Reviewer: Laurie-McLeod-Flypg
`
`.
`
`NDA No. 22030
`
`Investigation of the cytochrome P450 3A4 induction potential of the compound SPM
`8272 in cryopreserved human hepatocytes (BA 535-02)(December 2002). SPM 8272
`did not cause a detectable induction of CYP3A4 activity or an increase in CYP 3A4
`mRNA levels in cryopreserved human hepatocytes at a concentration of 9.5 nM
`(therapeutic plasma concentration); "“"
`‘ " ‘
`‘
`'
`'
`
`Determination of the cytochrome P450 induction potential of fesoterodine in human
`hepatocytes (Study no. 692, SPM 907)(December 2004). The cytochrome P450
`induction potential of fesoterodine (20 and 200 uM) was investigated in cryopreserved
`human hepatocytes (72 hour incubation). The cutoff for a positive induction was a more
`than 200% change in enzymatic activity oftreated versus non-treated hepatocytes
`(control). Down regulation was considered significant when the enzymatic activity of the
`treated hepatocytes was below 50% of that obtained for the non-treated hepatocytes. No
`notable effects on enzyme activities associated With CYP1A2, CYP2B6, CYP2C9,
`CYP2C19, and CYP3A4 were observed:
`
`Substrate
`
`
`_-0
`(concentration)
`
`
`
`
`
`Control inducer
`
`Fesoi‘emdine
`
`
`
`117I“
`
`CYP1A2
`
`417
`
`7-ethoxyrcsmufin Omepmzole
`
`462
`
`102
`
`CYP236
`
`417
`
`(S)-mephenytoin Phenobarbital
`
`604
`
`’
`
`121
`
`129
`
`
`
`9
`
`417
`m,
`
`“P2019 417
`
`CYP3A4
`
`417
`
`(sywaritaxin
`
`Rifzmpicizi
`’3
`(S)-mepheuytoin Rifzmpicin
`
`435
`
`595
`
`103
`
`97.6
`
`Testosterone
`
`Es
`'
`icin.
`
`
`.
`
`1276
`
`.
`
`131
`
`124
`
`L
`
`nonmabohc mum.
`
`
`
`
`n.
`
`
`
`
`
`
`
`
`
`V.
`
`SPM 8272: Effect on cytochrome P450 and related parameters in ‘male and female
`CD-1 mice following oral administration at dose levels of 0, 5, 25, and 75 mg/kg/day
`(increased to 100 mg/kg/day in males and 125 mg/kg/day in females from week 16)
`for 6 months (Study no. 0798/029)(July 2002). 7-Ethoxyresorufin O-deethylase was
`used as a marker for CYPlA, testosterone 6B- and ZB-hydroxylase for CYP3A,
`testosterone 16B-hydroxylase for CYP2B, testosterone 16a— and 2u-hydroxylase for
`CYP2C and lauric acid 1 1- and 12—hydroxylase for CYPQE and CYP4A. No notable
`effects on the concentrations of hepatic microsomal protein or cytochrome P450 activities
`were observed. A decrease in testosterone 16B—hydroxylase and 60-hydroxylase (to ca
`34% of the corresponding control value, relative to microsomal protein), was observed at
`the lowest dose level in male mice.
`
`‘
`
`SPM 8272: Effect on cytochrome P450 and related parameters in male and female
`Beagle dogs folloWing oral administration at dose levels of 0, 0.5, 2.5 and 12.5
`mg/kg/day for 9 months (Study no. 0798/030)(July 2002). There were no notable
`effects on the concentrations of hepatic microsomal protein and cytochrome P45Ovor on
`
`64
`
`

`

`Reviewer: Laurie McLeod-Flmn
`
`NDA No. 22030
`
`the activities of CYPIA, CYPZB, CYPZC, CYPZE, CYP3A and CYP4A in the beagle
`dog.
`
`Interaction of the compounds SPM 8272, SPM 7605, SPM 5509, SPM 6923, and
`SPM 9078 With the cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4
`(Study no. BA 474-02)(November 2001). ' Specific CYP-substrates were metabolized to
`fluorogenic molecules in the presence of test compounds (competitors) or specific control
`inhibitors in an automated microtiter plate-based competitive assay:
`
`$203301;
`SPM 3272:
`SPM 7605:
`SPM 5509:
`SPM 6923:
`swerve:
`‘ Katownazole:
`
`V
`
`'
`
`‘
`
`0319.200:
`SPM 8272:
`SPM 7505:
`5m 5509:
`SPM 6923:
`SPM 9070:
`Qulnldlna:
`
`mPtAZ:
`SPM 0272:
`SPM 1605:
`SPM 5509:
`SPM 0000:
`SPM 9078:
`Furafylline:
`
`'
`
`3212200.
`SPM 8272:
`
`SPM 7505:
`SPM 5509:
`SPM 8923:
`SPM 0075:
`swapbenazolaz
`
`LoglCm
`
`50» {PM}
`
`.
`4.3
`3.638 :1 0.120
`40.5
`4.635 :l: 0.071
`155.2
`5.191 1: 0.538
`no Interaction detectable
`401250.040
`10.3
`1.273 1 0.046
`0.019
`1.318200%
`0.021
`1.212 e. 0032
`0.015
`
`15.6
`4.193 t 0.043
`10.0
`4.001 5 0.040
`22.0
`4.342 a 0.052
`no interaction detectable
`3.526 t 0.023
`3.4
`118700.057
`0.015
`154050.025
`0.035
`1251 2 0.041
`0.010
`
`MIN!
`
`2.8
`30.9
`99.1
`
`6.4
`0.01 2
`0.013
`0.010
`
`7.0
`5.0
`10.9
`
`1.7
`0.003
`0.015
`0.009 '
`
`110 interaction-detectable, calcblatlon not reasonable
`no interaction detectable, calculation 00111005000010
`no Interaction detectable. calculation not reasonable
`no Interaction detectable, calculallon not reasonable
`no lntemclion detectable, oalwlatlon not reasonable
`2.994 i 0.058
`0.09
`.
`0.41
`3.052 50.042
`1.15
`0.18
`
`303050.047
`
`1.08
`
`‘
`
`. 0.45
`
`5&050512
`
`478.35
`
`24028
`
`law interacubn detectable, calculatlon not reasonable
`5.4645 0211
`291.32
`149.00
`low lmeracfion detectable, calculatlon not reasonable
`5.303: 0.151
`196.49
`-
`101.17
`250710.025
`054
`0.10
`2.546 $0.031
`0.35
`0.18
`
`.
`
`2.538: 0.059
`
`. 0.34
`
`0.18
`
`65
`
`

`

`Reviewer: Laurie McLeod-Flmn
`
`NDA No. 22030
`
`creams-
`SPM 8272:
`8PM 7605:
`8PM 6509:
`SPM 6923:
`
`8PM 9078:
`Omepmzoie:
`
`'
`
`‘
`no Interaction detectable. calculation not reasonable
`no interaction «We. calculation not reasonable
`no Interaction (iambic. calculation not reasonable
`no interaction detectable, calculation not reasonable
`
`5.073 t 0.099
`3.457 1 0.087
`3.458 a 0.083
`345610.031
`
`113.40
`2.87
`2.87
`2.86
`
`34.18
`1.55
`1 .56
`1.55
`
`No relevant (lower 31M range) lcmflQ—valuec oi the test compounds for CYP1A2,
`GYP209 and CYPZCaS Interactions were detectable.
`
`2.6.4.6 Excretion
`
`Excretion following single doses of [14C1-fesoterodine (animals) or fesoterodine
`(human) (majority of dose recovered within 24 hours)(sponsor’s summary table)
`
`
`%Adnfi—istereddose
`
`Ifrine' feces—Totnlb
`
`
`
`Male Fannie Male Female Male
`
`Female
`
`
`
`
`
`
`Human
`
`6.84
`69.7
`oral
`8 mg
`241
`82.3
`intravenous
`4mg
`Excretion oftotal radioactivity was determined over 168 hours after dosing (animal studies DHGYIOOS,
`DHGY1007, DHGY1006). In trial SP567, SPM 7605 and the 3 secondary metabolites were determined in
`urine and feces samples by LC-MS/MS. Values are means 5: SD (n=3 animals/sex) or means (n=11 male
`human subjects).
`a - includes radioactivity in cage wash in animal studies
`b - includes radioactivity in carcass and GI tract in mice and rats
`
`2.6.4.7 Pharmacokinetic drug interactions
`
`No drug interaction studies were performed in animals. Studies in vitro of drug
`metabolizing mechanisms are included under Metabolism above.
`
`2.6.4.8 Other Pharmacokinetic Studies NA
`
`2.6.4.9 Discussion and Conclusions
`
`Absorption, distribution, metabolism and excretion of fesoterodine were studied in mice
`(CD--1, C57BL), rats (Sprague—Dawley, Lister Hooded) anddogs (Beagle). Mice were
`most similar to humanin terms of metabollc profile, and dogs were most similarin terms
`
`66
`
`

`

`Reviewer: Laurie McLeod-F1an ' .'
`
`‘
`
`"
`
`NDA No. 22030
`
`of routes of excretion (primarily in urine). Mice and dogs were chosen as the primary
`toxicity species. Pigmented tissues were investigated in male mice and rats. Elimination
`. of drug-related materials fiom the eyes of pigmented rats was evident after 168 hours, but
`no drug accumulation or drug related ocular toxicity was observed in toxicology studies.
`Placental transfer was observed to occur in pregnant mice and rats. Fesoterodine and its
`major human metabolites were also monitored in toxicity studies in mice (CD-1), rats
`(Sprague—Dawley, CD), rabbits (Himalayan) and dogs (Beagle). Fesoterodine (dog only)
`and/or SPM 7605 (active entity / hydroxy metabolite), and carboxy (SPM 5509),
`carboxy-N—desisopropyl (SPM 7790) and N-desisopropyl metabolites (SPM 7789)(none
`pharmacologically active), as measured by LC-MS/MS, were adequately represented in
`toxicity studies. Parent drug was studied at about 30 times the expected clinical exposure
`via AUC in mice and at about 20 times in dogs. Metabolite profiles were similar among
`species. No inversion at the chiral centre of fesoterodine has been observed. The
`parameters for the method validations included accuracy, precision, selectivity,
`sensitivity, linearity, reproducibility, recovery, and stability. The analytes and matrix
`were the same as in clinical trials.
`
`2.6.4.10
`
`Tables and figures to include comparative TK summary
`
`Human pharmacokinetic summary:
`
`Parameter
`
`CYP2D6
`
`
`
`
`WW) -“°*“
`
`SPM7605
`
`SPM5509
`
`6-9i2.7
`
`7.53i1-0
`
`
`
`(ng/ml*h)
`
`
`
`
`
`
`
`»~
`
`A
`
`.
`
`,
`
`10.2:tl .9c
`
`
`
`3133:73'—
`
`
`
`
`
`* IfSevere renal impairment and strong CYP3A4 inhibitors are limited to 4 mg dose
`a severe renal impairment + 4 mg fesoterodine
`
`
`b keto + 8 mg in BM subjects
`
`
`° rifampicin + 8 mg in PM subjects
`d rifampicin + 8 mg in BM subjects, severe renal impaired + 4 mg also yielded similar
`
`
`
`exposures
`3‘
`I
`h
`'
`-'
`-‘~
`e moderate hepatic impairment + 8 mg
`
`
`case*
`
`.
`
`.
`
`Worst
`
`.
`i
`88.7i31.9
`132i25°
`
`-
`
`-
`
`_
`
`:
`
`-
`
`~
`
`209:}:55
`
`.
`117-—t14-2
`3763:123a
`
`67
`
`

`

`Reviewer: Laurie McLeod-Flmn
`
`NDA No. 22030
`
`2.6.5 PHARMACOKINETICS TABULATED‘SUNHVIARY
`
`Absorption after a single dose in mouse
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`
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`
`68
`
`

`

`Reviewer: Laurie McLeod-Flmg
`
`NDA No. 22030
`
`Absorption afier a single dose in dog
`
`MW W
`Letafionin CTD: “1.12.4
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`
`69
`
`

`

`Reviewer: Laurie McLeod-Flmg
`
`' NDA No. 22030
`
`Absorption afler repeated doses in rabbit
`
`2mm remain
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`NDA No. 22030
`Reviewer: Laurie McLeod-F1 nn
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`
`71
`
`

`

`Reviewer: Laurie McLeod-Flmn
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`.
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`NDA No. 22030
`
`Organ distribution in pregnant female mouse
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`72
`
`

`

`'
`Reviewer: Laurie McLeod-Fl
`NDA No. 22030
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`73
`
`

`

`Reviewer: Laurie McLeod-Flmn
`
`NDA No. 22030
`
`Organ distribution in female rat
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`74
`
`

`

`
`
`‘Reviewer: Laurie McLeod-Fl ‘ NDA No. 22030
`
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`NDA No. 22030
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`NDA No. 22030
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`Reviewer: Laurie McLeod-Flmn
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`NDA No. 22030
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`Reviewer: Laurie McLeod-Flmg
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`NDA No. 22030
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