CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-192
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S t
`
`

`

`Clinical Pharmacology/Biopharmaceutics Review
`
`
`PRODUCT (Generic Name):
`
`' Iloperidone
`
`PRODUCT (Brand Name):
`
`DOSAGE FORM:
`
`Tablets
`
`DOSAGE STRENGTHS:
`
`1mg, 2mg, 4mg, 6mg, 8mg,
`10mg, 12mg
`
`NDA:
`
`22-192
`
`NDA TYPE:
`
`New Molecular Entity
`
`SUBMISSION DATE:
`
`November 6, 2008
`
`SPONSOR:
`
`Vanda Pharmaceuticals
`
`REVIEWER
`Andre Jackson
`
`
`REVIEW OF NDA RESPONSES
`
`The Agency’s Not Approvable (NA) action letter of July 25, 2008 to the
`sponsor conveyed two Comments from OCP. These were:
`
`(1) The hepatic impairment study was inconclusive because the exposure
`for mild subjects was greater than that for moderately impaired subjects, and
`the sponsor was requested to repeat the study.
`(2) The sponsor should investigate the possible interaction of iloperidone
`and P—Gp.
`
`Since this was a NA letter the above Comments were not conveyed as Phase
`IV commitments but rather as regular clinical pharmacology comments with
`the understanding that both items could be fulfilled before the approval of
`the drug. Also, as is generally the case, the NA letter did not forward the
`
`

`

`Dissolution method and specification which had been completed in OCP’s
`review.
`
`The sponsor met with the Agency on September 10, 2008, and discussed the
`comments that they had received from all disciplines in the letter. The
`sponsor sent in their Responses to the NBA on November 6, 2008 also
`addressing the two OCP Comments. The firm’s responses has satisfactorily
`addressed the clinical issues; therefore, the clinical division is planning on
`issuing an Action letter.
`
`OCP in this review addresses the two earlier comments (Viz., hepatic
`impairment, and transporter interaction), since they have now become Phase
`IV commitments (see Items 1 and 2 below), and, restating the Dissolution
`method and specification for convey to the sponsor (see Item 3 below).
`Finally, the latest version of the Labelling received from the clinical division
`has been compared to the one is OCP’s review, and it is acceptable (see Item
`4 below; Appendix I)
`
`, Item 1
`
`A meeting was held with the firm to discuss Hepatic Study CIL0522A0103
`were discussed. The firm agreed to repeat the study in a moderately impaired
`group, comparing them to normals in the same study, as a post-marketing
`commitment.
`'
`.
`
`Vanda will also honor FDA's request to submit the genotyping information
`for the extensive metabolizers used in this study.
`
`Until the new hepatic data is provided to FDA, Vanda will agree to
`the following labeling in the package insert:
`
`r...
`
`Item 2
`
`

`

`In Vitro Interaction of Iloperidone and P-Glycoprotein (P-Gp) was
`discussed in the meeting with FDA and Vanda has agreed to perform an in
`Vitro interaction study as a post-marketing commitment.
`
`Comment on Phase IV Commitments (Items 1 and 2 above):
`
`The fulfilling of both items mentioned above as Phase IV commitments is
`acceptable to OCP.
`
`The timeline for completion is as follows:
`
`(1) Hepatic Impairment Study -- 2 years after receipt of Action letter
`(2) In Vitro P-Gp Transporter Study — 6 months afier receipt of Action
`letter.
`
`Item 3
`
`Dissolution Method and Specification (from OCP’S review of July 10,
`2008) —— for convey to the Sponsor:
`
`The dissolution method and specification for all strengths of the
`immediate release tablets should be:
`
`Apparatus 2 (rotating paddle)
`500 ml 0.1 N HCI
`
`50 rpm rotation speed.
`Q= -' in 30 minutes
`
`Item 4
`
`Labelling — see Appendix I
`
`b(4)
`
`

`

`SIGNATURES
`
`Andre Jackson
`
`Reviewer, Psychopharmacological Drug Section, DCP |
`Office of Clinical Pharmacology and Biopharmaceutics
`
`RD/FTinitialized by Raman Baweja, Ph.D.
`Team Leader, Psychiatry Drug Section, DCP l
`Office of Clinical Pharmacology
`RD/FTinitialized by Mehul Mehta, Ph.D
`Division Director
`
`Office of Clinical Pharmacology, DCP1
`C:\Data\REVIEWS\NDA\ILOPERIDONE_NDA22—192_VANDA\PHASE4(2).doc
`
`after this page.
`
` 28 pgs of draft labeling has been removed
`
`‘
`
`

`

`93/ Page(s) Withheld
`
`___Trade Secret / Confidential (b4)
`
`3
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Andre Jackson
`
`1/15/2009 07:36:26 AM
`BIOPHARMACEUTICS
`
`Raman Baweja
`1/15/2009 03:34:54 PM
`BIOPHARMACEUTICS
`
`Mehul Mehta
`1/15/2009 04:13:49 PM
`BIOPHARMACEUTICS
`
`

`

`Clinical Pharmacology/Biopharmaceutics Review
`
`PRODUCT (Generic Name):
`
`Iloperidone
`
`PRODUCT (Brand Name):
`
`DOSAGE FORM:
`
`'
`
`Tablets
`
`DOSAGE STRENGTHS:
`
`1mg, 2mg, 4mg, 6mg, 8mg,
`10mg, 12mg ,.
`
`NDA: ”g
`
`NDA TYPE:
`
`'
`
`22—192
`
`New Molecular Entity
`
`SUBMISSION DATE:
`
`September 27, 2007
`
`SPONSOR:
`
`Vanda Pharmaceuticals
`
`REVIEWER
`
`Andre Jackson
`
`REVIEW OF NDA
`
`EXECUTIVE SUMMARY
`
`The firm is seeking approval for an oral tablet of iloperidone at dosage
`strengths of 1mg, 2mg, 4mg, 6mg, 8mg, 10mg, and 12 mg with a
`recommended target dose of 12 mg/day. The drug is metabolized by
`CYP2D6 which catalyzes hydroxylation of the acyl group to form
`metabolite P94 which is converted to P95. There have been shown to be
`
`poor, intermediate, extensive (regarded as the normal phenotype) and
`ultrarapid metabolizers. However there are other routes of metabolism not
`involving CYP2D6. CYP3A4 causes demethylation to metabolite P89
`which is inactive. P88 is generated by cytosolic reduction of iloperidone and
`back conversion to iloperidone by cytosolic oxidation so that floperidone
`
`

`

`and P88 can be considered to be in equilibrium. There are two major
`metabolites P88 and P95 with P88 believed to be active.
`
`g
`
`In the clinical development program the sponsor studied the effect of
`polymorphisms in the CYP2D6 gene on iloperidone exposure and QT
`prolongation and in the ciliary neurotropic factor (CNTF) gene on efficacy.
`The sponsor presented four clinical studies in which the effect of genetic
`variation of CYP2D6 and/or CNTF on QT prolongation and iloperidone
`efficacy was investigated:
`1) Study CIL0522A0104: two-cohort, open-label study. Evaluated PK
`parameters of iIOperidone and its two main metabolites (P88 and P95)
`in healthy subjects genotyped as CYP2D6 extensive metabolizers
`(Cohort l) and poor metabolizers (Cohort 2-).
`2) Study..CIL_05_22A2328: pharmacogenetic sub—study conducted to
`identify CYP2D6' genetic polymorphisms associated with iloperidone
`exposure and risk for QT prolongation after treatment with
`iloperidone.
`3) Study ILP3005: pharmacogenetic sub-study to evalutate the effect of
`polymorphism in the ciliary neurotrophic factor (CNTF) gene on
`response to iloperidone
`4) Study VP-VYV-683—3'101: assessed the effect of the CNTF FS63Ter
`mutation on iloperidone efficacy and of CYP2D6 polymorphisms on
`QTc prolongation.
`
`Iloperidone has a relative bioavailability of approximately 96%. Iloperidone
`Cmax occurs at 2 hrs in healthy individuals and it has a half-life of 15-22
`hrs. Clearance is decreased by half in poor metabolizers. Half-lives for the
`metabolites are 25 hrs.
`
`Iloperidone prolongs the QT interval at all three doses studied (i.e., 8 mg
`b.i.d., 12 mg b.i.d., and 24 mg QD)
`
`There is an approximately 24% increase in exposure in subjects with severe
`renal failure, but renal is not a major route of excretion thus there was no
`effect of renal impairment on the excretion of iloperidone.
`
`Characterization of iloperidone pharmacokinetics in subjects with moderate
`and mild hepatic failure was inconclusive. Excretion of iloperidone in
`
`

`

`subjects with mild hepatic disease was confounded and could not be
`interpreted.
`
`Iloperidone exposure is not increased in the presence of the CYP2D6
`substrate dextromethorphan. However, dextromethorphan levels were
`increased by 15% in the presence Of iloperidone.
`
`Ketoconazole inhibits iloperidone’s metabolism mediated by CYP450 3A4
`resulting in a 50% increase in exposure to iloperidone AUC and Cmax.
`
`Iloperidone mean Cmax values increased to 1.6 in the presence of
`paroxetine. Simultaneous administration of ketoconazole plus paroxetine
`resulted in the ratio for least square means for iloperidone increasing to 2.3.
`
`Administration Of iloperidone and fluoxetine concomitantly increased
`exposure to iloperidone and P88 (ratio for AUCO—inf least square
`means=2.37 and 2.21, respectively), while exposure to P95 had a decrease in
`the ratio for the least square means (i.e., 0.46 for AUCO-inf). This is a result
`of blocking the CY2D6 pathway. Iloperidone did not alter the
`pharmacokinetics of fluoxetine and norfluoxetine,
`
`There is no effect of food on the absorption of iloperidone.
`
`EXECUTIVE SUMMARY ................................................................................................ I
`COMMENTS TO THE MEDICAL OFFICER .................................................................. 4
`COMMENTS TO THE SPONSOR .................................................................................... 5
`
`QUESTION BASED REVIEW .......................................................................................... 5
`DISSOLUTION ................................................................................................................ 34
`FIRM’S PROPOSED LABEL .......................................................................................... 34
`FDA LABEL.......................'. ............................................................................................. 41
`SIGNATURES ...................................................................................... -. ........................... 46
`REPORT FROM SCIENTIFIC INVESTIGATIONS ...................................................... 4s
`DETAILED STUDY REPORTS ...................................................................................... 52
`ASSAY VALIDATION................................................................................................ 52
`PLASMA PROTEIN BINDING ................................................................................... 53
`HUMAN LIVER MICROSOMES-STUDY IL0522 .................................................... 54
`BLOOD DISTRIBUTION OF 14C 1L0522 IN HUMANS ........................................... 57
`PERMEABILITY DETERMINATION OF ILOPERIDONE AND 14C -S-P88
`ACROSS CACO-2 CELL MONOLAYERS ................................................................ 58
`STUDY ILPB101/101A: SINGLE DOSES HEALTHY YOUNG MEN
`............... 60
`STUDY ILPB105:14 C LABELED IN HEALTHY MALE VOLUNTEERS ............. 62
`
`

`

`STUDY NO. CIL0522A 2301—ADME HEALTHY MALES ...................................... 64
`STUDY NO. ILPB203 -MTD FOR ILOPERIDONE IN PATIENTS .......................... 74
`STUDY NO. CIL0522 0112-SS DOSE PROPORTIONALITY PATIENTS ............. 76
`STUDY NO. CIL0522A 0102-SEVERE RENAL IMPAIRMENT ............................ 80
`STUDY NO. CIL0522A0103-MILD TO MODERATE HEPATIC IMPAIRMENT. 87
`STUDY NO. CIL0522 0104-DEXTROMETHORPHAN DDI....L .............................. 93
`STUDY NO. CIL05220107-KETOCONAZOLE DDI .............................................. 109
`STUDY NO. CIL0522 2328—PAROXET1NE DDI ................................................... 114
`STUDY NO. CIL0522 0108-FLUOXETINE DDI .................................................... 120
`BIOPHARMACEUTICS ............................................................................................ 128
`STUDY NO. CIL0522 0110-1 MG BE STUDY-3 FORMULATIONS
`..... 128
`STUDY VP-VYV—683-1002-BE 1 MG OVERENCAPSULATED .......................... 131
`STUDY NO. CIL0522 0105-FOOD EFFECT .......................................................... 135
`EXPERIMENTAL DISSOLUTION DATA .................................................................. 138
`STUDY NUMBER: VP-VYV-683-3101-POPULATION PK ................................... 141
`FDA ANALYSIS FINAL MODEL ................................................................................ 151
`STUDY ILP3005-PKPD .............................................................................................. 152
`
`GENOMICS REVIEW NDA 22-192—Sy1vana Borges ................................................... 162
`APPENDDC-FDA ANALYSIS ....................................................................................... 169
`BASE MODEL ....................................................................................‘....................... 169
`FINAL MODEL.......................................................................................................... 173
`
`COMMENTS TO THE MEDICAL OFFICER
`
`A. Hepatic Study
`
`The hepatic impairment study was inconclusive.
`
`The firm will be requested to do a reduced design hepatic impairment study
`using subjects in the moderate Child-Pugh category.
`
`Pending receipt of the hepatic impairment study data, iloperidone should not
`be administered to hepatically impaired subjects.
`
`B. Inspection Report .
`
`This study was also investigated by the Division of Scientific Investigations.
`The report concluded that Vanda had included information into their reports
`without verification which led to some errors, overall it did not impact study
`outcome. The report is appended to the review.
`
`C. Dissolution Comments
`
`

`

`The comments to the sponsor section contains dissolution comments that should
`be fowvarded to the sponsor.
`'
`
`COMMENTS TO THE SPONSOR
`
`1. The study CIL0522A0103 conducted in normal, mild and moderately
`impaired hepatic subjects'was inconclusive since the exposure for
`mild subjects was greater than for moderately impaired subjects. The
`sponsor should repeat the study in a moderately impaired group
`comparing them to normals in the same study. The genotyping for the
`extensive metabolizers used in this study should be submitted to OCP.
`2. The firm should conduct a study investigating the possible in vitro
`interaction of iloperidone and P-Gp as discussed in a prior
`communication with the firm.
`
`3. The dissolution method and specification for all strengths of the
`immediate release tablets should be:
`
`Apparatus 2 (rotating paddle)
`500 ml 0.1 N HCl
`
`50 rpm rotation speed.
`
`Q= .’ in 30 minutes
`
`QUESTION BASED REVIEW
`
`WHAT IS THE PLASMA PROTEIN BINDING AND RED CELL
`
`PARTITIONING FOR ILOPERIDONE AND IS THE PROTEIN
`
`BINDING LINEAR?
`
`The plasma protein binding for iloperidone is 93% and it is linear over the
`range of 5—500 ng/ml.
`
`The fraction of iloperidone in the red blood cells is 25% in the concentration
`range of 10-100 ng/ml.
`
`WHAT ARE THE MAJOR METABOLITES FOR ILOPERIDONE BASED UPON
`THE HUMAN LIVER ENZYME STUDIES?
`
`M4)
`
`

`

`110522 was metabolized in human liver microsom- to primarily four products, P22 (N-
`dealkylation), P94 (hydroxylation), P89 lO-danethylation), and P88 (carbonyl reduction).
`
`CYP2D6 was the most efficient in the formation of metabolite P94 (hydroxyiation)
`
`Table 1. Per Cent metabolism of IL0522 by recombinant cytochrome P450's
`ma)
`non: mwmroumd
`nowWhoW
`
`'
`
`GYP‘lM
`CYPlAZ
`CYP2A5
`
`cvm-
`. chzca
`(>va
`arm”
`GYPEDG
`ovum
`CYP3A4
`0YP3A5
`
`'
`
`-
`
`v
`
`a; official)
`21
`£7
`12
`
`b! mm
`
`P22. P55
`P22, P88
`P38
`
`32
`5-6
`1.6
`72
`15
`0.7
`9-15
`I3
`
`.
`
`-
`
`-
`
`»
`
`'
`
`922, pas
`P22, P"
`.
`P22
`.
`P22. P33. 989
`P94
`m .
`P22, P88. P89
`P22. P38. P59.
`
`WHAT IS THE MASS BALANCE FOR ILOPERIDONE?
`
`The mass balance for iloperidone was determined following the oral
`administration of 3 mg of 100 uCi of 14C-iloperidone to 3 male volunteers.
`
`Table 2. Total radioactivity excreted in urine and feces
`
`Mean :t: 8])
`Cm'mllative
`VoofDose
`563*”
`
`Subject 5
`Subject 4
`Subject 2
`
`Cumulative
`Cumulative
`Cumulative
`
`%ofDose
`%ofDose
`“AofDose
`
`
`
`
`
`Total % of
`.
`Radioactivity
`69.8
`77.0
`
`
`—m
`
`‘
`76.9 i 7.1
`
`
`
`
`
`
`Over the 21 day collection period most of the radioactivity was recoveredin the
`urine.
`'
`
`Themajorurinuyeomponufiwumwmfichmpfiudoftwowmpmmuyl
`carboxylic acidmehbolitc (P9542113) andmmbolito P88-8991. Tlfiseomponan
`munbdfmbdweenmmdmofthomimryndioacfivityinflnmplumm
`.. __._.u-- :_.....:....-1 a... ".4. achMImI-IM as. n-‘r
`
`Thammtotalftcalreooveryatthamdufthamdy(day42)wmimilarinall
`subjemrangingfium19.6%insubiect1lo225‘lfiinuihjmt5(mm20,fi:t
`1.6%).
`
`

`

`WHAT ARE THE MAJOR CIRCULATING SPECIES IN PLASMA for EMS and
`PM’s?
`-
`-
`
`A study was done with 3 mg [14C]lL0522 given as an oral solution to six healthy,
`nonsmoking, male subjects betWeen the ages of 18 and 45 years.
`
`Pharmacokinetic and safety assessments were made for up to 336 hours (14
`days). _ Four of the subjects were EMS and two were PM’s.
`
`Table 3. AUC(O-.t) (ngEq*h/ml) values for major species identified in plasma and
`the amount of total radioactivity associated with that component for two
`representative EM subjects and the two PM subjects
`
`I nc-Eth/ml of 'MaiorSecies Measured in. Plasma I.
`'
`_AUC O—t
`
`no 522 N-
`ilop'e'ridon‘e
`P88
`P95
`dealkyl
`
`.
`
`.
`
`j
`
`
`
` .J
`
`'
`‘
`Total'%'
`Radioactivity
`Extracted
`
`M4)
`
`7V
`
`,,
`
`The results indicate that there is a quantitative recovery of species in plasma for
`EMS and for PM’s.
`
`IS THERE A DIFFERENCE IN THE AMOUNT OF DRUG RECOVERY FOR
`SLOW AND FAST METABOLIZERS?
`
`A drug recovery study was done in 4 extensive and 2 slow metabolizers.
`
`Table 4. Excretion of dose (radioactivity and unlabeled metabolites, %
`close) in the six healthy human volunteers (4 EM, 2 PM) in the 14
`days following a single oral dose of 3 mg [14C]lL0522
`
`_1. """‘"'a .. “1r- ..._. __.-_ -- _ ".5 I —r-—-—
`
`-
`
`b(4)
`
`
`3-5101 6102 5103
`5106 Mutts!)
`5‘15
`51% Halli.
`
`
`[5.1 2 5.69
`
`221 2338
`
`Sum
`512: 10.1
`
`
`unabated
`Mdnboliea
`
`.
`
`Ur'ne
`Fem
`Sum
`
`
`
`J 88227.15
`
`Ianzzm
`29910.1
`1832292
`
`
`
`

`

`The recovery appears to be similar for slow and fast metabolizers and for all
`sampled fluids and for total dose recovery.
`
`HAS THE CLASSIFICATION OF CYP 2D6 EXTENSIVE AND POOR
`METABOLIZERS BEEN DONE CORRECTLY BY THE FIRM?
`
`CYPZD6 plays an important role in iloperidone metabolism. It also shows
`extensive genetic polymorphism, which determines a great variability in the
`activity of the enzyme in the population. Four phenotypes have been described:
`poor, intermediate, extensive (regarded as the normal phenotype) and ultrarapid
`metabolizers. The effect of CYP2D6 status on the PK of drugs metabolized by
`CYP2D6 is usually evaluated by comparing drug exposure in poor (PM) and
`extensive metabolizers (EM). The identification of PM and EM (also called
`CYP2D6*1I*1) wild type can be done by genotyping for the most common
`CYP2D6 alleles in the studied population (those alleles are different in different
`ethnic groups). However, there is no specific test to identify the *1 allele and its
`presence is defined by the absence of the tested alleles. Therefore, the accuracy
`of the *1 allele designation depends highly on the number of tested variants. in
`the case of testing only for one allele (*4), as is the case of the studies presented
`by the sponsor, assigning the *1 /*1 genotype (EM) to those patients that tested
`negative for *4 could lead to the misclassification of about 30% of the patients.
`This means that those so—defined "*1/*1" patients could actually be for instance
`*3/*5 (then PM), *1 O/*10 (then intermediate) or *1/*2xn (then ultrarapid
`metabolizers).
`
`WHAT IS THE IMPACT OF THIS LACK OF CLASSIFICATION ON THE
`ABILITY TO CORRECTLY PREDICT THE EFFECT OF PM IN THE
`POPULATION AND THE NEED FOR DOSE ADJUSTMENT?
`
`Although CYP2D6*4 is the most frequent knockout allele in Caucasians, that is
`not the case for other ethnicities, and other alleles such as CYP206*3 and *5 can '
`account for up to 30% of the PMs, even in Caucasians.
`In addition, as stated
`before, the number of tested alleles affects the identification of the EM as well. If
`the PM and EM groups are not clearly defined, the validity of any comparison of
`variables between these groups is questionable.
`
`WHAT IS THE PROPOSED METABOLIC SCHEME FOR ILOPERIDONE?
`
`Figure 2. Structures of IL0522 metabolites formed in human in vivo.
`Numbers in parentheses represent the average amount (% dose) of
`metabolite(s) in excreta from all six human subjects following a single oral dose
`of 3 mg 14c lL0522
`
`

`

`
`
`Iloperidone is metabolized through multiple pathways, but primarily through
`CYP2D6, CYP3A4 and cytosolic reduction. P88 is generated from .
`iloperidone by cytosolic reduction, a reaction that is in equilibrium causing
`the interconversion of iloperidone to P88 and vice versa. P88 is primarily
`eliminated by glucouronidation.
`
`Proposed pathway for conversion of P94 to P95 (carboxylic acid).
`
`0
`R/“x‘
`
`CYonfi
`
`0
`
`R
`
`0H
`
`dcohol
`dehydrogenase
`" R
`
`0
`
`.
`
`0
`
`aldehyde
`
`Hdehyclrogenase
`
`0
`
`R
`
`0
`
`+ (:02
`0
`OH decarbcmrlase
`*" RJLOH
`
`iloperidone
`
`P94
`
`aldehyde
`
`keto-acid
`
`P95
`
`P95 is eliminated by glucuronidation.
`
`

`

`ARE THE PHARMACOKINETICS FOR ILOPERIDONE AND ITS
`TWO MAJOR METABOLITES LINEAR?
`
`A 32 patient study was done to investigate the linearity of doses from 2—12
`mg bid at steady-state in schizophrenic patients.
`
`Table 5. Estimates and 90% CI for exponent parameters of power model for
`assessing dosenp oportionali
`"Ulla-‘3 0955“ HIDE-PlU
`.Iuumly
`
`(1.06. 1.17)
`(1.06, 124)
`,_(LIQ.1.21)
`
`(037,193)
`(9:93AM).
`
`.
`
`.
`
`..
`
`,_
`
`WWAmmhwfimbdeWdfll
`‘fihpvflmifimfisfingfiahwmvfluqmlbl.
`'
`
`The results indicate that |loperidone showed some non—linearity Over the dosage
`range of 2-12 mg bid while the' major metabolites all exhibited linear
`pharmacokinetics.
`
`IS THE RENAL EXCRETION OF ILOPERIDONE AFFECTED BY
`RENAL FAILURE?
`
`The firm conducted a study in two groups:
`
`Group 1: Subjects between 18 and 65 years of age with chronic, severe renal
`failure (CrCL <30 mL/min).
`
`Group 2: Healthy male and non-fecund female subjects matched by gender,
`age, height, body weight, and smoking status to Group 1 (CrCL >80
`mL/min).
`
`A total of 23 subjects completed the study, with 3 additional healthy
`subjects requiring dosing due to study site mismatching subjects (Subjects
`14, 15, & 18). No subject discontinued from the study.
`
`A single 3—mg dose (3 x 17mg capsules) was administered.
`
`10
`
`

`

`RESULTS
`
`Figure 3. Mean plots of iloperidone in healthy and renally impaired subjects
`following a 3 mg oral dose.
`L!
`
`3
`
`‘B
`Shum-hum(Wu,- F
`
`
`u
`‘-
`u
`I
`:
`js
`d
`u
`a
`II
`III.”
`.
`Table 6. Mean %CV parameters of ilolaeridone in healthy and renally
`impaired subjects following a 3 mg oral dose
`‘
`
`
`
`
`PK Parameters
`
`Mun (CW/o)
`
`W ———
`
`
`
`_—-_—___
`tn (hr)
`15.0 (20)
`33.7 (48)
`124
`
`
`
`
`
`
`
`—_—-_
`_——m-
`_—_—
`‘Medin(mge)
`-
`
`
`
`
`ll
`
`

`

`Figure 4: Mean concentration-time profiles of metabolite P8 8-8991 in
`healthy and renally impaired subjects following 3-mg single oral dose of
`iloperidone.
`1..
`
`
`
` Viluv.MWcommit-um[dial-I*-:
`
`E E
`
`.nk
`
`Table 7. Mean (CV%) of pharmacokinetic parameters of P88-8991 in
`healthy and renally impaired subjects following a 3-mg single oral dose of
`\u-w’
`_. :, n I, ‘0, no, unu- I} mun-mu,
`iloperidone (Subjects 9, 14, 15, 18, and 19 excluded)
`Mamet":
`
`.
`
`————
`
`———-
`
`.5
`
`
`
`
`AUCHOm'ht/ml.)
`5].! (53)
`48.l (49)
`
`mm
`
`
`
`
`
`
`
`———-I-
`——_—
`Median (wage)
`
`12
`
`

`

`Figure 5: Mean concentration-time profiles of metabolite P95 in healthy and
`renally impaired subjects following 3-mg single oral dose of iloperidone.
`
`V;,E‘.EEl‘.t
`(Id-ll
`
`
`MunPOO-R115cum-1M!“
`
`ah.
`
`Tn- 'rm
`
`Table 8. Mean (CV%) of pharmacokinetic parameters of P95-121 13 in
`healthy and‘renally impaired subjects following 3-mg single oral dose of
`_iloperidone (Subjects 9, 14, 15, 18, and 19 excluded)
`
`war-men
`
`
`
`_———
`
`aw
`mus-mu main—n——__
`use»
`m
`
`
`
`
`
`
`The 24% increase in exposure for iloperidone in this study does not warrant any
`change in dose for renally impaired subjects.
`
`
`
`
`
`For the active metabolite P88 there was also no effect of renal impairment on
`total or peak exposure.
`
`The inactive metabolite P95 had a 52% increase in total exposure for renally
`impaired subjects whereas there was no effect of renal
`impairment on peak
`concentration.
`
`13
`
`

`

`WHAT IS THE EFFECT OF MILD AND MODERATE HEPATIC FAILURE ON
`THE METABOLISM OF ILOPERIDONE?
`
`Study Group 1 consisted of 4 subjects with mild hepatic impairment (Child-
`Pugh Score 5-6; 2 males, 2 females) and 4 subjects with moderate hepatic
`impairment (Child—Pugh Score 7-9; 4 males). Group 2 consisted of 8 healthy
`subjects matched by gender, age, body height, weight, and smoking status (4
`subjects in each group) to Group 1.
`
`All subjects were extensive metabolizers.
`
`Figure 6. Mean plots of iloperidone in healthy and hepatically impaired
`subjects by severity following a 2-mg single oral dose of iloperidone
`
`Ina/III.)
`MeanPlasmanopendanaconcentration
`
`
`
`
`0
`
`'
`
`10
`
`-
`
`20
`
`30
`
`40
`
`50
`
`magnum
`
`man (hr)
`mus.” hepaticn impairment
`
`Illuminate hepatical inpaimz
`
`14
`
`

`

`Table 9. Mean (cl/%) pharmacokinetic parameters for iloperidone in healthy and
`hepatlcally impaired subjects by severity following a 2 mg oral dose of
`lloperidone.
`
`Hunky Subjects ,
`(F0)
`
`lien (WI)
`Btpflically Inpaind Subject:
`(3‘!)
`
`Hepatically 11‘:de Subject:
`(#4)
`
`PR Parameter:
`a...
`(11:)
`C.“ (lag/ml.)
`300.4 (ug‘hz/ml.)
`100.. (ng‘hrImL)
`w: (11:)
`.
`(lg/fa; (L/hz)
`VIIh (1.)
`l: (I of 60*)
`Cl, (uni-in)
`
`.
`
`'
`
`3.50 (2-5)
`1.75 (56.2)
`10.70 (40.0)
`22-00 (36.3)
`24.44 (29.9)
`102.71 (34.3]
`3702.29 (52.9)
`0.40 (69.9)
`7.02 (44.3)
`
`‘
`
`V
`
`‘
`
`)1in
`3.50 (3-5)
`2.23 (15.4)
`23.60 (17.7)
`30.33 (20.2)
`24.45 (14.3)
`- 68.35 (23.2)
`2394.25 (24.4)
`0.44 (56.2)
`6.40 (63.5)
`
`ll Difference
`0.0
`27.2
`25.7
`37.0
`0.0
`-33.5
`-35.3
`9.0
`-7.7
`
`-
`
`Moderate
`1.75 (1-3)
`1.13 (35.4)
`12.79 (67.0)
`20.77 (61.7)
`24.57 (26.7)
`122.07 (52.5)
`3955.33 (36.2)
`0.34 (56.5)
`13.05 (36.2)
`
`-
`
`-
`
`1-
`
`»
`
`7
`
`4 Difference
`'50.0
`'35.4
`'31.9
`-5.6
`0.5
`10.8
`6.8
`15.3
`05.9
`
`Figure 7. Mean plots of P8 8-8991 in healthy and hepatically impaired
`subjects by severity following a 2-mg single oral dose of iloperidone.
`
`1.6
`1.5
`1.4
`1.3
`1.2
`1.1
`1.0
`0.9
`0.8
`0.7
`0.5
`0.5
`0.4
`
`
`
`
`
`
`
`
`
`MeanPlasmaPea-3991concentration(no/m1.) 0.3
`
`0.2
`0.1
`0.0
`
`X.
`
`mflealchy
`
`Tame (hr)
`mmld hepatical impairment
`
`“-Madezace hepatical Winnie!“
`
`15
`
`

`

`Results were confounded and the firm will be requested to repeat the study
`using the modified design.
`
`Label should reflect the fact that a study has not been done for Iloperidone during
`hepatic impairment and that it should not be given to subjects with mild,
`moderate and severe hepatic impairment. The reasons for this decision are:
`
`1. the hepatic study was done at one of the lowest 'doses which could pose a
`more significant safety issue at higher doses.
`
`2. the pattern presented by the data has mild subjects exhibiting exposures
`approximately 50% higher than moderately impaired subjects for iloperidone.
`
`3. the active metabolite, P88, also appears to exhibit greater exposure for mild
`than moderately impaired hepatic subjects.
`
`WHAT IS THE EFFECT OF FAST AND SLOW METABOLISM ON
`
`THE DISPOSITION OF ILOPERIDONE?
`
`Nineteen subjects were genotyped as extensive CYP2D6 metabolizers and eight
`subjects were genotyped as poor CYP2D6 metabolizers. All subjects were
`between the ages of 18 and 45 years. The study objective was to compare the
`elimination pattern of iloperidone and its metabolites in EMS and PM’s.
`
`Figure 8. Mean plots of iloperidone in extensive and poor CYP2D6
`metabolizers following a 3 mg single oral dose of iloperidone
`
`
`
`
`
`as
`Time (hr)
`
`48
`
`ea
`
`12
`
`—.- Extensive CYP 208 Mohbollzals
`-Iv - Poor CYP 206 Motohollzau
`
`o
`
`12
`
`24
`
`16
`
`:7
`
`3
`
`2
`
`E’
`
`3 g
`
`g
`1,3.
`g i
`
`t:
`
`2 o
`'
`
`

`

`Table 10.'Mean (CV%) iloperidone pharmacokinetic parameters in extensive
`and poor CYPZDG metabolizers following a 3 mg single oral dose of
`Hopendone
`
`nsive
`
`% Dilferenoe“
`
`2-5 (2-3)
`2.7907)
`
`294 (as)
`
`17.6 (36)
`
`116.5(39)
`
`364) —
`
`‘
`
`46.3 (17)
`
`32.8021)
`
`66-4 (16)
`3095(19).
`
`.'_
`
`S 2868(49)‘
`
`As we of dose)
`animumm)
`'Medlan _.(Rangej
`"’ % Difference = (Poor —‘Extensiva)lExiensive X 100
`
`0.45 (69)
`.M
`
`v
`
`Figure 9. Mean plots of metabolite P88—8991 in extensive and poor CYP2D6
`metabolizers following a 3 mg single oral dose of iloperidone
`
`(8
`
`
`
`
`
`MeanPlasmaP888991Concentration(ngImL)
`
`
`
`
`
`Time (hr)
`
`17
`
`

`

`Table 11. Mean (CV%) P88-8991 pharmacokinetic parameters in extensive and
`poor CYP2D6 metabolizers following a 3 mg single oral dose of
`Hopendone
`.._'. ....... -
`
`PK Parameters
`
`0
`
`
`2343 (45)
`we? ”(LS '
`
`
`
`aorao)‘
`
`'
`
`515N162 V.
`
`.l
`
`.,
`
`Median (Range) _
`“ % Difference = (Poor — ExtensivayExtensiva X 100
`
`Figure 10. Mean plots of metabolite P95-121 13 in extensive and poor
`CYP2D6 metabolizers following a 3 mg single oral dose of iloperidone
`
`
`
`
`
`MeanPlasmaP9542113Concentration(nglml.)
`
`
`
`
`
`U
`
`-.—- Extomlvo GVF 208 metabolize”
`—I- - Poor CYP 208 motsbollzora
`
`
`
`
`
`0
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`Time (hr)
`
`18
`
`

`

`Table 12. Mean (CV%) P95-121 13 pharmaeokinetic parameters in extensive and
`poor CYP2D6 metabolizers following a 3 mg single oral dose of iloperidone.
`PK paramétérs " '
`"
`
`Cm(ngImL)
`
`153.8 (26)
`
`2/
`
`%Differenoe**
`
`8.01312)
`
`0.67 (44)
`
`32.1 (as)
`
`30.6131)
`
`-79.1
`
`380-9
`
`
`
`-76-5
`
`.
`
`4-5. (24)
`75.0 (25)" "
`664(26)“ ‘
`i
`CL..(ihuminj
`..
`.
`'Médiénmafiga‘)“ ..
`.
`..
`
`" % Difference = (Poor aExtensiveflExtensiva X 100
`
`
`
`Table 13'. Least-squares mean ratio of PK parameters from ANOVA of poor
`vs. extensive metabolizers
`
`‘ P
`
`arameter
`AUG”
`AUCN
`cm
`7 cm
`CL»;
`
`Least-squares mean ratio ‘
`‘
`1.659
`1.474
`0.860
`0.807
`1280
`
`90% confidence interval *
`(1306,2107)
`(1,161.1.871)
`(0691,1069)
`(0,695.0.938)
`(0.878.186?)
`
`lloperidone
`
`PBS-8991
`
`1 CLTIF
`
`A90;
`AucM
`
`AUG.H
`cm
`CLR
`A190.
`
`P9542113 AucM
`
`* Auc.n
`cm
`
`0.603
`
`1.599
`2.052
`
`1.85
`1476
`1.166
`1.93 .
`
`10208
`
`0.145
`0.147
`
`.
`
`(0,475.0.765)
`
`(1.0672396)
`(1,621.2.596)
`
`(1.4822308)
`(1203,1311)
`(0906,1501)
`(1.4262619)
`
`(0.1650261)
`
`(0,104.0.202)
`(0105,0204)
`
`(0940,1361)
`1.131
`CLR
`
`
` (0.148,D.261) -. n .. o . a - - - .. ‘3. «no: a. .
`0.197
`* A6m
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`19
`
`

`

`Conclusions based on LSM ratios:
`.liloperidone exposure (AUCO-t) was 47% higher for PM’s compared
`to EM’s
`
`2. active metabolite exposure was 85% higher for PM’S compared to
`EM’s
`
`3.
`
`the P95 metabolite exposure was 85% lower for PM’s compared to
`EM’s
`
`WAS THERE AN OBSERVED QT PROLONGATION?
`
`The firm conducted an open—label study comparing iloperidone at doses of 8
`mg bid, 12 mg b.i.d., and 24 mg q.d. on QTc interval duration in the
`presence and absence of metabolic inhibition. The effect of metabolic
`inhibition on iloperidone and the active comparators (ziprasidone 80 mg
`b.i.d,'and quetiapine 375 mg b.i.d., in the presence and absence of metabolic
`inhibition), in otherwise healthy patients diagnosed with schizophrenia or
`schizoaffective disorder was investigated.
`
`' Table 14. Study Design (Treatment phase)
`‘uwav as ”val-J "W's“ \‘nwvmvu- run-luv,
`
`_ Treamtmase
`Treamleaneriodt
`
`
`
`
`
`
`
`
`——-—(+paroxet'ne)
`
`
`
`
`
`_W_—+kemconazole
`
`Treatment Penod2
`
`TredmentPenodii
`
`(+paroxethe)
`
`as 24 28
`(+pamefineam ketoommzole)
`
`(+paroxet‘ne}
`
`(+pMne and Ketoconazole)
`
`(+pamxeme)
`
`(+pmmefina and ketmazole)
`
`(+ketoconazole)
`
`20
`
`

`

`Table 15. Summary statistics of QTcF change (95% CI) from baseline to
`steady state at Tmax during Treatment Periods 1, 2, and 3 (Primary QTc
`population).
`
`Sample size
`Baseline
`Raw muni- SD
`Change in QTcF
`Rawmnnzl: SD
`LS mean"
`(95% CI forLS mean)
`Period 2
`p
`p
`Samplesize
`.
`Baselina_ .
`Rawmuilzl: SD
`Charge in QTcF .
`RawmenuiSD _
`_ LSmean
`-
`(95% CI forLS man)
`Period 3
`'
`_
`.
`Sample size
`Baseline
`Raw mean i SD
`
`.
`
`'
`3853 :h 16.4
`
`8.5:1: 10.5
`9.1
`(4.9, 13.3)
`
`26
`
`3873 i 16.1
`
`“2:120
`11.9
`.
`(72. 15.6)
`'
`
`25
`
`llllll
`
`34
`
`33
`
`386.5 :I: 17.1
`
`379.0-.1: 14.7
`
`383.4 :1: 13.5
`
`383.2 :1: 18.9
`
`90:1: 12.5
`9.7
`(5.8. l3.6)
`_
`
`31
`
`386.1 3: 17.7
`-
`
`“63:16.8 ;
`11.9
`.
`(7.6. 16.3)
`
`15.4:E11.7
`14.6
`(10.6, 18.9)
`
`31
`
`9.63: 11.0
`9.7
`(5.7, 13.7)
`_
`
`30
`
`1.3:E11.1
`1.3
`(-2.5, 5.2)
`
`32
`
`379.0 :E 14.7
`
`383.0 i 13.2
`
`382.8 i 19.1
`
`l7.5:h10_3
`16.0
`(11.7, 203)
`
`15.9:1:11,.8__~
`15.4
`.
`(11.1, 19.8)
`
`30
`
`29
`
`387.5 :t 16.4
`
`384.5 3: 15.6
`
`379.6 :1: 14.9
`
`15.7 :I: 14.1
`
`19.3 :1: 17.1
`
`19.5 :1: 11.9
`
`"IheleastsquascmeansandconfidenceimavalsforPaiod 1 arepmvidedbydwmviewcr. Thcsctesults
`areslighflydifietmnhmflmmstfltsrepottedonTable921.2,pagc308asthcsponsorsresultsincludedtwo I
`additiomlpafiemsfiomflie secondary QTc population)
`
`The results indicated that the 95% l—sided CI contained 10 msec at the doses
`
`of 8 mg, 12 mg and 24 mg.
`
`WERE THERE ANY DESIGN ISSUES RELATED TO THE QT
`DATA PRESENTED THAT WOULD LIMIT THE PRECISE
`ESTIMATION OF THE EFFECT?
`
`The major-limitations were as follows:
`
`1. This study was not a placebo-controlled study. There were two active
`controls, ziprasidone 80 mg b.i.d. and quetiapine 375 mg b.i.d., but the
`magnitude of their effects on the QT interval is not well characterized.
`
`2. All treatments were administered open-label. Thus, the studyis subject to
`potential bias.
`
`21
`
`

`

`3. Assay sensitivity could not be established. The study included two active
`comparators: quetiapine (375 mg b.i.d.) and ziprasidone (80 mg b.i.d.).
`Based on the FDA analysis of the exposure-response analysis for quetiapine
`in two other QT studies (Study A750—1001 in NDA 22,192 and Study
`R076477-SCH—1014 in NDA 2