CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 2 - 1 1 7
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTIC S REVIEWg S 1
`
`

`

`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS REVIEW
`________________________________________________________________
`NDA 22117 Sponsor : Organon USA
`Drug: Asenapine (ORG5222)
`Sublingual Tablets
`
`Formulation:
`
`
`Schizophrenia
`
`Proposed Indication:
`
` Acute Mania Associated w/Bipolar
` Disorder
`Correspondence Date:
`
`
`July 25, 2008
` September 4, 2008
`
`
`
`
`
`
`September 23, 2008
`Reviewer:
`
`
`
` Andre Jackson
`________________________________________________________________
`Review History of Additional Plasma Metabolic Profile Data Submitted by the
`Firm
`
`HISTORY
`
`The firm submitted a letter on July 25th 2008 making the following points related
`to the clarification of the metabolite profile for Asenapine (see Appendix I).
`(cid:190) Nearly 50% of the drug-related material in human plasma has been
`unequivocally identified and/or quantified by LC-MS/MS.
`(cid:190) The remaining radioactivity (~50%) corresponds to at least 15 different
`very polar peaks, none of which represent more than 6% of the plasma
`radiocarbon profile.
`(cid:190) A significant percentage (~71%) of the excreted radioactivity has been
`characterized by LC-MS.
`
`
`The FDA responded to that July 25th correspondence with comments in the
`format of a review (see Appendix II).
`
`The amount of information presented by the firm related to metabolite analysis
`required an in depth re-analysis of all submitted data which was completed and is
`presented in Appendix III.
`
`Questions were sent to the firm on September 3, 2008 seeking further
`clarification (see Appendix IV).
`
`The firm’s response is presented in Appendix V.
`
`The firm’s response response to FDA questions is presented in Appendix VI.
`
`Information presented at the internal meeting on September 15, 2008 (see
`Appendix VII).
`
`The firm’s final response and data summary are presented in Appendix VIII.
`
`
`
`1
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`
`HISTORY ........................................................................................................................... 1
`TABLE OF CONTENTS.................................................................................................... 2
`OVERALL COMMENT .................................................................................................... 2
`OCP LABEL....................................................................................................................... 2
`APPENDIX 1 July 25th 2008 LETTER FROM FIRM....................................................... 4
`APPENDIX II- FDA RESPONSE TO FIRM JULY 25TH LETTER ................................ 9
`APPENDIX III-IN DEPTH RE-ANALYSIS OF ALL SUBMITTED DATA ................ 13
`APPENDIX IV QUESTIONS SENT TO THE FIRM ..................................................... 28
`APPENDIX V FIRM’S RESPONSE TO OCP QUESTIONS ......................................... 29
`APPENDIX VI :RESPONSE FROM FIRM ON September 18, 2008 FOR FDA
`QUESTIONS AND FDA REPLY.................................................................................... 34
`APPENDIX VII: INFORMATION PRESENTED AT INTERNAL FDA MEETING .. 41
`APPENDIX VIII-FIRM’S FINAL RESPONSE AND DATA SUMMARY................... 47
`
`OVERALL COMMENT:
`
`The metabolite data presented by the firm is acceptable to OCP and has been
`included in the label text.
`
`OCP LABEL
`Metabolism and Elimination
`
`In a mass balance study about 50% of the circulating species in plasma have been
`
`identified and they are asenapine-N-glucuronide (34%), N-desmethylasenapine (5%),
`
`N-desmethylasenapine N-carbamoyl glucuronide (7%) and unchanged asenapine (4%).
`
`There are other non-identified metabolites which account for 32% of the plasma
`
`circulating species.
`
`
`
`
`SIGNATURES
`
`Andre Jackson_______________________________________
`
`RD/FT Initialed by Raymond Baweja, Ph.D.
`
`
`
`2
`
`

`

`Team Leader_______________________
`
`Cc-NDA 22117, HFD-860(Jackson, Baweja,Mehta), Central Documents
`Room(Biopharm-CDR)
`C:\Data\REVIEWS\NDA\ASENAPINE_NDA22117ORGANON\FINALREV_METAB.
`doc
`
`
`
`3
`
`

`

`APPENDIX 1 July 25th 2008 LETTER FROM FIRM
`
`
`
`4
`
`
`
`

`

`NDA 22-11?
`Org 5222 (asenapine) Sublingual Tablets
`
`July 2008
`
`-
`
`In addition to very acceptable total recovery (>90%) of the radioactive
`dose within 7 days, a significant percentage (~71%) of the excreted
`radioactivity has been characterized by LC—IVIS. There were no major
`human-specific biotransformation pathways identified in plasma, urine and
`feces (Figure 2).
`
`in human plasma
`In summary, a majority (>70%) of the drug-related material
`following sublingual administration of asenapine is associated with conjugated
`metabolites. Other than desmethyl-asenapine,
`for which adequate exposure
`multiples have been established with validated LC-MSIMS methods, any other
`unconjugated metabolite likely represents less than 6.0% of the total plasma
`profile. The known metabolites of asenapine have much reduced affinity for CNS
`receptors considered to be involved in mediating the pharmacological effects of
`asenapine or have low brain penetration and are thus unlikely to contribute
`towards the pharmacodynamic properties of asenapine. In addition, all metabolic
`pathways as observed in human have been observed in preclinical species.
`In
`conclusion, given the well-characterized metabolic pathways and their respective
`identified metabolites there is strong evidence that we have adequately exposed
`non-clinical safety species to all relevant human metabolites.
`
`
`
`
`
`5
`
`

`

`NDA22-117
`Org 5222 (asenapine) Sublingual Tablets
`
`July 2008
`
`Figure 1. Radiochromatographic profile of a pooled (1.5 —12hr} plasma
`sample following administration of 14C-asenapine to 4 healthy male
`subjects.
`
`
`Pooled plasma 1.5-12 hours
`
`1200 —
`
`PC12/13
`
`A 1000 _
`
`E 9
`
`800 _
`
`.
`3‘
`E 500 -
`
`l
`
`
`
`PC10i11
`
`Fem
`
`P019
`Pc1e
`
`page
`
`PC?
`PC4-6
`
`P01
`
`
`
`
`
`H313 A’
`l
`
`
`3
`2 400 —
`
`E 200
`
`0
`
`_
`
`
`1o
`15
`20
`25
`30
`35
`40
`
`
`
`
`
`Time (minutes)
`
`
`
`
`
`
`
`
`6
`
`

`

`NDA 22-117
`Org 5222 (asenaplne) Sublingual Tablets
`
`July 2008
`
`Figure 2. Major biotransformation pathways of asenapine in human and
`preclinical species
`
`
`
`asenaplne
`maisarra-JF)
`u, mung. a.
`rabhit F'Fl
`drglP Ll‘Fl
`humaan'F]
`
`/ \M
`
`
` nyzmxyiamn hllweu
`\\"a
`
`‘97
`H,C.'
`asenaD'rveJI-unde
`mouseiRUf
`ral .r=,u F_.
`'abbll [PF-
`
`
`ina‘F' LPF}umanl )
`
`bvcon uqatlnn
`
`\i-dumemyugupne
`mousetF'M F.
`rai [F.U.F.B|
`r: in» LP u F;
`doch'J,F.
`human fPJI
`
`\
`
`
`
`Hzc’ 7"
`owi-CODH
`HO’
`_
`l
`HO
`w «CH
`asename-N'glummnde
`muse
`mus.
`
`rathli [P.u:no:
`hummF‘ u.
`
`
`
`
`cH,
`1c-,- i-d hyd'uzyiganapinz
`rabbit
`menu
`*1”:ch
`
`/ \
`g
`\
`
`/ \
`¢
`(yoffi
`mm 10»
`
`HO’ Wu \ H
`2‘3
`xo’\\/H-‘-¥ «(E/“Cl
`N
`M
`\
`K ’3
`)
`(:40
`CH:
`H
`ccnjugabeil
`1l-luydmxy-Ndesmslhvassnapne
`M-fu'rflyLN-r‘esn-Elhyla 5! marine
`1 mydmyasanapina
`ux=su Maul Qluouronida)
`
`Hark
`
`N
`
`N desmethbiasenaane—
`‘lrcarba'noylgluaurmlds
`rat (PMEi
`dug
`ratbii
`hLma'itF‘U-
`
`\‘
`‘
`\/
`
`.
`
`cm:
`“my“,uwmmrmw
`N-dpsmelhvlassnapne
`mm“
`“a,“
`dog
`numancF-
`
`Wimrwwmyl,
`Ndzsmemylasenanirz
`muse
`71th
`dog
`nu-nanm
`
` mauseiF‘I
`
`on
`”5:" EU)
`hummPU}
`
`Hc,
`
`"
`
`N
`
`I C
`
`.
`cn'ljugahed1fl,l ‘l-dhyd nary
`H5
`asenaaine
`{‘(=:u|1.lb:. glucumnicu. mamfij
`nnuse
`duo
`ruman
`about [u-
`
`.‘
`o
`\,
`'/‘\’ fl
`H / CI
`H
`m H JK
`N|
`H
`W Il-dlhydrnxy-‘l-dlimnhflaisnapmi
`“5”“
`ranmt
`duo
`humanIF-
`
`3'
`
`canlugmmMydmxy.
`N'“*£“*”‘"““"ap‘"e
`(Kifilumrol‘lflg
`muse
`rahblt
`““5
`rumanm
`
` cunJugal'zd m H-dihyqu-
`
`Nicesme'thyiasenaplne
`cX=§ulfale. glucumnlde. mehylj-
`mafia
`rabbit
`org
`rumanlm
`
`P: plasma, U = urine, F = feces‘ B = bile
`
`
`
`7
`
`
`
`
`
`

`

`NDA22-117
`Org 5222 (asenapine) Subllngual Tablets
`
`July 2006
`
`Table 1: Summary of Radioactive peaks found in human plasma and urine
`after sublingual administration of asenapine (Org 5222 plus [14C]-Org 5222}
`to male volunteers.
`
`
`Identity
`
`Peak
`Number
`(human)
`
`Retention
`time
`
`% radioactivity Presence
`of run,
`verified in at
`corrected for
`least one
`noise
`preclinical
`species (excreta
`
`or plasma)
`
`PC1
`Unknown
`15.2
`3.6
`+
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PC2
`PCB
`
`Methyl- and glucuronlde of
`the 10,11 dihydroxy of N-
`desmethylasenapine. with
`the posltlons of the
`conjugates 10,11 and
`reverse
`
`16.6-17.6
`
`5.1
`
`18.5-22.0
`
`13.3
`
`+
`
`+
`
`PC4-P06 Methyl and sulfate of the
`10.11 dihydroxy of the N-
`desmethylasenapine. with
`the posltlons of the
`conjugates 10,11 and
`reverse; 11-0-glucuronide
`of asenapine and of N-
`desmethylasenapine;
`other conjugates
`
`(sulfateslglucuronides)
`
`PC?
`Unknown
`22.?
`2.7
`+
`
`PCB-9
`Sulfates and glucuronldes
`23.3-23.6
`5.9
`+
`PC10
`11-O-sulfate asenaplne;
`25.1
`7.4
`+
`PC11
`other sulfates and
`25.6
`
`glucuronldes of the N-
`
`oxide asenapine
`
`P012
`N+ glucuronlde
`26.8
`33.6
`+
`
`PC13
`27.2
`
`PC16
`N-desmethylasenapine N-
`28.7
`6.9
`+
`
`carbamoyl glucuronlde
`N-desmethylasenapine
`
`P019
`
`29.7
`
`5.1
`
`+
`
`+
`4.3
`30.2
`Asenapine
`PC20
`
`
`
`
`
`
`
`
`
`
`
`8
`
`
`
`

`

`APPENDIX II- FDA RESPONSE TO FIRM JULY 25TH
`LETTER
`TITLE RESPONSE TO FIRM JULY 25, 2008 LETTER
`CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS REVIEW
`________________________________________________________________
`NDA
`
`
`
`
`22117
`Sponsor :
`
`
`
`
`Organon USA
`Drug:
`
`
`
`
`Asenapine (ORG5222)
`Formulation:
`
`
`
`Sublingual Tablets
`Proposed Indication:
`
`
`Schizophrenia
` Acute Mania Associated w/Bipolar
` Disorder
`Correspondence Date:
`
`
`July 25, 2008
`Reviewer:
`
`
`
` Andre Jackson
`________________________________________________________________
`Review of Additional Plasma Metabolic Profile Data Submitted by the Firm
`
`The firm has submitted a document with additional information related to the
`metabolite issues. This review will only focus on metabolite identification and
`quantitation in plasma. Feces and urine will not be discussed.
`
`Firm Comment 1.
`
`Nearly 50% of the drug-related material in human plasma has been
`unequivocally identified and/or quantified by LC-MS/MS. The remaining
`radioactivity (~50%) corresponds to at least 15 different very polar peaks, none of
`which represent more than 6% of the plasma radiocarbon profile.
`
`FDA Reply:
`
`OCP agrees that, “nearly 50% of the drug-related material in human plasma has
`been unequivocally identified and that The remaining radioactivity (~50%)
`corresponds to at least 15 different very polar peaks, none of which represent
`more than 6% of the plasma radiocarbon profile.” However OCP does not agree
`with the use of the word quantified. The profiles were a mixture of plasma
`samples from (1.5-12hrs) and the firm has stated in (see Module 5.3.3.1, CTR
`25532,Table 4, page 31), “At a later stage the remainder of the plasma samples 1.5-
`12h of all four subjects was pooled. The same was done for the 1h plasma sample. Both
`pooled samples were analyzed on HPLC system 2. The pooling of these samples was
`not performed quantitatively and therefore these chromatograms were only evaluated in
`a qualitative way.” What is being reported is a mixture of times so one can not be sure
`of how much is parent and how much are metabolites. The statement “6% of the
`plasma radiocarbon profile” is non-informative related to the parent drug.
`
` Firm Comment 2.
`
`
`
`
`9
`
`

`

`Metabolites eluting in this region have been characterized by LC-MS and
`correspond mostly to Phase II (sulfate, glucuronide and methylated) products.
`Overall more than 70% of circulating radioactivity is associated with conjugated
`metabolites.
`
`FDA Reply:
`
`OCP agrees with this statement but it is not quantitative relative to the parent
`and the major metabolites and the time course is unknown.
`
`Firm Comment 3.
`
` •
`
` The most representative profile which illustrates total exposure to plasma
`metabolites and unchanged drug comes from a pooled (1.5-12 hr) plasma
`sample. Referring to the radiochromatogram (Figure 1), we can see that
`asenapine (PC20) is extensively metabolized. While >9% the circulating
`radioactivity can be accounted for by asenapine and the desmethyl
`metabolite (PC19), an additional 40.5% is associated with asenapine N+-
`glucuronide (PC12/13; 33.6%) and N-desmethylasenapine N-carbamoyl
`glucuronide (PC16; 6.9%). The N+-glucuronide, N-desmethylasenapine
`and asenapine-11-hydroxysulfate metabolites have also been quantified
`by validated bioanalytical assays in clinical PK trial 25546 (included in the
`dossier). These results reproduced the ratios found in the human
`14C-AME study. With the exception of the N-carbamoyl glucuronide, these
`metabolites have also been tested pharmacologically and showed
`decreased activity and/or no entrance into the brain.
`• The remaining radioactivity which elutes between 13 and 25 min (Figure
`1) corresponds to at least 15 different peaks, none of which represent
`more than 6% of the plasma radioprofile.
`
`
`
`
`10
`
`

`

`
`
`
`FDA Reply:
`
`OCP agrees but there is no quantitation of the major species other than the
`desmethyl metabolite (PC19) and the N-oxide. What is required is a quantitative
`time course for the identified species ( i.e., asenapine, desmethyl metabolite
`(PC19), asenapine N+-glucuronide, N-oxide and N-desmethylasenapine N-
`carbamoyl glucuronide as a function of time. This will allow for a quatitative
`assessment of the contribution of each species which is not possible from
`pooled plasma samples.
`
`Overall FDA Comment:
`
`The accepted good scientific standard for NME metabolites adhered to by the
`FDA is that a quantitative assessement of metabolites as a function of time is
`done so that any relevant exposure response can be determined. For
`Asenepine only a total quantitation for pooled samples (2-12 hr) but not a true
`metabolic profile for parent and major metabolites has not been done over time.
`
`SIGNATURES
`
`Andre Jackson_______________________________________
`
`
`
`11
`
`

`

`
`RD/FT Initialed by Raymond Baweja, Ph.D.
`Team Leader_______________________
`
`Cc-NDA 22117, HFD-860(Jackson, Baweja,Mehta), Central Documents
`Room(Biopharm-CDR)
`C:\Data\REVIEWS\NDA\ASENAPINE_NDA22117ORGANON\METABOLITEREV.d
`oc
`
`
`
`12
`
`

`

`APPENDIX III-IN DEPTH RE-ANALYSIS OF ALL
`SUBMITTED DATA
`
`
`TITLE: INITIAL REVIEW ASENAPINE DEFINING STUDY
`INFORMATION PRESENTED IN THE NDA
`DOSING
`
`
`
`TABLE 1. Dosing schedule1: SOURCE(Module 4.2.2.5, Report INT00003211)),PAGE
`2/94
`Day-1 D1
`
`D10
`10
`mg+[14C]
`
`D2
`
`D3
`
`D4
`
`D5
`
`D6
`
`D7
`
`D8
`
`D9
`
`0.3 mg 1 mg
`
`3 mg
`
`Plac.
`
`
`FDA COMMENT :DOSING SCHEDULE-INFORMATION ONLY
`
`5 mg
`
`10 mg
`
`10 mg
`
`10 mg
`
`10 mg
`
`10 mg
`
`
`
`13
`
`

`

`HPLC SYSTEMS
`HPLC system 1-SOURCE(Module 4.2.2.5, Report INT00003211)),PAGE 23/94
`
`Radioactivity in the HPLC effluent was determined on-line (urine and feces (partly))
`using a flow-through detector or off-line by the collection of fractions (plasma and feces
`(partly)) followed by Solid Scintillation Counting (SSC). Radioactive peaks in the HPLC
`metabolite profiles were assigned by visual inspection.
`
`Gradient : 5% B isocratic during 5 minutes
`5 to 35% B in 30 minutes (linear)
`35 to 90% B in 20 minutes (linear)
`90 to 100% B in 1 minutes (linear)
`100% B isocratic during 9 minutes
`100% to 5% B in 5 minutes (linear)
`
`HPLC system 2(Module 4.2.2.5, Report INT00003211)),PAGE 24/94
`
`Gradient : 10% B isocratic during 3 minutes
`10 to 40% B in 17 minutes (linear)
`40 to 90% B in 30 minutes (linear)
`90 to 95% B in 1 minute (linear)
`95% B isocratic during 3 minutes or 8 minutes
`95 to 10% B in 1 minute (linear)
`
`Radioactive peaks in the HPLC profiles were numbered assigned on the basis of
`retention time.
`
`FDA COMMENT : The systems will have different elution patterns. Based upon
`information from the firm only HPLC System 1 gives a quantitative analysis. On the
`other hand, “HPLC system 2 was considered to achieve the best separation and ended
`up being used for all (plasma, urine and fecal) human samples so that direct comparison
`of radiochromatographic profiles among these matrices can be made. In addition to the
`qualitative information (correspondence with standard retention times and mass spectral
`data) embedded in these analyses, quantitative determinations from the radioactivity
`contained within individual peaks and total radioactivity eluted during the run were also
`made.”
`
`
`
`14
`
`

`

`
`
`METABOLITE PROFILING
`METABOLITE PROFILING-SOURCE(Module 4.2.2.5, Report
`INT00003211)),PAGE 2/94
`
`
`Blood samples for the determination of the concentration of radioactivity in plasma
`(coded B)were taken from day 10 onwards at 0 (=pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12,
`24, 36, 48, 60,72 h post dosing and blood samples for the metabolite profiling (coded C)
`were taken at day 1 at 0 h (=pre-dose (just before the first dose of asenapine)) and on
`day 10 at 1, 1.5, 2, 4, 8, 12 and 24 h post dosing.
`
`They were extracted after which the metabolite profiles of [14C]-asenapine in plasma,
`urine and feces samples were determined by HPLC analysis using HPLC system 1 and
`2 followed by Liquid Scintillation Counting (LSC) or Solid Scintillation counting (SSC).
`Afterwards metabolites of asenapine were isolated from plasma, urine and feces.
`Identification of the isolated metabolites was performed by MS and/or NMR
`
`(Module 4.2.2.5, Report INT00003211)),PAGE 31/94
`At first plasma samples (1.5-12h) were measured per time point per subject on HPLC
`system 1. These data are used to give quantitative data. At a later stage the remainder
`of the plasma samples 1.5-12h of all four subjects was pooled. The same was done for
`the 1h plasma sample. Both pooled samples were analyzed on HPLC system 2. The
`pooling of these samples was not performed quantitatively and therefore these
`chromatograms were only evaluated in a qualitative way.
`
`FDA COMMENT : These statements by the firm are confusing since they are using
`HLPC system 2 to profile but clearly state “ The same was done for the 1h plasma
`sample. Both pooled samples were analyzed on HPLC system 2. The pooling of these
`samples was not performed quantitatively and therefore these chromatograms were only
`evaluated in a qualitative way.” OCP has interpreted this to mean that for HPLC system
`2 only radioactivity was quantified.
`
`
`
`
`15
`
`

`

`RADIOACTIVE RECOVERY
`Table 2. Radioactive recovery.
`SOURCE Module 4.2.2.5, Report INT00003211)) PAGE 3/94
`
`
`
`
`FDA COMMENT : The table clearly shows the percentage of radioactivity (ie mass
`balance for asenapine recovered ~90%).
`
`
`
`
`16
`
`

`

`RAW DATA USED FOR PLASMA PROFILES IN FIGURE 1
`Table 3. Concentrations of individual peaks in HPLC chromatograms (HPLC system 1) of
`plasma samples per time point of male human volunteers after sublingual
`administration of asenapine (Org 5222 plus [14C]-Org 5222) SOURCE Module 4.2.2.5,
`Report INT00003211)) PAGE 47/94
`
`
`
`FDA COMMENT: The data in Table 3 is incomplete however the firm has used
`this data to construct Figure 1 below which is misleading since it is composed of
`the observed values from Table 3 which clearly show that none of the subjects
`has a complete profile not even for peak # 15 asenapine. They have only
`connected the dots with the limited data collected. OCP could not locate data
`that would support the graph past 12 hrs as shown in Table 3. The firm needs to
`give the location of that data.
`
`
`
`17
`
`

`

`REPRESENTATIVE MEAN PLASMA GRAPH HPLC SYSTEM 1
`
`INDIVIDUAL ASSAY HPLC SYSTEM 1 –SOURCE (Module 4.2.2.5, Report
`INT00003211)),PAGE 3/94
`
`
`
`SUBJ 1
`SUBJ 2
`SUBJ 3
`SUBJ 4
`
`
`
`
`Figure 1. Profile obtained from HPLC system #1.
`
`
`
`
`INDIVIDUAL SUBJECT DATA TABLE 3
`
`0
`
`2
`
`4
`
`6
`TIME hrs
`
`8
`
`10
`
`12
`
`01234
`
`Ng equiv/ml Plasma
`
`
`FDA COMMENT-See comments on Table 3.
`
`
`
`
`18
`
`

`

`
`
`TOTAL RADIOACTIVITY IN PLASMA
`
`Figure 2. Profile obtained for total radioactivity. SOURCE Module 4.2.2.5, Report
`INT00003211)) PAGE 46/94
`
`
`Table 4
`
`
`
`
`Concentration of radioactivity in plasma samples after sublingual administration
`of asenapine (Org 5222 plus [14C]-Org 5222) to male human volunteers
`
`Plasma
`Radioactivity (ng equivalents.mL-1)
`
`
`
`time
`(h)
`Subject
`1
`Subject
`2
`Subject
`3
`Subject
`11.7
`4
`13.3
`Mean
`5.5
`SDa
`a SD = standard deviation
`
`FDA COMMENT : Figure 2 is consistent with the data in Table 4, however this is only
`total radioactivity data as a function of time. There is no information on individual
`metabolites.
`
`0.5
`
`1.0
`
`1.5
`
`2.0
`
`3.0
`
`4.0
`
`6.0
`
`8.0
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`6.68
`19.6
`
`13.7
`53.6
`
`23.6
`64.7
`
`39.8
`64.0
`
`65.7
`61.7
`
`69.7
`64.7
`
`60.5
`43.7
`
`46.9
`30.9
`
`36.1
`27.0
`
`22.9
`16.2
`
`16.2
`13.0
`
`10.9
`10.2
`
`9.01
`7.28
`
`7.00
`8.35
`
`15.1
`
`45.2
`
`75.3
`
`77.4
`
`84.4
`
`91.4
`
`77.1
`
`62.1
`
`40.9
`
`24.6
`
`18.1
`
`16.2
`
`13.5
`
`11.3
`
`55.6
`42.0
`19.4
`
`69.2
`58.2
`23.5
`
`68.8
`62.5
`16.1
`
`77.1
`72.2
`10.4
`
`87.8
`78.4
`13.2
`
`55.4
`59.2
`13.9
`
`45.0
`46.2
`12.8
`
`30.5
`33.6
`6.1
`
`19.9
`20.9
`3.7
`
`13.4
`15.2
`2.4
`
`10.7
`12.0
`2.8
`
`7.03
`9.2
`3.0
`
`6.69
`8.3
`2.1
`
`
`
`19
`
`

`

`
`
`
`
`REPRESENTATIVE CHROMATOGRAM
`
`
`Figure 3. Radiochromatographic profile of a pooled (1.5 – 12hr) plasma
`sample following administration of 14C-asenapine to 4 healthy male
`subjects. HPLC SYSTEM 2. SOURCE POOLED ASSAY 1.5-12HR SUBMITTED
`JULY 25 2008
`
`
`
`
`
`
`
`
`FDA COMMENT : Chromatogram is acceptable to OCP.
`
`
`
`
`
`
`
`
`
`
`
`
`20
`
`

`

`PEAKS IDENTIFIED BASED UPON CHROMATOGRAM IN
` FIGURE 3.
`TABLE 5. Metabolites identified in plasma and urine.SUBMITTED BY THE FIRM DATE:
`JULY 25 2008 HPLC SYSTEM 2
`
`
`Peak
`Number
`(human)
`
`Identity
`
` Retention
`time
`
`% radioactivity
`of run,
`corrected for
`noise
`
`Presence
`verified in at
`least one
`preclinical
`species
`(excreta or
`plasma)
`+
`+
`
`Unknown
`PC1
`PC2 PC3 Methyl- and glucuronide of
`the 10,11 dihydroxy of N-
`desmethylasenapine, with
`the positions of the
`conjugates 10,11 and
`reverse
`
`15.2
`16.6-17.6
`
`3.6
`5.1
`
`18.5-22.0
`
`13.3
`
`+
`
`PC4-PC6 Methyl and sulfate of the
`10,11 dihydroxy of the N-
`desmethylasenapine, with
`the positions of the
`conjugates 10,11 and
`reverse; 11-O-glucuronide
`of asenapine and of N-
`desmethylasenapine;
`other conjugates
`(sulfates/glucuronides)
`
`
`PC7
`PC8-9
`PC10 *
`PC11 *
`
`
`PC12 *
`PC13 *
`PC16 *
`
`PC19 *
`
`22.7
`Unknown
`Sulfates and glucuronides 23.3-23.6
`11-O-sulfate asenapine;
`25.1
`other sulfates and
`25.6
`
`glucuronides of the N-
`oxide asenapine
`26.8
`N+ glucuronide
`
`27.2
`N-desmethylasenapine N- 28.7
`
`carbamoyl glucuronide
`N-desmethylasenapine
`29.7
`
`Asenapine
`
`PC20 *
`
`Sum of plasma metabolites in brackets=57.3%
`
`30.2
`
`
`
`21
`
`2.7
`5.9
`[7.4]
`
`
`
`[33.6]
`
`[6.9]
`
`[5.1]
`
`[4.3]
`
`+
`+
`+
`
`+
`
`+
`
`+
`
`+
`
`

`

`PEAKS IDENTIFIED BASED UPON CHROMATOGRAM IN
` FIGURE 3.
`
`% of total
`radioactivity
`5.1
`
`
`13.3
`
`
`
`5.9
`7.4
`
`33.6
`
`6.9
`5.1
`4.3
`81.6
`
`
`TABLE 6. Metabolites identified in plasma and urine. TABLE SUBMITTED BY THE
`FIRM IN SEPTEMBER 2008 TO MY REQUEST FOR INFORMATION HPLC SYSTEM 2
`
`Name
`Peak
`
`
`Methyl- and glucuronide of the 10,11 dihydroxy of N-desmethylasenapine,
`PC2/3
`with the positions of the conjugates 10,11 and reverse; mono conjugates
`
`of 10,11-OH-N-desmethylasenapine
`
`Methyl and sulfate of the 10,11 dihydroxy of the N-desmethylasenapine,
`PC4-6
`with the positions of the conjugates 10,11 and reverse; 11-O-glucuronide
`
`of asenapine and of N-desmethylasenapine; other conjugates
`
`(sulfates/glucuronides)
`
`Sulfates and glucuronides
`PC8-9
`PC10
`11-O-sulfate asenapine; other sulfates and glucuronides of the N-oxide
`asenapine
`PC11
`PC12
`N+ glucuronide
`PC13
`
`PC16
`N-desmethylasenapine N-carbamoyl glucuronide
`PC19
`N-desmethylasenapine
`PC20
`Asenapine
`
`SUM
`Note: “BOLDED” metabolites have been unequivocally identified.
`Please note that the total for those bolded the PC10 and PC 11 have been excluded so the
`total now becomes 57.3%-7.4%=49.9%. Nonbolded metabolites have not been found in
`plasma.
`
`FDA COMMENT ON Tables 5-7 and Figure 3. OCP agrees with Figure 3 for the
`chromatogram. However, the firm changes the metabolites which they believe they can
`identify between the July and September submissions. In July P10 and P11 were
`included whereas in September they were excluded. This is very inconsistent and not
`explained by the firm. Based upon the firms statements related to the performance of
`HPLC System2, the results are at best semi-quantitative. Summed identifiable material
`in plasma for AUC 1.5-12h is either 57.3% or 49.9%. Most notable is that neither the
`57.3% or 49.9% values is defining a profile only a 1.5 to 12 AUC window for a drug with
`a half-life of 27 hrs.
`
`
`
`22
`
`

`

`PRESENCE OF QUANTIFIED CHROMATOGRAM PEAKS AT
`SAMPLED TIMES
`SOURCE Module 4.2.2.5, Report INT00003211)) PAGE 48/94
`
`Table 7. Peaks found in HPLC chromatograms (HPLC system 2) of the pooled plasma
`samples of male human volunteers after sublingual administration of asenapine
`(Org 5222 plus [14C]-Org 5222)
`
`
`FDA COMMENT-Table 7 shows the level of confusion that exists related to the time
`profile for asenapine and its metabolites. For example, metabolite PC10/11 is present at
`1hr but is not found in the 1.5-12 hr pooled sample. On the other hand PC19 is not
`present at 1 hr but is present in the pooled sample from 1-5-12 hr. These results are very
`confusing.
`
`
`
`
`
`23
`
`

`

`
`
`
`Figure 4.
`
`1.5 -12 hrs pooled sampling time for “quantitation” of asenapine and metabolites using
`HPLC System 2. Source module 5.3.3.1.1 page 56
`
`
`
`THE FIRM NEEDS TO REPEAT THE METABOLISM STUDIES WITH A
`QUANTITATIVE ASSAY AND COLLECT COMPLETE PROFILES.
`
`C:\Data\REVIEWS\NDA\ASENAPINE_NDA22117ORGANON\METABOLITERE
`V2.doc
`
`
`
`24
`
`

`

`
`
`
`Results from study 25511 :
`Dose-0.15 mg/BID
`Cmax :0.127 ng/ml on Day 1
`
`APPENDIX:
`
`
`
`
`
`25
`
`

`

`
`Study 25532
`Dose-0.27 mg
`Cmax :78 ng/ml on Day 1
`
`[14C]-labeled asenapine was provided to PBR as an alcohol containing solution. The
`responsible pharmacist was to drop a volume corresponding to 50 µCi and 0.27 mg
`asenapine on a 10 mg tablet according to instructions provided by Organon. A test
`batch was prepared and analyzed prior to the final preparations.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`26
`
`

`

`ASSAY
`
`6.4 METABOLITE PROFILES
`6.4.1 General
`Since the resolution of the obtained metabolite signals of urine and feces samples
`obtained on HPLC system 1 (Section 3.3.6) was sub-optimal, the integration of the
`metabolite profiles appeared to be non-conclusive. The resolution on HPLC system 2
`(Section 3.3.6) was much better and therefore the metabolite profiles of urine and feces,
`obtained with HPLC system 2 were used to give quantitative data. Indication of major or
`minor metabolites is done by visual inspection.
`
`At first plasma samples (1.5-12h) were measured per time point per subject on HPLC
`system 1. These data are used to give quantitative data. At a later stage the remainder
`of the plasma samples 1.5-12h of all four subjects was pooled. The same was done for
`the 1h plasma sample. Both pooled samples were analyzed on HPLC system 2. The
`pooling of these samples was not performed quantitatively and therefore these
`chromatograms were only evaluated in a qualitative way.
`
`
`
`
`27
`
`

`

`APPENDIX IV QUESTIONS SENT TO THE FIRM
`TITLE- REQUEST OF INFORMATION FROM THE FIRM
`I have been reviewing your submission related to the identity of plasma metabolites and I need
`some clarification.
`In the study Clinical Trial Report for study 25532 you produced the following graph which appears
`in your synopsis page 5 of 612:
`
`
`
`It is not clear to me how this graph was constructed. What I would like to have from you would be
`an example calculation based upon any standard curves and dpm dated employed for all of the
`species represented. Please start from the raw cpm/dpm data. You can reference any data
`submitted in the NDA giving its location so that it can be located.
`
`Please give all formulas. Make sure you list whether it is based upon HPLC system 1 or 2.
`Please base your example only upon Cmax which would be the same procedures for the area
`calculation.
`C:\Data\REVIEWS\NDA\ASENAPINE_NDA22117ORGANON\Questiontofirm_9-3-
`08.doc
`
`
`
`
`28
`
`

`

`APPENDIX V FIRM’S RESPONSE TO OCP QUESTIONS
`
`
`
`29
`
`

`

`
`AP PEND IX V
`
`Asenapine Sublingual Tablets
`NDA 22—117
`
`Metabolite Response Document
`Page 'I
`September 2008
`
`Comment 1:
`
`I have been reviewing your submission related to the identity of plasma
`metabolites and I need some clarification.
`
`In the study Clinical Trial Report for study 25532 you produced the following
`graph which appears in your synopsis page 5 of 612:
`
`
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`
`It is not clear to me how this graph was constructed. What I would like to have
`from you would be an example calculation based upon any standard curves
`and dpm dated employed for all of the species represented. Please start from
`the raw cpml’dpm data. You can reference any data submitted in the NDA giving
`its location so that it can be located.
`
`Please give all formulas. Make sure you list whether it is based upon HPLC
`system 1 or 2. Please base your example only upon Cmax which would be the
`same procedures for the area calculation.
`
`BCILJHE‘ 'c Etc-.13 [lit-Ft
`
`
`EIIIIEIilI'm- LIJ-Zi¥e|:--2'I"I'-E- 21:15
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`
`
`
`
`
`30
`30
`
`

`

`Asenapine Sublingual Tablets
`Metabolite Response Document
`
`Page 2
`
`NDA 22-11?
`September 2003
`
`Response 1:
`
`First, we would like to point out that in the human ADl‘le study different methods
`have been used for:
`'I) determination of “E3 in plasma, 2) determination of
`asenapine, N-desmethylasenapine and asenapine N-oxide concentrations in
`plasma and 3} metabolite profiling. Samples for the different assessments were
`taken at the same time points in each subject (see Module 5.3.3.1, CTR 25532,
`Table 4, page 32}.
`
`(green
`N—desmethylasenapine
`symbolslcurve},
`{black
`asenapine
`The
`plasma
`(blue
`symbolsfcurve)
`and N-oxide
`asenapine
`symbolsfcurve}
`concentration data as presented
`in
`this graph
`have been quantified
`bioanalytically, is. by means of LC—MS, as described in the bioanalytical report
`for this study [Module 5.3.3.1, CTR 25532, Appendix Bil—1, page 125), and are
`not based on radioactivity data. These LC-l‘vlS methods are different methods
`than those used for metabolite profiling (as described in the metabolite profiling
`report (Module 4.2.2.5, Report INTGUUD32'I 1)], but are the exact same methods
`as have been applied for the determination of plasma concentrations of these
`compounds throughout the clinical program for asenapine (Module 2.?1, Section
`2.?.'l.1.2.2, page 13).
`
`In other words, the concentration data for the different analytes presented in the
`above graph are a direct reflection of the bioanalysis results, and no calculations
`have been performed on them {other than averaging by time point). Further,
`it
`should be noted that these ‘cold’, bioanalytical concentration data reflect the
`complete multiple dose (10 mg BID} asenapine regimen, whereas
`the
`radioactivity data are associated with the final, single ”ES—labeled asenapine dose
`of 15 mg.
`
`The 1413 total radioactivity data in the above graph {red symbolsfcurve) are based
`on liquid scintillation counts of the plasma samples. A calculation has been made
`on these count data to translate them into 'asenapine equivalents'. This has been
`done using the specific activity of the administered radiolabeled asenapine,
`which was 5.08295 ngfdpm. All
`individual count data (corrected for baseline
`radiation} were transformed into asenapine equivalent plasma concentrations as
`follows:
`
`C’asenapine equiv. [fig "r leL] =
`
`counts [dpm]—-5 eciflc activit
`aliquot analyzed [mL]
`p
`
`n
`H G
`
`Id at
`p ]
`
`As an example, the calculation of the 13mg,C of total radioactivity in asenapine
`equivalents [concentration at 4 h) for subject 'I is presented below. For reference,
`see also the table below from the bioanalytical report on 1“IS (Modul