CL?
`Location In Dosaler:
`
`Study NIL/Document Control No. aormmsoozzzss
`Excretion Into rnllk
`Species:
`Lactating date/Number of Animals:
`Feeding condition:
`
`Rat/Sprague Dawlcy
`7 In 9 days postpartum/21 lactating rats
`Non-fated
`
`'
`
`Vehicle/Formulation:
`Method ofAdministration:
`Dose (mg/kg):
`Analytic:
`Assay:
`
`50 mM citrate can“, pH ill/Solution (radiolabelcd trilluoracetia acid salt combined with non-labeled fies base
`monohydrato to grvc t nag/ml. free base
`Single doac oral gavage
`5 mg/kg fm base cquivalcnts (radioactive done: IOO uCi/kg)
`Total [MC] radioactivity
`Liquid scint