CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22—030
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTIC S REVIEW! S 2
`
`

`

`
`
`‘
`
`
`
`DEPARTMENT OF HEALTH AND
`Division of Clinical Pharmacology 3
`HUMAN SERVICES
`Office of Clinical Pharmacology
`PUBLIC HEALTH SERVICE
`
`
`
`FOOD AND DRUG ADMINISTRATION
`Tracking/ActiOn Sheet for Formal/Informal Consults
`
`
`
`
`To: DOCUMENT ROOM (LOG-IN and LOG-OUT)
`
`
`From:
`Hyunjin Kim, Pharm.D., M.S.
`Please log-in this consult and review action for the specified
`IND/NDA submission
`
`DATE OF DOCUMENT
`NDA No.: 22-030
`IND No.:
`Serial No.: DATE:
`
`
`
`Serial No.:
`
`
`05/28/2008
`5/1/2008 and 6/18/2008
`
`
`NAME OF DRUG
`Date of informal/Formal
`
`
`Consult:
`Fesoterodine fumarate
`
`
`
`PRIORITY CONSIDERATION
`
`
`
`
`
`
`
`
`E] Oral communication with
`[:1 NAI (N0 action indicated)
`Formal Review/Memo (attached)
`
`
`I] E-mail comments to:
`DUSee comments below
`Name:
`[
`]
`DMedicalEIChemistDPharm-Tox
`DDSee submission cover letter
`[1 Comments communicated in
`DMicroDPharrnacometricsEIOthers
`[I OTHER (SPECIFYBELOW):
`meeting/Telecon. see meeting minutes
`
`
`(Check as appropriate and attach e—mail)
`]
`dated:
`I
`I
`[
`
`
`NAME OF THE SPONSOR: Pfizer (distributor), Schwarz Pharma (manufacturer)
`
`TYPE OF SUBMISSION
`
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS RELATED ISSUE
`
`[3 PRE—IND
`D ANIMAL t0 HUMAN SCALING
`El IN-VITRO METABOLISM
`E] PROTOCOL
`'3 PHASE II PROTOCOL
`'3 PHASE III PROTOCOL
`D DOSING REGIMEN CONSULT
`[I PK/PD- POPPK ISSUES
`D PHASE IV RELATED
`
`' D DISSOLUTION/IN—VITRO RELEASE D FINAL PRINTED LABELING
`El BIOAVAILABILITY STUDIES
`1:] LABELING REVISION
`E] IN-VIVO WAIVER REQUEST
`E] CORRESPONDENCE
`E] SUPAC RELATED
`E] DRUG ADVERTISING
`El CMC RELATED
`D ADVERSE REACTION REPORT
`D PROGRESS REPORT
`El ANNUAL REPORTS
`El SCIENTIFIC INVESTIGATIONS
`D FAX SUBMISSION
`D MEETING. PACKAGE (Pre—IND)
`OTHER (SPECIFYBELOW:
`,
`[complete response to AE letter]
`
`REVIEW ACTION
`
`REVIEW COMMENT(S)
`1:1 NEED To BE COMMUNICATED TO THE SPONSOR
`IX! HAVE BEEN COMMUNICATED TO THE SPONSOR
`
`This is a clinical pharmacology memo of complete response to FDA’s “Approvable (AE)” action taken on NDA 22-
`030 (January 25, 2007).
`
`Submission history
`The sponsor submitted NDA 22—030 for fesoterodine fumarate, 4 and 8mg sustained release tablets on March 17,
`2006 for the treatment of overactive bladder (OAB). This application received an approvable action pending
`sponsor’s response to the following:
`
`
`
`
`
`
`
`
`1. Pre-approval inspection of active pharmaceutical ingredient manufacturing facility, Schwarz Phanna LTd.,
`located in Shannon, Ireland, which was not available during the review cycle.
`2. Labeling revision. Reference is made to the revised labeling by FDA conveyed to the sponsor on January 24,
`2007 for the basis for the future discussions. If additional information relating to the safety or effectiveness
`of fesoterodine becomes available, revision of the labeling may be required.
`
`
`
`On May 1, 2008, the sponsor provided complete response to the AE letter with four modules (module 1, 2, 3 and 5)
`0 Module 1: revision of labelin; cOnve ed to Schwarz biosciences on Janna
`24, 2007.
`
`
`
`

`

`_
`
`0 Module 2: common technical document summaries
`-_ Module 3: quality, summary of the CMC information proposed to be included in the quality module
`of the complete response
`‘
`0 Module 5: five phase 1 clinical study reports and three study reports of uncontrolled clinical studies;
`Each study title and the conclusions by the sponsor are listed below.
`i. SP857: single-dose PK in Japanese subjects (Japan); “Randomized, double blind, placebo
`controlled, single site, dose escalation trial to investigate safety, tolerability and
`pharmacokinetics of fesoterodine after single oral administration of 4, 8, and 16mg doses in
`12 young healthy male Japanese subjects”
`0 Relative bioavailability of the pharmacologically active compound SPM 7605 was
`comparable for all dose levels in Japanese subjects. SPM 7605 and it metabolites
`(SPM 5509, SPM 7789, and SPM 7790) showed a similar plasma concentration—time
`profile with each dose level
`ii. SP877: single-dose proportionality (US); “Randomized, opemlabel, 2-fold crossover trial to
`investigate the dose-proportionality of fesoterodine administered as single dose
`administration of one 4mg tablet or one 8mg tablet in 24 healthy, male subjects” (Clinical
`trial report submitted in the previous NDA review cycle)
`0 PK data show dose proportionality for the 2 dosage strengths (4mg and 8mg)
`investigated.
`iii. A0221004: multiple—dose (once daily for five days) PK in Japanese subjects (US); “A double
`blind, placebo controlled, multiple dose, randomized study to evaluate the safety and
`pharmacokinetics of fesoterodine sustained release tablets (SR) in Japanese healthy male
`subjects”
`
`0 Cmax and AUCI of SPM 7605, the active metabolite of fesoterodine, increased with
`dose after first and multiple-dose administrations and plasma concentrations reached
`steady state within 48 hours.
`iv. A0221015: multiple-dose (once daily for five days) PK in Korean subjects (Korea); “A
`double blind, placebo controlled, multiple dose, randomized study to evaluate the safety and
`pharmacokinetics of fesoterodine sustained release in Korean healthy male subjects”
`0 Following single and multiple dose administrations of 4mg and 8mg once daily
`fesoterodine SR tablets to healthy Korean subjects, the PK profiles were consistent
`with those seen in Caucasian and Japanese subjects.
`0 The systemic exposures of SPM 7605 increased approximately in the same proportion
`as the fesoterodine dose between 4mg and 8mg once daily.
`v. A0221044: single-dose proportionality and BE (US); “A phase 1, open label, randomized,
`single dose, 3 way crossover study to determine bioequivalence of two dose normalized E1
`formulation doses as well as between formulations (E1 and F) of similar doses of fesoterodine
`SR tablets in healthy subjects”
`0 Dose proportionality of SPM 7605 was established between the fesoterodine 4mg
`(El) and fesoterodine 8mg (El) SR tablets.
`o Bioequivalence was established between the fesoterodine 8mg (E1) and fesoterodine
`8mg (F) SR tablets
`vi. SP669: Two-phase extension trial of SP668 to investigate the safety and tolerability of
`sustained release fesoterodine in subjects with overactiVe bladder: a double—blind phase
`followed by an open-label extension phase
`vii. SP738: Long-term open—label extension trial for subjects completing the phase 3 trial of
`fesoterodine (SP583) for the treatment of overactive bladder syndrome
`viii. SP739: Long-term open—label extension trial for subjects completing the Phase 3 trial of
`fesoterodine (SP584) for the treatment of overactive bladder syndrome
`
`‘
`
`Background
`Fesoterodine is a new chemical entity in the class of antimuscarinic agents. Fesoterodine itself is a relatively weak
`muscarinic receptor antaonist with no selectivity for any of the receptor sub n es. Nonclinical in vitro and in Vivo
`
`

`

`
`
`treatment of symptoms of OAB.
`
`
`
`
`
`
`
`
`
`
`
`pharmacokinetic and toxicokinetic studies have shown a rapid deesterification of fesoterodine to its hydroxy
`metabolite, SPM 7605. SPM 7605 is also formed in vivo by metabolization of tolterodine, which is approved for the
`
`Review of submissions
`
`Module 1, labeling revision contains a modification of METABOLISM in the Clinical Pharmacology section.
`CYP2D6 was previously proposed to be a major metabolic pathway to further metabolize the major active
`metabolite, SPM 7605 to SPM 5509. In this current submission, the sponsor is proposing to add CYP3A4 metabolic
`pathway, which is responsible for metabolizing SPM 7605 to SPM 7789, along with CYP2D6 as two major
`metabolic pathways responsible to metabolize SPM 7605. This proposal was made based on the observation of the
`similar increase (2 to 2.5 fold) of the exposure of SPM 7605 in CYP2D6 poor metabolizers and subjects with
`CYP3A4 inhibition by ketoconazole (SP564, SP567, SP683' SP684 — studies submitted at the time of original
`submission; March 2006) The relevant studies will be reviewed to address the label revision proposed by the
`sponsor in the NDA review
`Sponsor suggests that the results of the five phase 1 clinical studies confirm that the PK of fesoterodine1s dose
`proportional and independent ofthe ethnicity of subjects and that the formulation E1is bioequivalent to the final
`commercial formulation (F).
`
`c There was a change of engraving from \~ to “FT” to the final formulation F product. A dissolution
`comparison to bridge this change in engraving was found to be acceptable by the OffiCe of New Drug
`Quality Assessment (ONDQA).
`
`Table 1. Compositions of Fesoterodine 4mg SR Tablets
`F‘linnsvhfitm
` Fesorarodme fumarare
`
`M43
`
`Tam
`
`: 011134 mgsizangzhi‘samflsbkfm‘ formmafiona '
`
`Table 2. Compositions of Fesoterodine 8mg SR Tablets
`
`
`
`' Only 8 mg string-2h is available for formulation C
`
`
`II
`
`
`
`
`
`
`film
`
`
`
`
`
`
`
`
`

`

`Table 3. Composition of Fesoterodine Fumarate Film Coated 4 mg SR Tablets Formulations E, E(l) and F
`
`Formulation
`
`E
`\Vhi'lefiim coated
`
`m)”
`\Vl'filie mm waged
`
`'
`1“
`light blue Em coated :
`
`33412 Hwameflnwmu A. mwuw .
`
`4“ vlvcexvlbeh-emte
`[Talc
`
`
`
`
`
`Table 4. Composition of Fesoter d e Fumarate F'l Coated 8 mg
`
`'Fofhinlitliurii"
`,
`
`’
`\
`
`
`Tablets Formulations E, E0), and F
`V
`E
`)5...
`. \Vlfifefi‘m maid mam“ £21151 canted
`
`..
`
`.
`F
`.
`Bluelfihncoated
`
`Xvfixolf
`,
`V7 W...—
`
`Lactosemomhvmte:
`:__.. _____,,..::——».~_-.,
`mfromellosel \— _._.._.__..____.....___._
`
`H‘mummaflasc
`/ Elm-42M behma‘le.
`.
`Tale
`
`'7 “
`
`/‘
`
` x
`
`V7,.x__*
`
`b I )
`
`‘
`;
`5
`
`1 Blue- fiEn- coated.-
`
`Fotmutafion F
`Lightblue. film coated
`
`Formfimion I?
`
`

`

`Table 6. Summary of formulations and bridging performed"
`
`whiten.deseiepmem.
`
`8533'mphphase 1 and 2
`studies as multiples eéttmg.
`BE | SPBBTJ.
`
`2
`mfg“ B was BE be ”5
`Each 8mgC was SE to
`fcnmlafionswith mm a
`.‘x
`"19
`
`irSmeBE @214
`, mgB
`
` UsedIn Sam: Oniyfer
`
`doé‘uéé’érmfifiilmy
`SPBBdi
`Corsets mngasehai-ged
`temtdwjrrufleoceie
`sari/tease
`indhodl’sseluhnncfl mg}:
`was mutated-mg B
`D and E were usedm
`primary trials. No BE study
`was needed-due in level 1
`Chan 3" .
`Tobe-marketedWm
`Smile: 'r: vita: desolation
`profiles betneen F and E. Marietta 1 change in film
`Similar dissolution profiles
`_ coat \
`bet-item F
`~ '
`'
`'
`v.
`*From Dr. Doan Tran’s Clinical Pharmacology Review of fesoterodine (DFS, 12/05/2006), Please refer to his review for more detailed information
`
`Smile:n vii-re easelufinn
`4 and 8 n9
`{Usedin phase 3} profiles hem-sen:r- and 9
`
`mg
`
`List of clinical trials using extended release tablets and the corresponding formulations and strengths
`SP857: 4mg (E)
`
`SP877: 4mg (F) and 8mg (F)
`A0221004: 4mg (El) and Sing (El)
`A0221015: 4mg (E1) and 8mg (E1)
`A0221044: 4mg (E1) and 8mg (E1, F)
`SP669: 4mg (B, D, E, F) and 8mg (D, E, F)
`SP738: 4mg (E, F) and 8mg (E, F)
`SP739: 4mg (E, F) and 8mg (E, F)
`
`Referring to the Dr. Doanh Tran’s Clinical Pharmacology review (Division Files System - DFS, 12-05-2006), the
`sponsor has developed 6 extended release formulations designated as A, B, C, D, E and F. Formulations A and C
`were used only for formulation development. Phase 3 trials for safety and efficacy used formulations D and E.
`Formulation F is the to-be—marketed formulation. Changes from D to E to F were minor and successfully bridged
`with similar in vitro dissolution profiles. Formulation E1 has been developed due to the anticipated need for drug
`blinding from placebo and/or key drug competitors in future comparative trials. Formulation E1 has a tablet core
`identical to formulation E and F and has a White coating slightly different in composition from that of formulation
`E. Formulation E1 was used in studies, A0221004, A0221015, and A0221044.
`
`Review comments
`0 The appropriateness of sponsor’s suggested two major metabolic pathways, CYP2D6 and CYP3A4, for SPM
`7605 will be addressed.
`
`0 The appropriateness of sponsor’s suggested dose proportionality and ethnicity independent pharmacokinetic
`profile of fesoterodine will be addressed.
`
`. The appropriateness of sponsor’s suggested bioequivalence between formulations El and F will be
`addressed.
`'
`
`Comments to the sponsor
`Submit or provide the location of the following information, if submitted previously
`0 Method validation report (07020VCJ_PSU; A0229001) of studies A0221004, A0221015, and A0221044.
`0 Method validation reports and study specific bioanalytical reports of studies SP857 and SP877
`0 Clari Whether fesoterodine 4 and 8mg of formulation E1 were used in studies A0221004 and A0221015.
`
`

`

`

`

`-mun--Inn-.----------._------_--____------.--------—------------------------------—------------------------------------
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/5/
`
`Hyunjin Kim
`7/2/2008 02}29:55 PM
`BIOPHARMACEUTICS
`
`Myong~Jin Kim
`7/3/2008 08:40:57 AM
`BIOPHARMACEUTICS
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`“mm——
`
`NDA: 22-030
`Brand Name
`Generic Name
`Reviewer
`Team Leader (Acting)
`OCP Division
`0ND Division
`Sponsor
`Relevant IND(s)
`Submission Type
`Formulation; Strength(s)
`Indication
`
`Submission Date(s): 5/1/2008, 6/18/2008
`Toviaz
`Fesoterodine fumarate
`Hyunjin Kim, Pharm.D., M.S.
`DOanh Tran, R.Ph., Ph.D.
`Division of Clinical Pharmacology 3
`Division of Reproductive and Urologic Products
`Pfizer
`51,232
`Resubmission
`Extended-release tablet, 4 and 8mg
`Treatment of overactive bladder with symptoms of
`urge urinary incontinence, urgency and urinary
`frequency
`
`M
`
`Table ofContents
`
`1
`
`l
`Executive Summary ..................................................................................................
`1.1
`Recommendation ............................................................................................................................ I
`1.2
`Phase IV Commitments ............................................. 1
`1.3
`Summary of Important Clinical Pharmacology and Biophannaceutics Findings ........................... 2
`2 Question BasedReview ......, ...................... 4
`2.1
`General Attributes........................................................................................................................... 4
`2.2
`General Clinical Pharmacology ...................................................................................................... 4
`2.3
`Analytical Section ........................................................................................................................ l3
`3 Appendices ................................................................................................................. 14
`3.]
`Individual Study Summary ................................................... 14
`3.2
`Orignial NDA Review by Dr. Doanh Tran ..................................................................................24
`
`1
`
`Executive Summary
`
`1.1
`Recommendation
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology 3 finds the
`resubmission for NDA 22—030 for fesoterodine acceptable from a Clinical Pharmacology
`perspective. Please see the original NDA’ review prepared by Dr. Doanh Tran in DFS ~
`dated on December 5, 2006,
`
`1.2
`None
`
`Phase IV Commitments
`
`

`

`Summary of Important Clinical Pharmacology and Biopharmaceutics
`1.3
`Findings
`Fesoterodine is a new chemical entity in the class of antimuscarinic agents. Fesoterodine
`itself is a relatively weak muscarinic receptor antagonist with no selectivity for any of the
`receptor subtypes. Nonclinical in vitro and in vivo pharmacokinetic and toxicokinetic
`studies have shown a rapid deesterification of fesoterodine to its hydroxy metabolite,
`SPM 7605. SPM 7605 is also formed in vivo‘ by metabolization of tolterodine, which is
`approved for the treatment of symptoms of Overactive Bladder (OAB).
`
`The sponsor submitted NDA 22-030 for fesoterodine fumarate, 4 and 8mg extended
`release tablets on March 17, 2006 for the treatment of OAB. This application received an
`approvable action pending labeling revision and pre-approval inspection of active
`pharmaceutical ingredient manufacturing facility, Schwarz Pharma.
`
`In this current submission, sponsor has submitted four newly conducted PK studies along
`with one PK study which was submitted and reviewed at the time of original NDA
`submission.
`
`Fesoterodine exposures, in terms of AUC and Cmax, observed in studies with Japanese
`(study SP857 and A0221004) and Korean (A0221015) were similar to that in study with
`Caucasian (study SP565 and SP566, submitted at the time of original submission) within
`4 to 8mg range.
`
`Labeling revision in metabolism section: The major metabolic enzymes responsible for
`the metabolism of SPM 7605 were reevaluated based on the studies submitted at the time
`of original NDA submission per sponsor’s request. No additional studies regarding the
`metabolic pathways of fesoterodine were submitted.
`
`The previous label reflects the involvement of CYP2D6 and CYP3A4 in the metabolism
`of SPM 7605 with identifying CYP2D6 as the major metabolic enzyme. However, a
`similar increase (approximately 2-fold) of exposure to SPM 7605 was observed in
`CYP2D6 poor metabolizers (PM) vs. CYP2D6 extensive metabolizers (EM) and subjects
`with CYP3A4 inhibition by ketoconazole vs. subjects without CYP3A4 inhibition
`(SP564, SP567, SP683, SP684 — studies submitted at the time of original submission;
`March 2006). Therefore, CYP3A4 and CYP2D6 were identified as two major metabolic
`enzymes responsible for the metabolism of SPM 7605.
`
`Dose proportionality of SPM 7605: Study 857 indicated that the Cmax and AUC of SPM
`7605, the active metabolite of fesoterodine, increased 10—21% more than dose
`proportional within 4 to 16mg range following a single oral dose in Japanese subjects. In
`a separate study, Cmax and AUC of SPM 7605 increased 23-33% less than dose
`proportional within 4 to 8mg range and plasma concentrations reached steady state within
`48 hours following administration of fesoterodine in study A0221004, a multiple dose
`study in Japanese. The cause of these inconsistent results is not clear.
`
`

`

`The systemic exposure of SPM 7605 in terms of Cmax and AUC increased 17-23% more
`than dose proportional within 4 to 8mg range in study A0221015, a multiple dose study
`in Korean.
`
`Study A0221044, in which the majority of the subjects were Caucasian with some blacks,
`showed the dose proportionality of fesoterodine within 4 to 8mg range.
`'
`
`Bioequivalence between formulation E1 and F: Formulation E was used in phase 3
`trials for safety and efficacy and formulation F is the to-be-marketed formulation.
`Changes from formulation E to F was successfully bridged with similar in vitro
`dissolution profiles in the original NDA review. The sponsor explained that they have
`developed formulation E1 due to the anticipated need for drug blinding from placebo
`and/or key drug competitors in future comparative trials. Formulation E1 was employed
`in study A0221004, A0221015, and A0221044. Formulation E] has a tablet core
`identical to E and F with different composition of white coating from E and F. The 8mg
`formulation E1 was found to be bioequivalent to 8mg formulation F under fasting
`condition based on the 90% CI for the ratio of AUC and Cmax of 8mg E1 and 8mg F
`within the acceptable range (80-125%, study A0221044 —~ submitted in the current
`submission).
`
`Appears This Way
`On Original
`
`

`

`2
`
`Question Based Review
`
`2.1
`
`General Attributes
`
`2.1.1 What is the regulatory history of this NDA?
`Fesoterodine is a new chemical entity in the class of antimuscarinic agents for the
`treatment of overactive bladder (OAB). The sponsor submitted NDA 22-030 for
`fesoterodine fumarate, 4 and 8mg extended release tablet on March 17, 2006 for the
`treatment of OAB. This application received an approvable action pending labeling
`revision and pre-approval inspection of active pharmaceutical ingredient manufacturing
`facility, Schwarz Pharma.
`
`2.1.2 How is this review organized?
`This NDA review contains the review of studies which have been submitted in the
`current submission and the sponsor’s new labeling proposal regarding the metabolism of
`SPM 7605 since original NDA submission on March 2006.
`
`Please see the original NDA review prepared by Dr. Doanh Tran in DFS dated on
`December 5, 2006 for detailed review of data submitted in the original NDA.
`
`2.2.
`2.2.1
`
`General Clinical Pharmacology
`ls sponsor’s proposal to include CYP3A4 in addition to CYP2D6 as the major
`metabolic enzymes responsible for the metabolism of SPM 7605 acceptable?
`The effects of CYP3A4 inhibition and CYP2D6 metabolism were examined in the study
`SP 684, where 18 healthy male subjects were given ketocona'zole twice daily for 6 days
`with a single dose of 8mg fesoterodine given on the fifth day.
`
`The sponsor’s proposal is acceptable based on the similar increase (approximately 2-fold)
`of exposure to SPM 7605 was observed in CYP2D6 poor metabolizers (PM) vs. CYP2D6
`extensive metabolizers (EM) and subjects with CYP3A4 inhibition by ketoconazole vs.
`subjects without CYP3A4 inhibition (studies SP564, SPS67, SP683, SP684 — submitted
`at the time of original submission; March 2006). This indicated that both CYP2D6 and
`CYP3A4 play equally important role in the metabolism of SPM 7605.
`
`CYP2D6 PM have values for AUC and Cmax that are about 2-fold higher than CYP2D6
`EM. A summary of effects of CYP2D6 PM, presented as PM/EM ratios for AUC and
`Cmax; are listed in table 1.
`
`Table 1. Effects of CYP2D6 PM presented as PM/EM ratios for AUC and C,mm
`
`
`EEEII. N for PM
`N for EM AUC PM/EM ratio
`cm, PM/EM ratio
`SP 564 “—_—
`
`SP 683' _——-_
`[emu——
` SP 684 n—_—
`
`
`3 SP 565 is the primary PK study.
`'
`
`b The small increase in SP 683may be due to its small sample size as the result is
`inconsistent with the 3 other studies.
`'
`
`

`

`The pharmacokinetic (PK) data indicated an increase of exposure to SPM 7605 during
`~co-administration of ketoconazole caused by CYP3A4 inhibition (figure 1 and table 2).
`Plasma concentrations were increased when ketoconazole was co-administered with
`fesoterodine in both subgroups of poor and extensive metabolizers. Exposure to SPM
`7605 expressed as AUCOLtZ and Cmax was approximately twice as high after the combined
`treatment of fesoterodine and ketoconazole compared to the treatment with fesoterodine
`alone. This result was observed in both poor and extensive metabolizers.
`
`In conclusion, the major metabolic enzymes responsible for the metabolism of SPM 7605
`are CYP3A4 as well as CYP2D6.
`
`
`
`hours
`
`- - I- - - Fesolerodim Poor n=8
`*Fewerodine Exten. n=11
`
`- - D - - Fesolemdlne + Ketoconazole Poor n=6
`-o-Ffioterodlne 4- Kelownazole Exten. n= I 1
`
`Figure 1. Plasma concentrations of SPM 7605 (arithmetic mean, study SP684) in
`CYP 2D6 EM and PM in the present or absent of ketoconazole 200mg twice daily* '
`*Original NDA review by Doanh Tran (DFS - December 5, 2006)
`
`Table 2-. PK parameter of SPM 7605 (geometric mean) in CYP 2D6 EM and PM in
`the present or absent of ketoconazole 200mg twice daily (study SP684)*
`
`*Original NDA review by Doanh Tran (DFS -.December 5, 2006)
`
`
`
`
`Parameter
`
`Extensive metabolizers (n-ll)
`feso
`fcso + keto
`
`
`
`AUCmuymg/mLm)
`
`38.18(39.3%)
`
`cmmg/mL)
`
`2.98 (50.2%)
`
`AUC(o.,,)(ng/mL)
`
`39.01 (38.5%)
`
`Aemulg)
`
`cuami)
`
`CLR (Uh)
`
`MRT (h)
`
`max)
`
`tm(h)*
`" median (range)
`
`553.00 (25.1%
`
`205.09 (38.5%
`
`14.78 (23.9%)
`
`12.60(ll.9%)
`
`6.95 (17.4%)
`
`6.0(3.0—8.0)
`
`
`
`
`
`88 28 (4o 1%)
`
`
`
`Poor metabolizers (IF-6)
`feso
`feso + kcto
`
`88.27 (35.3%)
`
`217.16(3l.9%)
`
`6.36 (51.1%)
`
`13.36 (27.9%)
`
`89.50 (35.6%)
`
`224.16(32.7%)
`
`1263.18(36.2%)
`
`1373.63 (32.3%)
`
`89.39 (35.6%)
`
`35.69 (32.7%)
`
`
`
`14.29 (38.1%)
`
`6.33 (42.0%)
`
`13.05(15.7%)
`
`6.98 (22.3%)
`
`6.0 (4.0—6.0)
`
`
`
`15.41(2o.2%)
`
`8.42 (31.9%)
`
`6.0 (6.0—8.0)
`
`
`
`

`

`.
`2.2.2 Does fesoterodine exhibit dose proportionality in Japanese?
`Study SP857 indicated that the doubling the dose resulted in approximately 10-21% more
`than 2-fold increase of the mean Cmax and AUCo_tZ within 4 (1x4mg) to 16mg (4x4mg)
`range in Japanese males following administration of a single dose of formulation E (table
`4). The confidence interval (CI) of the ratio of the dose normalized mean Cmx and AUCo_
`tz failed to meet the 80 to 125% range. (table 3). In a separate study, the mean Cmax and
`AUC, of SPM 7605 increased 23-33% less than proportional to dose within 4 (lx4mg) to
`8mg (1x8mg) range on days 1 and 5 in Japanese males in multiple dose study A0221004
`employing formulation F (table 5 and 6).
`
`The different trend of PK in regard to dose proportionality may be explained by several
`factors. The samples sizes (n=12 in SP857, n=20 in A0221004) of two studies are
`relatively small with high variations of Cmax and AUC reflected by 27—47% of coefficient
`of variations (CV). There were differences of formulations in two studies, although they
`were successfully bridged and reviewed in the original NDA cycle. In addition, there
`were demographic differences, although the inclusion criteria were similar for both
`studies. The mean body weight and Body Mass Index (BMI) of subjects who were
`enrolled in study SP857 were 58.0kg (50.0-67.0) and 19.9kg/m2 (18.0-22.1). Those for
`study A0221004 were 68.5kg (54.0-92.0) and 22.9kg/m2 (18.8-29.2). It is not clear which
`factors mentioned aboVe have caused the different PK profile of two studies in regard to
`the dose proportionality.
`
`Therefore, this reviewer finds that the dose proportionality of fesoterodine in Japanese
`inconclusive based on different trends of dose proportionality shown in study SP857 and
`A0221004.
`'
`’
`'
`
`Table 3. Statistical analysis of dose normalized AUC and Cmax (study SP857)
`Parameter
`Treatment LS-Mean
`Ratio
`Estimate
`90% confidence
`.
`interval
`
`AUC(w)mm,
`
`341.548
`
`4
`
`/8
`
`0.8794, 1.5741
`
`Cum...
`
`388.358
`n 413.903
`34.398
`39.902
`
`l6mg/8mg
`16mg/4mg
`4mg(8mg
`16mg/8
`
`40.472
`
`l6mg/4
`
`0.8795
`
`1.0658
`1.2118
`0.8621
`1.0143
`
`1.1766
`
`0.6635,1.1657
`
`0.8041, 1.4126
`0.9143, 1.6062
`0.6444,1.1s34
`0.7581,1.3570
`
`

`

`Table 4. Pharmacokinetic parameters of SPM 7605 following a single dose of
`fesoterodine in Japanese males (study SP857)
`
`
`
`
`
`
`
`
`
`
`24.461 (38.3%)
`
`53.715 (28.3%)
`
`111.091 (24.3%)
`
`341.55 (37.8%)
`
`388.36 (31.7%)
`
`2.464 (46.5%)
`
`5.519 (23.5%)
`
`34.398 (45.4%)
`
`39.902 (26.9%)
`
`9.671 (19.5%)
`
`9.370 (22.3%)
`
`13.622 (18.5%)
`
`12.921 (11.1%) '
`
`25.621 (36.5%)
`
`55.587 (28.7%)
`
`357.74 (36.0%)
`
`401.90 (32.0%)
`
`156.1 (36.5%)
`
`143.9 (28.7%)
`
`13.973 (19.0%)
`
`12.100 (12.6%)
`
`2178.3 (41.1%)
`
`1945.5 (29.3%)
`
`5.00 (4.0-5.0)
`
`5.00 (5.0-6.0)
`
`375.47 (4132.35)
`
`685.37 (4144.49)
`
`
`
`1505.65 (4410.38)
`
`
`
`
`
`
`
`
`
`
`
`
`Results for tum show median (range)
`Results for Ae show arithmetric mean (rhSD)
`All other parameters Show geometric mean (CV)
`n=8 subjects per treatment
`
`Table 5. Summary of Pharmacokinetics by Treatment Group (Day 1, study
`A0221004)
`
`
`
`
`
`40
`
`
`Fesoterodine 4 mg
`Fesoterodine 8 mg
`
`
`
`w___§ummal ' Statistics
`__
`=8) __“_
`(N=8)
`_
`AUG,
`11
`8
`8
`
`
`
`(iig'h’mL)
`Geometric mean
`19.9
`26.9
`
`
`
`Arithmetic mean
`21.1
`29.7
`
`
`
`Standard deviation
`8.95
`1 1.9
`
`
`
`
`
`
`40
`42
`Coefficientgf variation (%)
`8
`8
`n
`
`
`2.89
`1.96
`Geometric mean
`3 .09
`Arithmetic mean
`2.07
`
`Standard deviation
`0.856
`1.14
`
`
`41
`37
`Coefficient of variation (‘54))
`
`n
`8
`8
`
`Median
`5.0
`5.0 0
`
`Minimum
`2 O
`2.0
`
`
`Maximum
`6.0
`-
`6.0
`
`he
`11
`8
`8
`
`
`
`Arithmetic mean
`(h)
`8.13
`6.86
`Standard deviation
`3 21
`1.25
`
`
`_
`Coefficient ofvariation (%)
`
`
`
`n = number of subjects, N = Number of subjects in total population, PK = pharmacokinetic
`
`
`
`.
`
`2... 2. 18
`
`__i
`
`

`

`Table 6. Summary of Pharmacokinetic Parameters by Treatment Group (Day 5,
`
`study A022 1004)
`Fosotcrodinc 4 mg
`Fesotcrodine 8 tug—E
`i
`
`
`PK Parameters
`Summary Statistics
`EV=8)
`fl)
`ADC,
`8
`8
`11
`(ug-lt’ufl.)
`23.4
`32.8
`Geometric mean
`25.7
`Arithmetic mean
`35.1
`Standard deviation
`1 1.9
`13.1
`
`Coefficient of variation (%)
`46
`37
`I!
`S
`S
`Geometric mean
`2.32
`3.59
`Arithmetic mean
`2.55
`3.77
`'
`Standard deviation
`1 .19
`[.25
`
`Coefficient ofvnriation (%)
`‘—
`47
`33
`n
`S
`8
`Geometric mean
`0.254
`0.379
`Arithmetic mean
`0.323
`0.491
`Standard deviation
`0.155
`0.352
`
`Coefficient ofvnriatiou (9’9)
`48
`72
`8
`8
`n
`Arithmetic mean
`189
`262
`Standard deviation
`92.3
`107
`
`___ Coetiicient of variation (9-6)
`_h
`49
`41
`n
`S
`8
`Median
`5.0
`5.0
`Minimum
`2.0
`5.0
`
`Maximum
`5.0
`5.0
`t,.;
`n
`8
`8
`(h)
`Arithmetic mean
`5. i 3
`4.86
`Standard deviation
`2.54
`1.69
`
`Coefficient of variation (%)
`49
`35
`MRT
`n
`8
`8
`(h)
`Arithmetic mean
`1 1.0
`10.7
`2.22
`2.10
`Standard deviation
`
`20
`20
`Coefficient of variation (°/o)
`n
`8
`8
`Arithmetic mean
`1.20
`1.25
`Standard deviation
`0.264
`0.308
`Coefficient of variation (%)
`22
`25
`MRT = mean residence time, n = number of subjects. N = number of subjects in total population.
`PK = phantmcokinctie. R“ = observed accumulation ratio
`
`
`
`3
`
`
`
`
`
`
`
`
`
`Cm“
`(ng/ittL)
`
`Cm,“
`(ng’tnL)
`'
`
`CL’F
`(L'h)
`
`Tina):
`(11)
`
`R...
`
`
`
`2.2.3 Docs fesoterodine exhibit dose proportionality in Korean?
`The mean Cmax and AUCT of SPM 7605 increased 17-23% more than proportional to dose
`within 4 to 8mg range on day 1 and day 5 in Korean subjects in multiple dose study
`A0221015. The mean total clearances on day 5 were 166i49.5 and 145i51.1L/h for 4
`and 8mg fesoterodine, respectively. Therefore, fesoterodine appears to be slightly more
`than dose proportional in Korean. However, there are some limitations of this study
`including the parallel design of the study, small sample size (n=8), and high variability of
`Cmax and AUC reflected by 31-39% CV.
`
`The sponsor has concluded that the pharmacokinetics of fesoterodine are dose
`proportional and independent of the ethnicity of subjects in regard to Japanese and
`Korean. However, this reviewer finds that there are differences in pharmacokinetics of
`fesoterodine in regard to the dose proportionality as described in section 2.2.2 and 2.2.3.
`
`_.W dose proportionality of Japanese and
`Korean 9/ considering variability of data to draw the conclusion of dose
`proportionality and the unavailability of a study directly comparing the AUC and Cmax of
`fesoterodine in Caucasian, Japanese, and Korean.
`
`33(4)
`
`

`

`Table 7. Summary of Pharmacokinetic Parameters, by Treatment Group (Day 1,
`
`study A0221015)
`
`Cum
`(ng/mL)
`
`
`Jwratneteri“
`Singing Statistics
`AUC,
`(ugh/ml.)
`
`Fesoterodine 8 mg
`Fesoterodine 4 mg
`__ N=9
`______
`tN=8§
`9
`8
`n
`53.1
`21.5
`Geometric mean
`56.7
`22.5
`Arithmetic mean
`Standard deviation
`7.2
`21.8
`
`Coefficient of variation (%)
`2
`38
`n
`8
`9
`Geometric mean
`2.29
`5.42
`Arithmetic mean
`2.40
`5.84
`Standard deviation
`0.75
`2.30
`
`Coefficient of variation (%)
`31
`39
`n
`8
`9
`Median
`5.0
`5.0
`Minimum
`3.0
`3.0
`
`Maximum
`6.0
`_ 8.0
`n
`8
`9
`Arithmetic mean
`7.90
`7.16
`Standard deviation
`2.85
`1.12
`
`Coefficient of variation %)
`36
`16
`n, number of subjects. N, Number of subjects in total population. PK. pharmacokinetic.
`
`Tim“
`(11)
`
`t”;
`(11)
`
`__
`
`Table 8. Summary of Pharmacokinetic Parameters, by Treatment Group (Day 5,
`study A0221015)
`
`
`PK Parameters
`Summary Statistics
`(N=8)
`(N=8)
`AUC,
`8
`S
`n
`(ng-h/mL)
`25.1
`59.1
`Geometric mean
`26.1
`64.2
`Arithmetic mean
`Standard deviation
`8.0
`30.4
`
`Coeflicient of variation (%)
`31
`:17
`Cm“
`n
`8
`8
`(ngme)
`Geometric mean
`2.47
`5.76
`Arithmetic mean
`2.55
`6.04
`Standard deviation
`0.68
`2.03
`
`27
`M
`34
`_mw Coefficient of vag'tion (%)
`Ctmugti
`n
`8
`8
`(ngi'mL)
`Arithmetic mean
`0.35
`0.91
`Standard deviation
`0.18
`0.53
`
`Coefficient of variation (%)
`50
`58
`CL/F
`u
`8
`8
`(L111)
`Arithmetic mean
`166
`145
`Standard deviation
`49.5
`51.1
`w Coefficient of variation (%)
`30
`35
`n
`8
`8
`Tm
`(11)
`Median
`5.0
`50
`Minimum
`4.0
`2.0
`
`-
`- Moan“ ,
`,m-.-
`_ m- 6-9 -_. 7m- _
`.--..... ._
`,6-0
`n
`8
`8
`tn
`(b).
`Arithmetic mean
`7.05
`6.07
`Standard deviation
`1.84
`1.95
`
`Coefiicient of variation (%)
`26
`32
`MRT
`n
`8
`8
`(h)
`Arithmetic mean
`11.6
`10.8
`Standard deviation
`1.99
`1.77
`
`Coefficient of variation (%)
`17
`16
`n
`8
`8
`Arithmetic mean
`1 . 17
`1 . 17
`Standard deviation
`0.13
`0.19
`
`Coefficient of variation (%) 16 1 l
`
`MRT, mean residence time. n. number of subjects. N. number of subjects in mud population. PK.
`pharmacokinetic. Rmobscrvcd accunndation ratio.
`
`_
`
`_
`
`.....-
`
`K,c
`
`

`

`2.2.4 What are the formulations used in the new studies in the current submission?
`The following formulations were used in each study.
`SP857: 4mg (E)
`_
`A0221004: 4mg (E1) and 8mg (E1)
`A0221015: 4mg (B1) and 8mg (E1)
`A0221044: 4mg (E1) and 8mg (E1, F)
`
`Is formulation E1 bridged to formulation F?
`2.2.5
`Formulation E was used in phase 3 trials for safety and efficacy and formulation F is the
`to-be-marketed formulation. Changes from formulation E to F was successfully bridged
`with similar in vitro dissolution profiles in the original NDA review. The sponsor has
`developed formulation El due to the anticipated need for drug blinding from placebo
`and/or key drug competitors in future comparative trials. Formulation E1 has a tablet core
`identical to formulations E and F (table 9-and 10). However, Formulation E1 has a white
`coating slightly different in composition fi‘om E and F (table 11). The formulation E1 was
`used in the studie