CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`022567Orig1s000
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`

`

`NDA
`Submission Dates:
`Brand Name:
`
`Generic Name:
`Strength and Formulation:
`Sponsor:
`Indication:
`Submission Type:
`CP Reviewer Team:
`
`Clinical Pharmacology Review Amendment
`22567
`March 22, 2010, August 31, 2010
`Viibryd
`Vilazodone
`10, 20, and 40 mg IR tablets
`PGxHealth, LLC
`Major Depressive Disorder (MDD)
`Original NDA (NME)
`Bei Yu, Ph.D., Huixia Zhang, Ph.D., Jee Eun Lee,
`Ph.D., Joga Gobburu, Ph.D. Atul Bhattaram, Ph.D.
`Yaning Wang, Ph.D., Issam Zineh, PharmD, MPH,
`FCCP., Li Zhang, Ph.D.
`
`
`
`
`
`
`Reference ID: 2875789
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BEI YU
`12/10/2010
`
`JOGARAO V GOBBURU
`12/10/2010
`The original full OCP review was signed-off on 8Dec2010. This review amends a typo in the
`labeling recommendations.
`
`Reference ID: 2875789
`
`

`

`ONDQA BIOPHARMACEUTICS REVIEW
`
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`
` 22-567 (N-000)
`03/22/10, 10/29/10, and 11/30/10
`Pending
`Vilazodone HCl
`Oral immediate-release (IR) tablets
`10, 20, and 40 mg
`PGx Health
`Original
`Tien-Mien Chen, Ph.D.
`
`
`
`
`NDA#:
`Submission Date:
`Brand Name:
`Generic Name:
`Formulation:
`Strength:
`
`
`Sponsor:
`
`
`Type of submission:
`Reviewer:
`
`
`SUMMARY
`Vilazodone HCl, is reportedly a dual-acting potent and selective serotonin reuptake
`inhibitor and 5-HT1A receptor partial agonist. Vilazodone is a new chemical entity (NME)
`which was developed (up to 20 mg strength) by Merck and GSK as the first in a new
`class of antidepressants – the dual-acting serotonergic antidepressants.
`
`On 03/22/10, PGx Health submitted NDA 22-567 (N-000) for Vilazodone HCl tablets.
`Vilazodone HCl is formulated as 10 mg, 20 mg, and 40 mg, film-coated IR tablets and is
`indicated for the treatment of major depressive disorder (MDD). The to-be-marketed
`(TBM) tablets are manufactured using a
`
` All 10, 20 and 40 mg tablets are
` and dose
`proportional and have been used in the Phase 3 clinical trials and several Phase 1 studies.
`Therefore, there is no biowaiver issue.
`
`Six batches of Vilazodone HCl Tablets (three for each of 10 mg and 40 mg tablet
`strengths) are included in the primary registration stability study. These batches were
`manufactured using the intended commercial formulation, at the intended commercial
`facility using the intended commercial process. All batches were manufactured at
`
`scale, which is
` of the intended commercial scale
`). Each batch was
`packaged in container closures intended for commercial products. The 20 mg strength is
`bracketed and not included in the stability studies.
`
`The dissolution data on the 10 and 40 mg TBM tablet strengths were submitted, however,
`the dissolution data on the 20 mg TBM tablet strength could not be located in this
`submission. On 10/15/10, an information request was sent to the sponsor and the sponsor
`responded on 10/29/10 and 11/30/10. The dissolution development report, dissolution
`methodology and data/profile for all three strengths, and the proposed dissolution
`specifications are, therefore, reviewed here.
`
`The following dissolution method and the specifications are proposed as shown below.
`
`
`
`
`
`
`USP Apparatus: 2 (Paddle) x 60 rpm
`Medium:
`0.1% Acetic Acid (pH 3.1), 1000 mL at 37ºC
`Specifications: Q=
` at 30 min
`
`
`Reference ID: 2876037
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`

`The results of dissolution testing show that all three strengths meet the proposed
`dissolution specifications.
`
`RECOMMENDATION
`From the Biopharmaceutics perspective, the proposed dissolution methodology and
`specifications are acceptable. No further comments need to be sent to the sponsor.
`
`
`Reference ID: 2876037
`
`2
`
`

`

`BACKGROUND
`Vilazodone HCl, is reportedly a dual-acting potent and selective serotonin reuptake
`inhibitor and 5-HT1A receptor partial agonist. Vilazodone is a new chemical entity (NME)
`which was initially developed (up to 20 mg) by Merck (KGaA) and GSK as the first in a
`new class of antidepressants – the dual-acting serotonergic antidepressants.
`
`CURRENT SUBMISSION
`On 03/22/10, PGx Health submitted NDA 22-567 (N-000) for Vilazodone IR tablets.
`Vilazodone HCl is formulated as 10 mg, 20 mg, and 40 mg, film-coated IR tablets and is
`indicated for the treatment of major depressive disorder (MDD). The to-be-marketed
`(TBM) tablets are manufactured using a
`
`. The TBM tablet strengths, 10 mg (Formulation No. PG-10) and 20 mg
`(PG-20), were used in the second and third Phase 3 clinical trials (Nos. CLDA-07-DP-02
`and CLDA-08-DP-04) as well as in several Phase 1 studies. The 40 mg (PG-40) was also
`used in the third Phase 3 clinical trial (CLDA-07-DP-04). Therefore, there is no
`biowaiver issue.
`
`Six batches of Vilazodone HCl Tablets (three for each of 10 mg and 40 mg tablet
`strengths) were included in the primary registration stability study. These batches were
`reportedly manufactured using the intended commercial formulation, at the intended
`commercial facility using the intended commercial process. All batches were
`manufactured at
` scale, which is
`of the intended commercial scale (
`
`Each batch was packaged in container closures intended for commercial products. The
`20 mg strength is bracketed and therefore, not included in the stability studies.
`
`The dissolution development report and the dissolution data on TBM 10 and 40 mg IR
`tablet batches are included in the submission. During the pharmaceutical development of
`Vilazodone IR tablets, a rotational speed of 50 rpm was employed initially. However,
`the speed was changed to 60 rpm at a later time, therefore, for the stability batches, the
`dissolution data using 60 rpm are only available at one time point (at 30 min) at the 12th
`and the 18th month.
`
`The dissolution data on the 20 mg TBM tablet strength, however, could not be located in
`this submission. On 10/15/10, an information request was sent to the sponsor and the
`sponsor responded on 10/29/10 and 11/30/10. The dissolution development report,
`dissolution methodology and data/profile, and the proposed dissolution specifications are,
`therefore, reviewed here.
`
`FORMULATION COMPARISONS
`The composition of the TBM formulation of vilazodone 10, 20 and 40 mg IR tablets is
`shown below. The 3 tablet strengths are
` and dose proportional.
`
`
`
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`
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`Reference ID: 2876037
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`Table 1. The Composition of the TBM Formulation of Vilazodone IR Tablets
`
`
`
`
`DISSOLUTION METHODOLOGY AND SPECIFICATIONS
`The dissolution method development was discussed with the Agency in the EOP2
`meeting dated 09/28/09. The dissolution development report included the investigation
`on drug substance
`), apparatus, medium (water, 0.1%
`Acetic Acid, or pH 6.8 phosphate buffer; with or without surfactant), medium volume,
`and rotational speed (50, 55, 60, and 75 rpm). Please see the dissolution development
`report under Module 3.2.P.2.2.3.1 “Method History Report” for details.
`
`The following dissolution method was selected based on the dissolution development
`report and the specifications are also proposed as shown below.
`
`
`
`
`
`The mean dissolution data (n=6 tablets/batch) and profiles of vilazodone HCL 10 and 40
`mg IR tablets using the proposed dissolution method are shown below.
`
`Table 2. Mean Dissolution Data of Primary Stability Batches of 10 and 40 mg IR
`Tablets (n=6 tablets/batch)
`Batch No
`Mean Vilazodone HCL % Dissolved (n=6 Tablets/Batch
`
`USP Apparatus: 2 (Paddle) x 60 rpm
`Medium:
`0.1% Acetic Acid (pH 3.1), 1000 mL at 37ºC
`Specifications: Q=
` at 30 min
`
`Strength
`
`5 Min
`
`10 Min
`
`20 Min
`
`30 Min
`
`45 Min
`
`60 Min
`
`10 mg
`
`40 mg
`
`MTSCL331E
`MTSCL332E
`MTSCL333E
`MTSCL328E
`MTSCL329E
`MTSCL330E
`
`
`Reference ID: 2876037
`
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`

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`Figure 1. Mean Dissolution Profiles of Vilazodone HCl 10 mg IR Tablets (3
`Primary Stability Batches)
`
`
`Figure 2. Mean Dissolution Profiles of Vilazodone HCl 40 mg IR Tablets (3
`Primary Stability Batches)
`
`
`
`
`
`
`Upon request, the sponsor provided on 10/29/10 and 11/30/10 the dissolution
`data/profiles for vilazodone 20 mg IR tablets as shown below.
`
`Table 3. Mean Dissolution Data of the Biobatch of 20 mg IR Tablets (n=12
`tablets/batch)
`Batch No
`
`Strength
`
`Mean Vilazodone HCL % Dissolved (n=6 Tablets/Batch
`
`5 Min
`
`10 Min
`
`20 Min
`
`30 Min
`
`45 Min
`
`60 Min
`
`07T6431*
`20 mg
`*. The batch was used in a Phase-1 bioavailability study No. CLDA-07-DP-01.
`
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`Reference ID: 2876037
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`Figure 3. Mean Dissolution Profiles of Vilazodone HCl 20 mg IR Tablets (3
`Primary Stability Batches)
`
`
`
`
`Please see individual and mean dissolution data in Appendix 2 for details.
`
`Reviewer’s Comment:
`The proposed dissolution methodology and specifications are reviewed and found
`acceptable. The results of dissolution testing show that all three strengths meet the
`proposed dissolution specifications.
`
`
`
`
`
`________________________________
`Tien-Mien Chen, Ph.D.
`
`Reviewer
`ONDQA Biopharmaceutics
`
`
`
`________________________________
`Patrick Marroum, Ph.D.
`
`ONDQA Biopharmaceutics
`
`
`
`
`
`CC:
`
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`
`
`
`
`______12/10/10__________
`
`Date
`
`______12/10/10__________
`
`Date
`
`NDA
`Patrick Marroum, Angelica Dorantes, Tien-Mien Chen
`
`
`Reference ID: 2876037
`
`6
`
`(b) (4)
`
`7 Page(s) have been Withheld in Full as b4 (CCI/TS)
`immediately following this page.
`
`

`

`NDA
`Submission Dates:
`Brand Name:
`
`Generic Name:
`Strength and Formulation:
`Sponsor:
`Indication:
`Submission Type:
`CP Reviewer Team:
`
`Clinical Pharmacology Review
`22567
`March 22, 2010, August 31, 2010
`Viibryd
`Vilazodone
`10, 20, and 40 mg IR tablets
`PGxHealth, LLC
`Major Depressive Disorder (MDD)
`Original NDA (NME)
`Bei Yu, Ph.D., Huixia Zhang, Ph.D., Jee Eun Lee,
`Ph.D., Joga Gobburu, Ph.D. Atul Bhattaram, Ph.D.
`Yaning Wang, Ph.D., Issam Zineh, PharmD, MPH,
`FCCP., Li Zhang, Ph.D.
`
`
`Required office level OCP Briefing held on December 6, 2010.
`
`Table of contents
`1. Executive Summary ............................................................................................................................2
`1.1
`Recommendations..................................................................................................................2
`1.2
`Post-Marketing Studies..........................................................................................................6
`1.3
`Clinical Pharmacology Summary..........................................................................................7
`2. Question Based Review (QBR) ..........................................................................................................9
`2.1
`Specific Questions..................................................................................................................9
`2.2 Standard Questions ..............................................................................................................10
`Individual Study Review...................................................................................................................22
`3.1
`Clinical Pharmacology Review ...........................................................................................22
`BA/BE STUDIES .....................................................................................................................................22
`IN VITRO METABOLISM STUDIES....................................................................................................28
`PHARMACOKINETIC AND TOLERABILITY STUDIES..................................................................46
`MASS BALANCE STUDY .....................................................................................................................60
`PHARMACODYNAMIC STUDIES.......................................................................................................68
`INTRINSIC FACTORS............................................................................................................................70
`EXTRINSIC FACTORS...........................................................................................................................76
`ANALYTICAL SECTION.......................................................................................................................88
`3.2
`Pharmacometric Review......................................................................................................92
`3.3
`Pharmacogenomic Review ..................................................................................................99
`
`3.
`
`
`
`
`
`Reference ID: 2874615
`
`1
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`

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`Executive Summary
`1.
`The sponsor is seeking approval Viibryd (vilazodone 40 mg QD with food after
`uptitration) for the treatment of patients with major depressive disorder (MDD) via 505
`(b)(1) approach. Vilazodone HCl is an indolalkylamine new chemical entity purported to
`be related to its potentiation of serotonin activity in the CNS, through selective inhibition
`of serotonin reuptake and partial agonist activity at 5-HT1A receptor.
`
`Vilazodone 40 mg QD with food was shown to be superior to placebo in two registration
`trials. Early studies evaluated a dose range of 5 mg – 100 mg. Although not conclusive,
`20 mg and higher doses result in similar effectiveness; however adverse events such as
`nausea, diarrhea, dizziness, somnolence, and excessive dreaming are dose-dependent.
`Hence a 20 mg dose will likely have a more favorable benefit-risk and is worth studying
`in future studies.
`
`Vilazodone exhibits a dose-proportional PK with an absolute bioavailability of about
`72% with food. Food approximately doubles vilazodone’s AUC. About 40% of parent
`drug is possibly metabolized by carboxyl esterase and 60% by CYP pathways in which
`CYP3A4 is a major isoenzyme. Ketoconazole increases vilazodone AUC and Cmax by
`50% - and thus a maximum dose of 20 mg is recommended.
`
`
`1.1 Recommendations
`The Office of Clinical Pharmacology has determined that there is sufficient clinical
`pharmacology and biopharmaceutics information provided in the NDA to support a
`recommendation of approval of vilazodone. The acceptability of specific drug
`information is provided below.
`
`Decision
`Overall
`
` Yes
`
` No
`
` NA
`
` Yes
`
` No
`
` Yes
`
` No
`
` NA
`
` NA
`
`Acceptable to OCP? Comment
`Pending labeling and PMC agreements
` Yes
` No
` NA
`with sponsor.
`2 positive registration trials; dose-response
`supportive
`40 mg is acceptable; Effectiveness of 20
`mg should be studied (PMC)
`Vilazodone dose should not exceed 20 mg
`when given with strong CYP3A4
`inhibitors.
`Effect of CYP3A4 inducer on vilazodone
`should be studied (PMC)
`Severe hepatic impairment study (PMC)
`
`Pending satisfactory agreement with
`sponsor.
`
`Evidence of
`Effectiveness
`Proposed dose for
`general population
`Proposed dose
`selection for others
`
`Pivotal BE
`Labeling
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`Reference ID: 2874615
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` Yes
` Yes
`
` No
` No
`
` NA
` NA
`
`2
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`3 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page.
`
`

`

`1.2 Post-Marketing Studies
`Office of Clinical Pharmacology proposes the following post-marketing studies.
`
`PMC
`or
`PMR
` PMC
` PMR
`
`Key drug development
`question
`
`Rationale
`
`Design summary
`
`Does 20 mg exhibit a
`more favorable benefit-
`risk?
`
`Effectiveness of 20 mg
`and 40 mg are likely
`similar; AEs are lower
`at 20 mg.
`
`Study population: MDD
`Patients
`Study design: AWC, Parallel
`Sample size: 85% Power
`Dose(s): Placebo, 20 mg, and
`40 mg fed (titrated from 10
`mg)
`Study length: 8 wks
`Endpoints: MADRS Score
`
`Study population: Healthy
`Subjects
`Study design: Crossover
`Sample size: 20% SE for
`Mean AUC
`Dose(s): 40 mg vilazodone
`single-dose, 400 mg daily
`carbamazepine (7 days)
`Study length: One week
`Endpoints: Vilazodone AUC,
`Cmax
`Submit protocol by: Jul-11
`Start study by: Oct-11
`
` PMC
` PMR
`
`Should vilazodone dose
`be increased when taken
`with relevant CYP3A4
`inducers? If so, by how
`much?
`
`Vilazodone is
`metabolized by
`CYP3A4. Information
`on effect of induction
`was not submitted.
`
` PMC
` PMR
`
` PMC
` PMR
`
`
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`
`
` PMC
` PMR
`
`Is vilazodone a Pg-P
`substrate, or inhibitor?
`
`CYP3A4 substrates
`typically also effect or
`affected by Pg-P
`
`Method: A bi-directional
`assay in Caco-2 cells.
`Submit protocol by:
`Start study by: Dec-10
`
`
`
`
`
`1.3 Clinical Pharmacology Summary
`The current submission consisted of 24 clinical pharmacology studies including a
`thorough QTc study and 9 in vitro studies.
`
`Figure 1. Mean (± SD) vilazodone plasma concentration versus time profile after oral single
`dose of 40 mg vilazodone tablet under fed conditions.
`
`20
`
`40
`
`60
`
`80
`
`100
`
`120
`
`140
`
`160
`
`Time (h)
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Vilazodone Plasma Concentration
`
`(ng/mL)
`
`0
`
`-20
`
`
`Table 1. Important PK properties of vilazodone
`
`
`PK Property
`Dose-proportionality
`
`PK Parameter
`PK dose-proportional for doses 5 – 80 mg
`Tmax (median), hour
`4-5
`T1/2, hour
`~25
`Absolute Bioavailability
`72
`(with food), %
`
`Food Effect
`
`Protein Binding, %
`
`Pathways
`
`High fat/light meal
`increased Cmax and AUC by
`~2-fold.
`96-99
`CYP (3A4 is the primary
`isoenzyme, with the minor
`contributions from
`
`Absorption
`
`Distribution
`
`Metabolism
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`

`CYP2C19 and 2D6) and
`non-CYP (possibly by
`carboxylesterase). No
`active metabolites.
`A mass balance study for vilazodone showed ~85% of the
`administered radioactivity was recovered in the urine
`(~20%) and feces (~65%) combined, while ~ 3% of the
`administered dose of vilazodone was recovered as
`unchanged drug (~1% in urine, and ~2% in feces).
`
`Excretion
`
`
`PK properties of vilazodone are summarized in Table 1. Food (light or high fat meal)
`significantly increased systemic exposure (AUC) of vilazodone. Vilazodone is
`extensively metabolized through CYP and non-CYP pathways, and mainly excreted
`through feces.
`
`The figure below depicts the dose-MADRS and AE relationships. The depression
`symptoms decrease with increasing dose. Doses beyond 20 mg do not offer additional
`reduction in MADRS. However, the AEs increase such as abnormal dreams, nausea with
`dose between 5 mg – 80 mg.
`
`
`Ketoconazole, a strong CYP3A4 inhibitor, increased vilazodone systemic exposure
`(AUC) by ~50%. CYP2C19 and 2D6 genotypes are not associated with different drug
`response. The PK profiles were comparable between hepatic impairment patients (mild
`and moderate only) and healthy subjects, and between renal impairment patients (mild
`and moderate only) and healthy subjects. There was no substantial PK difference
`between elderly subjects and young subjects. Although systemic exposure in female
`subjects is higher than that in male subjects, lower body weight in females was correlated
`with the higher exposure. Additionally, ethanol and proton pump inhibitor did not affect
`PK of vilazodone.
`
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`

`2. Question Based Review (QBR)
`
`2.1
`
`Specific Questions
`
`2.1.1 Is there a need to assess effectiveness of vilazodone at doses < 40 mg?
`Yes, effectiveness at 20 mg should be assessed in a definitive manner post-marketing.
`Patients who cannot tolerate 40 mg might benefit from the 20 mg dose. Two positive
`registration trials support the effectiveness and safety of the proposed 40 mg dose. Based
`on the Phase 2 studies, 20 mg consistently demonstrated numerically similar placebo-
`corrected changes in MADRS to those of 40 mg. More over, these changes across 5 mg –
`80 mg exhibit a clear dose-response relationship. Doses closer to 5 mg have small
`changes in MADRS, and the changes are larger at higher doses. Doses beyond 20 mg do
`not offer additional reduction in symptoms. Although the Phase 2 studies allowed flexible
`dosing, a clear dose-response is reassuring about effects at 20 mg i.e. it follows an
`expected trend. Further, adverse events such as dizziness, somnolence, excessive
`dreaming, nausea, and diarrhea are clearly dose-dependent. Hence a 20 mg dose will
`likely have a more favorable benefit-risk especially in patients who cannot tolerate 40 mg
`and is worth studying in future studies.
`
`
`2.1.2 Should dose of vilazodone be adjusted with concomitant use of strong,
`moderate, and mild CYP3A4 inhibitors?
`The dose of vilazodone should be adjusted from 40 mg to 20 mg when vilazodone is
`coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole).
`Vilazodone dose should be reduced to 20 mg for patients with intolerable adverse events
`when the drug is co-administered with moderate inhibitors of CYP3A4.
`No dose adjustment is recommended when vilazodone is co-administered with mild
`inhibitors of CYP3A4.
`
`In vivo data showed that strong CYP3A4 inhibitor (i.e., ketoconazole) increased the AUC
`of vilazodone by 50%. This increase for 40 mg of proposed dose is equivalent to a dose
`of “60 mg”. Due to dose-dependent AEs for vilazodone, the dose should be adjusted
`(details see Section 2.2.4.8.1). The AUC of vilazodone can be increased with
`concomitant use of moderate CYP3A4 inhibitors, but the increase can not exceed by
`50%.
`
`2.1.3 Is a drug-drug interaction study of vilazodone with CYP3A4 inducer needed?
`Vilazodone is a low extraction ratio drug. Its systemic clearance is about one fifth of
`total hepatic blood flow. Under inducing conditions, its clearance could potentially be
`increased four fold, which could then lead to decreased exposure to vilazodone.
`
` A
`
` random two-way crossover design in healthy subjects treated with 20 mg vilazodone
`under basal conditions and after pretreatment with 400 mg carbamazepine once daily for
`7-14 days is recommended.
`
`
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`

`2.1.4 Is a drug-drug interaction study of vilazodone with CYP2C8 substrate needed?
`No.
`
`In-vitro experiment with hepatocytes indicates that vilazodone does not have a strong
`potential to inhibit CYP2C8 in-vivo. However, in vitro experiment with microsomes
`indicates that the [I]/Ki = 0.72 which is greater than 0.1 and suggests a need for in vivo
`evaluation. As the hepatocyte experiment represents a more physiologically relevant
`system, an in vivo study is not necessary. PBPK simulations also support no drug-drug
`interaction between vilazodone and CYP2C8 substrate, rosiglitazone.
`
`2.1.5 Should dose be adjusted in patients with severe renal impairment?
`No.
`
`Vilazodone eliminated primarily by hepatic metabolism with 2% unchanged drug in feces
`and 1% unchanged drug in urine. Vilazodone PK did not show difference between
`mild/moderate renal impaired patients and healthy subjects. Additionally, mild/moderate
`hepatic impairment did not show increased systemic exposure of vilazodone. It’s
`unlikely there is a clinically relevant elevation in vilazodone systemic exposure in severe
`renal impairment. However, vilazodone should be used with caution in severe renal
`impaired patients.
`
`2.2 Standard Questions
`
`2.2.1 What are the PK characteristics of the drug?
`
`2.2.1.1 What are the single and multiple dose PK parameters of parent drug and
`relevant metabolites in healthy adults?
`
`
`Single dose
`The single dose PK of vilazodone between 20 mg and 80 mg was characterized mainly in
`two Phase I studies. Table 2 shows the single dose PK parameters following different
`doses of vilazodone. In study CLDA-07-DP-01 with 44 healthy subjects exposed to
`vilazodone, the inter-subject variability (% CV) was 29% for Cmax and AUC.
`
`
`Table 2. Single dose PK parameters following different doses of vilazodone in healthy subjects
`
`Study
`
`CLDA-07-DP-01
`BE study
`Tablet (PG-20*/T-20)
`40
`Fed
`5 (4-10)
`
`Formulation
`Dose (mg)
`Diet
`Tmax (median,
`rang), h
`Cmax (mean
`(CV%)), ng/mL
`T1/2 (mean
`(CV%)), h
`
`
`
`Reference ID: 2874615
`
`GPP-007-CLN-CP1-1997-232
`Dose rising
`Capsule (C-10/C-40)
`40
`Fasted
`4.8 (2 – 8)
`
`80
`
`4.8 (2-8)
`
`20
`
`5 (3.5 -5.5)
`
`96.96 (28.83)
`
`28.5 (45.96)
`
`36.8 (38.59)
`
`58.4 (47.09)
`
`24.57 (36.18)
`
`24.1 (14.94)
`
`21.4 (15.89)
`
`20.4 (11.76)
`
`10
`
`

`

`502 (30.88)
`
`741 (28.88)
`
`1195 (30.38)
`
`AUCinf (mean
`1711.82 (29.11)
`(CV%)), ng h/mL
`*To-be-marketed formulation.
`
`Multiple doses
`The multiple dose PK of vilazodone between 10 mg and 80 mg was characterized in two
`Phase I studies. After multiple daily doses, the Cmax and AUC of vilazodone increased
`and steady-state plasma levels of vilazodone were reached on the third day of multiple
`dosing. The accumulation factor is ~1.8 folds. Table 3 shows vilazodone PK parameters
`at steady state following different doses of vilazodone in healthy subjects.
`
`Table 3. Multiple dose PK parameters following different doses of vilazodone in healthy subjects
`
`Study
`
`GPP-007-CLN-CP1-1998-230
`Dose rising
`Capsule (C-10/C-40)
`20
`40
`Fasted
`4.5 (2.5-
`5)
`45.5
`(38.9)
`29.5
`(15.59)
`528
`(35.61)
`1.54
`(21.43)
`
`10
`
`Formulation
`Dose (mg)
`Diet
`Tmax (median,
`rang), h
`Cmax (mean
`(CV%)), ng/mL
`T1/2 (mean
`(CV%)), h
`AUC0-24 (mean
`(CV%)),
`ng.h/mL
`Accumulation**
`
`3.5 (2.5-
`5)
`24.8
`(21.37)
`30.9
`(22.65)
`293
`(27.65)
`1.78
`(23.6)
`*To-be-marketed formulation.
`** AUC0-24 on Day 16/AUC0-24 on Day 1.
`
`4 (2-6)
`59.5
`(36.97)
`28.9
`(11.07)
`755
`(33.11)
`1.64
`(26.83)
`
`PGX-08-P1-06 (TQT study)
`Dose rising
`Tablet (PG-10/PG-20*)
`40
`60
`
`20
`
`4
`(3-10)
`70.09
`(43.13)
`_
`
`Fed
`
`4
`(0-12)
`156.28
`(43.23)
`_
`
`4
`(3-8)
`253.1
`(44.67)
`_
`
`80
`
`4
`(0-8)
`315.38
`(53.75)
`_
`
`776.83
`(45.31)
`
`1645.25
`(43.81)
`
`2506.1
`(44.19)
`
`3269.76
`(52.60)
`
`_
`
`_
`
`_
`
`_
`
`2.2.1.2 Based on PK parameters, what is the degree of the linearity or non-linearity
`in the dose-concentration relationship?
`Dose proportional increase in Cmax and AUC was observed in healthy subjects after
`single and multiple-dose administration of vilazodone dose ranging from 5 mg to 80 mg.
`
`
`2.2.1.3 How do the PK parameters change with time following chronic dosing?
`PK does not vary with time. Refer to Section 2.2.1.1 Multiple Doses.
`
`
`2.2.1.4 What are the general ADME (Absorption, Distribution, Metabolism and
`Elimination) characteristics of vilazodone?
`
`
`
`• What are the characteristics of drug absorption?
`The absolute bioavailability of vilazodone is 72% under fed conditions. The maximum
`concentration is reached at a median of 4-5 hours after drug administration.
`
`
`
`11
`
`Reference ID: 2874615
`
`

`

`• What are the characteristics of drug distribution?
`The protein binding was determined in vitro human serum at vilazodone concentrations
`of 0.05 – 5 ug/mL. Vilazodone is approximately 96-99% protein bound. Vilazodone is
`widely distributed with a volume of distribution of 605 L after 5 mg IV infusion for 4
`hours.
`
`
`• Does the mass balance study suggest renal or hepatic as the major route of
`elimination?
`Fecal excretion is the major route of vilazodone elimination. During the collection
`interval of 14 days, approximately 85% of the administered radioactivity was recovered
`in the urine (~20%) and feces (~65%) combined, while approximately 3% of the
`administered dose of vilazodone was recovered as unchanged drug (~1% in urine, and
`~2% in feces).
`
`
`• What is the percentage of total radioactivity in plasma identified as parent
`drug and metabolites?
`In the mass balance study, vilazodone metabolites were rapidly formed and peak
`radioactivity levels for the metabolites occurred at about 5 hours (vilazodone Tmax 4
`hours). The AUC for radioactivity is approximately 2.5 times the value for vilazodone
`(2071 h.ng/mL v.s., 850 h.ng/mL), i.e., ~40% of total radioactivity in plasma was
`identified as parent drug. Vilazodone and the radioactivity were eliminated at a similar
`rate (half-life of 27 hours for vilazodone v.s., 32 hours for radioactivity).
`
`
`• What are the characteristics of drug metabolism?
`
`
`Figure 2. Proposed metabolic pathways of vilazodone in humans (OCP’s figure)
`
`
`M10
`~36%
`
`CE?
`
`Vilazodone
`
`CYP
`
`CYP+
`FMO?
`
`M11
`
`Oxidative Metabolites
`
`
`
`The proposed metabolic pathway is provided in Figure 2. Vilazodone is extensively
`metabolized through CYP and non-CYP pathways (possibly by carboxylesterase (CE)).
`CYP3A4 is the primary isoenzyme for vilazodone metabolism among CYP pathways,
`with minor contributions from CYP2C19, and CYP2D6.
`
`In vitro studies with human microsomes and human hepatocytes indicate that vilazodone
`is unlikely to inhibit or induce the metabolism of other CYP (except for CYP2C8, 2C19,
`and 2D6 inhibition) substrates, and an in vivo study with probe substrates for 2D6 and
`3A4 showed vilazodone did not alter pharmacokinetics of the probe substrates. However,
`an in vivo study showed a minor induction of CYP2C19.
`
`
`
`12
`
`Reference ID: 2874615
`
`

`

`Vilazodone is not a potent inhibitor of CYP2C8 in hepatocytes. In vitro studies have
`shown that vilazodone is a moderate inhibitor of CYP2C19 and CYP2D6.
`
`2.2.2 Exposure-Response
`
`2.2.2.1 What are the design features of the clinical studies used to support dosing or
`claims?
`
`Design Features
`Well-controlled, randomized, double-blind, placebo-controlled,
`MDD patients, 40 mg QD (fed) for 8 weeks, primary endpoint
`of MADRS
`Well-controlled, randomized, double-blind, placebo-controlled,
`MDD patients, 5-100 mg QD (fed) for 8 weeks, primary
`endpoint of HAM-D; MADRS also collected
`
`Well-controlled, randomized, double-blind, placebo-controlled,
`MDD patients, 5-20 mg QD (fed) for 8 weeks, primary endpoint
`of HAM-D; MADRS also collected
`
`
`Study
`GNSC-04-DP-02,
`CLDA-07-DP-02
`Registration trials
`GPP-007-CLN-CP2-
`2001-244,
`GPP-007-CLN-CP2-
`2001-245
`GPP-007-CLN-CP2-
`2003-248,
`GPP-007-CLN-CP2-
`2003-246,
`GPP-007-CLN-CP2-
`2003-247
`
`
`2.2.2.2 What is the basis for selecting the response endpoints and how are they
`measured in clinical pharmacology studies?
`Standard endpoints for an MDD claim accepted by the Agency were employed. The
`primary effectiveness endpoint was the mean change from baseline to end of treatment
`(EOT) on MADRS (the Montgomery-Asberg Depression Rating Scale) for the
`registration trials. HAM-D was used for the early studies (listed above). Routine safety
`was collected in these trials.
`
`2.2.2.3 What are the characteristics of the exposure-response relationship for
`efficacy? What is the time to the onset and offset of the desirable
`pharmacological response or clinical endpoint?
`Based on the data from registration trials and early dose finding studies it appears that a
`lower dose of 20 mg will also have similar benefit as 40 mg based on change of MADRS
`score (details see Section 3.2 Pharmacometric Review).
`
`2.2.2.4 What are the characteristics of the exposure-response relationships for
`safety? What is the time to the onset and offset (or duration) of the
`undesirable pharmacological response or clinical endpoint?
`Most of the adverse events occurred during the initial titration phase (10 mg/day for 7
`days (Days 1-7), 20 mg/day for 7 days (Days 8-14) in comparison to maintenance phase
`(40 mg/day for 42 days (Days 15-56)). Adverse events are dose dependent (details see
`Section 3.2 Pharmacometric Review).
`
`
`
`13
`
`Reference ID: 2874615
`
`

`

`2.2.2.5 Does this drug prolong QT/QTc Interval?
`No, vilazodone does not meaningfully prolong QTc. (Refer to Dr. Joanne Zhang’s
`Thorough QT Study Review for details).
`
`
`2.2.3 Intrinsic Factors
`
`Figure 6. Impact of intrinsic factors on vilazodone PK.
`
`
`2.2.3.1 What intrinsic factors influence exposure (PK usually) and/or response, and
`what is the impact of any differences in exposure on efficacy or safety
`responses?
`Higher body weight correlated with lower Cmax and AUC. Elderly and young subjects
`showed similar PK profiles for vilazodone. After adjustment for body weight, the
`systemic exposures (AUC) between males and females are similar. See Figure 6 above.
`
`
`
`14
`
`Reference ID: 2874615
`
`

`

`2.2.3.2 Effect of Renal Impairment
`The effect of mild and moderate renal impairment on the single-dose PK of orally
`administered vilazodone 20 mg tablet