Reviewer: Kathleen Young, Ph.D.
`
`NDA No.22—304
`
`Summary of pharmacokinefic. parameters in monkeys after repeated i.v. administration of
`5 mg/kg once daily (Mean :l: SD on day 14)
`
`5.8 d: 0.2
`
`1035i230
`
`862i111
`
`0.22 :l: 0.09
`
`1.0 :l: 0.2
`
`71.3 i 14.8
`
`3.3.4 Distribution
`
`Tapentadol is rapidly and widely distributed in tissues. The volumes of distribution Vd
`values are 5-11 L/kg across species and in humans. Protein binding was low'in all
`species in an radiolabeled drug-binding assay in vitro (Study PK582), primarily to serum
`albumin. Protein binding across the concentration range of 42.9 to 687 ng/ml was
`l6.3%—16.7% in mouse, l7.2%—18.5% in rat, 9.2%-12.0% in rabbit, 15.6%-18.9% in dog,
`and l9.3%—20.7% in human plasma. The results of that study also showed tapentadol
`binding to sepia melanin, at 26.7%—482%.
`
`The results of a tissue distribution study using whole-body autoradiography in albino
`Sprague Dawley and pigmented Lister Hooded rats (Study PK432) given a single IV C”-
`tapentadcl (10 mg/kg) showed distribution to the following tissues at 15 minutes after
`treatment, in decreasing order of tissue concentration: kidney medulla and cortex,
`preputial gland, intra-orbital lachrymal gland, exorbital lachrymal gland, salivary glands,
`liver, Harderian gland, pituitary, pancreas, spleen, adrenal, lung, bone marrow,
`mandibular lymph nodes, bulbo-urethral gland, thyroid, brain, spinal cord, and blood. Fat
`and muscle concentrations were very low. The patterns of distribution were similar in the
`albino and pigmented species, except for melanin binding in ureal tract and skin tissues in
`the Hooded rats. Tapentadol levels in most of the tissues were below the level of
`quantification at 24 hours afier IV injection in that study, and melanin-bound
`radioactivity decreased ever the next 1—3 days. CNS levels decreased from peaks of 9.40
`and 6.97 mcg equiv/g in brain and spinal cord at 0.25 h, to 4 meg equiv/g in the CNS at 1
`h, 1 mcg equiv/g at 2 h, 0.13 mcg equiv at 4 h, and were below the level of detection at 8
`hours. There is a low potential for penetration of tapentadol and its metabolites into red
`blood cells. Comparison of radioactivity in whole blood and in serum revealed lower
`concentrations in whole blood than in the serum in dogs (-36%) "and humans (-90% to -
`95%) administered CM-tapentadol.
`
`Tapentadol crosses the placenta, indicated by detection of the parent drug and the main
`glucuronide metabolite in albino rat fetuses in a dose range-finding study conducted prior
`to evaluation of Pre- and Post-Natal Development (Study TP2772, andeK432).
`
`58
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`However, the concentrations measured in the fetuses were extremely low in that study,
`probably due in part to sampling times at 24 and 72 hours after the last maternal dose. A
`microdialysis study in Sprague Dawley rats administered non-labeled tapentadol at 6 oral
`gavage doses of 80 mg/kg each, 6 hours apart (Study PK664) demonstrated blood-brain
`penetration by the parent drug. Exposure to the parent drug in extracellular fluid in the
`corpus striatum was approximately half that in the peritoneal cavity samples collected to
`represent plasma concentration. Blood-brain penetration of the main glucuronide
`metabolite was lower, producing exposure of approximately 6% that in plasma following
`the first dose and 18% the plasma exposure after the last of the 6 doses. The results of
`that study are presented below (table provided from the original NDA submission):
`
`After “1113115178be
`Tunes I organs
`C6550.) base
`Paxflomnlat-its
`Emaceflahxfluidin thebnin
`Plasma I
`KW-
`Paitonealmixy
`Emahthr fluid in the binin
`Flam
`
`Mutilati-Enamehzsjtnun t smug
`- 311Mn W 9.4mm
`«mm
`L“
`SLR
`1;!
`.52
`15
`1—5!
`
`51‘
`
`an
`
`mm
`L
`
`Q
`
`annexe]
`9720:1234
`604': 117
`
`2499:1608
`1437;11002
`Imam
`
`47771£2147
`2634:1607
`4373154872
`
`6737867524
`[2485:7771
`61 SDHUSS
`
`044':le
`
`0.6]:‘013
`
`006g 0.03
`
`018* 0.05
`
`mafia:
`441:6”
`4785.16!
`
`1046:690
`491:453
`1602:1484
`
`1.03:0.55
`0.99:0.29
`121:0.25
`
`”7&0.”
`2.13:1.49
`1:15:05!)
`
`2D?‘=0.58
`2.13t039
`2.06é0.40
`
`234:023
`3.151451
`2.11é0.4.2
`
`.
`
`NEH!“
`708.H920
`1293932696
`
`31169257143
`1464 ¢848
`163845715
`
`057i0.13
`15.3 it0.57
`1.49g033
`
`1.66:1.11
`245i 0.79
`2.03 i 1.05
`
`14320.20
`4.07 i 0.52
`3.14 a:0.40
`
`233*115
`4.07 #085
`3.18 t 114
`
`3.3.5 Metabolism
`
`Tapentadol is rapidly and extensively metabolized after oral administration. The results
`of in vitro evaluation in hepatic microsomes demonstrated that the main route of
`metabolism is by Phase II glucuronidation, in all species tested including humans (Study
`(PKN233/A). The results of this study, showing the intrinsic clearance of tapentadol by
`O-glucuronidation' and oxidation across species are presented below (table provided from
`the original NDA submission):
`
`Species
`Sex
`
`lnlrinsir tlearantes
`(ml’mln’kfl'
`
`Set
`Peteent-ual lottes‘
`
`ns.
`99.2
`
`.113.
`0.52
`
`Hamster
`as1
`
`Minipi;
`F
`
`.\i
`
`Dag
`M
`
`0.1555
`
`0.0300
`
`0.0929
`
`0.0525
`
`ns.
`73.9
`
`ns.
`9.6
`
`_
`
`Rabbit
`nis.
`
`00350
`
`M.
`26.7
`
`Rat
`F
`
`M
`
`00244
`
`0.0331
`
`M
`28.5
`
`}‘
`14.3
`
`Mouse
`as.
`
`0.0117
`
`n5.
`20.4
`
`Cynonwlgns
`M
`Y
`
`Guinea pig
`F
`
`M
`
`Human
`n;
`
`0.0128
`
`0.0108
`
`0.0108
`
`0.0038
`
`0.0019
`
`n5.
`51.5
`
`u.
`78.3
`
`n;
`06
`
`U01:
`Penentngn niglntuwnide'
`
`19:1.
`0.17
`
`1:14.
`0.15
`
`150
`1.19
`
`1&2 E _31315
`1.98
`1.6-1
`0.3!
`
`Additional Information :Httulnn hepatic glnmwnidalian ms catalysed by seven] isofonns but mainly by UGTIAG. UGTIA9 and L‘GTZBI
`The fact that seven] isofornv. appear to be involved in the ghteuronidation oftapentadol means that there is little fish that its metabolic clearance “i110! diminished in humans
`who at: homozygous for a deficient allele ofone or other ofthe iml'enns.
`a) no! speeified
`b) me Kn[ml.r'm'in1ng] mictuwmnl ptotein determined for glncntcnidah'ons by microsomes
`c) Percenmal losses of the initial amount! of tapentadol in oxidation assays performed with equivalent amounts an450 (300 melIDli). an initial concentration of 10 1.1.“
`tapentadol and incubating for 30 min.
`'
`d) decomhinanl human ghtctunnyl transfemse isofom:
`2) formed by variety. recombinant human ghxuronyl transfemse isofmms (UGTS) afler 90 minutes
`
`59
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Tapentadol is more extensively glucuronidated in the animal species than in humans,
`based on the results of the study in hepatic microsomes. Oral bioavailability assessments
`in the nonclinic‘al and clinical pharmacokinetic studies showed higher tapentadol
`bioavailability in human (32%) than in rat, dog and monkey (9%, 3% and <1%,
`respectively). The main metabolic enzymes involved in human tapentadol metabolism
`by glucuronidation‘ are the UDP-glucuronosyltransferases UGTlA9, UGT2B7, and
`UGT1A6 (StudyPK528). The percentages of glucuronide formed in human microsomes
`.by the isoforms of UGT are shown in the following table (provided from the original
`NDA submission):
`
`Table. 4—2:
`
`
`
`
`
`
`
`
`Percentages ofglucuronide formed by various recombinant human glucumnyl
`transferase isoforms (UGTs) after 90 minutes
`
`
`
`UGT 1A1 UGT 1A3 UGT 1A4 UGT 1A6 UGT 1A9 UGT 2B7 UGT 2B15
`
`
`
`
`
`
`
`
`
`Additionally, tapentadol undergoes oxidation to a greater extent in the animal species
`tested than in humans. In vivo liver metabolism assay showed percent loss of tapentadol
`parent drug by hepatic microsomal P450 oxidation of 99.2% in minipig, 78.9% in
`hamster, 78.3% in guinea pig, 51.5% in Cynomolgus monkey, 28.5% in rat, 26.7% in
`rabbit, 29.4% in mouse, 14.3% in rat, 9.6% in dog, and 0.6% in human microsomes
`(Study PKN233/A). The Phase I metabolites were CYP2C9, CYP2C19, and CYP2C8
`catalyzed N—demethyl tapentadol (M2), and hydroxy—tapentadol (M1) by CYP2D6,
`CYP2B6, and CYP2C19 catalysis, in microsomes from all species tested including
`human. Of all species tested, the metabolic profiles in rat and dog most resembled that in
`human.
`-
`
`The proposed tapentadol metabolic pathways in mice, rats, rabbits, dogs, and humans are
`diagramed in the following figure (providedfrom the original NDA submission):
`
`APPEARS THiS WAY
`0N ORIGINAL
`
`60
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304.
`
`M: 0-
`'da
`Mi O—qumxonide
`+
`W
`.m
`II
`M:N glntoside
`I!
`ml
`1.2:...
`:1.
`W
`cu
`g ‘_
`I
`I M)
`w / m
`J
`on
`on
`
`’1‘“
`
`n
`
`9
`3“
`P
`3'"
`M‘
`a?“
`1
`M5 O—glucuzonide
`
`m
`I
`
`7.?"
`MS
`M”
`i
`MS O—glummnide
`
`m-m
`hum
`
`no
`3’
`I
`,
`Tspsnmdolaetncosme
`
`m
`
`on
`
`-
`
`’de
`hill 04h:
`_ mom
`w...
`T
`:1
`32.. a“
`34
`
`M“
`
`eta-a3,
`
`_
`mum
`on
`cm:
`a“
`"V’
`n
`E
`T’
`m
`cm
`ll"
`~— W
`E
`‘ T/
`W) on
`on ow
`Ml \ _
`we
`r’
`firm
`5
`on
`an
`M7
`
`I
`
`anon:
`V g,
`f
`
`M8
`
`mmmomm
`
`mm
`.
`o —> MS O-glucumeide j;
`if
`PM
`. N’
`l
`——>
`5
`l
`Inpenmdol \K‘
`on
`I/
`'
`.51
`fl}:
`me?“
`0
`
`W
`m,
`
`‘
`
`M9
`
`°~ ‘3
`5:5”
`‘3
`u”
`l
`
`u‘
`nun
`"‘ i
`do;
`m"-
`s
`Tflnmdnl 05mm.
`
`o
`
`o
`
`H
`n/
`l
`
`a“
`m
`OH
`m
`"I“
`"M;-
`:2...
`.
`Tarantula] 0.2;me
`
`Ana
`l
`54.9L “ammo QW'
`m...
`m
`an
`“'4'”
`
`The results of in vivo studies on tapentadol metabolism also showed qualitatively similar
`metabolic profiles in mice, rats, dogs and humans. HPLC analysis of urine samples
`collected over 48 hours in the animals and for 24 hours in humans after oral tapentadol
`administration (50 mg/kg in mice,150 mg/kg in rats, 20 mg/kg in dogs and 100 mg in
`human volunteers, given by gavage in the animal species) revealed the following results
`(table provided from the original NDA submission):
`
`Sgeci 5
`Mite
`
`RM male
`
`Rat female
`
`Dogs
`
`Humans
`
`Sam le
`Usine
`Feces
`
`Sampling Time
`or Period (h)
`0—48
`0—48
`
`% ofDose
`in Sample
`82
`6.6
`
`% of Compound in Sample (mean values)
`Parent
`conjngn (es
`44
`-
`
`Anion.
`20
`-
`
`Mkon.
`2.8
`-
`
`Parent
`4.9
`-
`
`Urine
`Feces
`
`Urine
`Feces
`Urine
`Feces
`
`Urine
`Feces
`
`0—43
`0-48
`
`0—18
`0—48
`0-24
`048
`
`0-24
`0-24
`
`69
`26
`
`94
`5
`8!;
`18
`
`99
`1
`
`0‘8
`-
`
`3.2
`—
`—~:l
`-
`
`4.5
`-
`
`25
`-
`
`39
`-
`58
`-
`
`'.’0b
`-
`
`18
`-
`
`39
`-
`ll
`-
`
`2
`-
`
`14
`—
`
`S
`-
`3.3
`-
`
`13
`-
`
`Study
`No.
`PK581K/A
`PK531K/A
`
`PK581K/A
`PKSSIKJA
`
`PKSXIKIA
`‘ PKSSIK/A
`PK581KIA
`PKSSIKIA
`
`I’KSSIK/A
`PUNK/A
`
`a) quantitative investigations with HPLC and radiodetection ofurine samples are from 3 males
`b) total dose
`c) MBqlgmnp
`d) Mquanimal
`e) 3118qu body weight
`1) capsule of 100 mg CG5503 labeled will: 1.85 3-qu radiocarbon
`g) sampling Time is 0—48 11
`ll) lapentadol O-glucuronide: 55% of dose; tapemadol 0—sulfate: 15% of dose
`
`61
`
`n
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Total radioactivity in urine collected for 48 hours after a single oral dose was similar
`across species, when comparing data from several excretion studies (87%, 82%, 91%,
`and 90% in mice, rats, dogs and humans, respectively). In another comparative study on
`tapentadol metabolic profiles (PK581/A), the following pharmacokinetic parameters
`including excretion data were seen (table provided from the original NDA submission):
`
`Species
`
`Terminal
`half-life.
`
`Total
`clearance
`(in)
`
`Volume of
`distribution
`.(i.v.)
`
`Absolute
`bio-
`availability
`
`tun
`
`F
`
`Excretion of
`
`CGSSOB
`base
`Total
`unchanged
`radioactivity
`[% of oral dose]
`
`32 (fasted)
`
`Mouse
`(M)
`
`0.29 (i.v.)
`
`70 (M)
`94 (F)
`31
`
`26 (M)
`4.9 (F)
`18
`
`0.8 (M)
`3.2 (F)
`4:: 1.0
`
`99
`
`11.11. = not determined
`
`D data after repeated iv. or oral dosing
`
`Minor metabolites (<5% total dose) are described in the figure on metabolic pathways of
`tapentadol, above. Nearly all (99.6% in dog and 96.6% in humans) of the eleven
`metabolites identified in plasma were found to be conjugated, with the remaining
`radioactivity associated with the parent drug.
`
`APPEARS THIS WAY
`0N ORIGiNAL
`
`62
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`.
`
`NDA No. 22—304
`
`The potential for chiral interconversion of tapentadol’s two chiral centers (pictured below
`in a figure from the Sponsor) to form the diastereomer (-)-(1S,2R)-3-(3-dimethylamino-
`1-ethyl-2-methyl-propyl)-phenol (GRT4045Y) and it’s enantiomer (+)-(1R, ZS)-3-(3-
`dimethylamino-l-ethy1-2-methyl-propyl)-phenol was evaluated in plasma samples from
`mice, rats, rabbits, dogs and humans (Study PK58lK/A).
`
`OH
`
`HCl
`
`H C
`.3
`
`,
`(265503
`
`CH
`
`1.
`[34/
`-_-
`CH3 CH3
`
`3
`
`(-H1R.2R)-
`
`The percentages of tapentadol base found converted to the GRT4045Y+ enantiomer in
`the species tested are presented in the following table (provided from the original NDA
`submission):
`
`-
`
`Species
`
`
`GRT4045Y+enantiomer—“-
`
`
`——_
`“——
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Conversion ofthe chiral centers is unlikely to have taken place, because batch. analyses
`showed up to "Wf the diastereomer in the formulations administered.
`
`W4}
`
`3.3.6 Excretion
`
`Tapentadol is primarily excreted in urine as the glucuronide and sulfate metabolites, with
`minor excretion in feces. In several mass balance studies animals and humans were
`administered radiolabeled oral tapentadol, and urine and feces were collected for 48
`hours post-dose (Studies PK586/A, PK583, PK480/A, and HP5503/05). The methods
`and results are shown in the following table (provided from the original NDA
`submission):
`
`63
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`’
`
`Min
`Species
`Gender (M15)! Numhu‘ofanimals 25“
`Fueling condition:
`rested
`thlkllli‘ormhfion:
`Aqua bids! Solution
`mum ofAdmin‘ntntion:
`Garage
`Dos-(mam)
`so
`Andy“:
`IRA”
`Assay:
`xsc'
`
`.
`
`Rats
`5M
`Fasted
`Aqua bids: 1 Solution
`Gang:
`150
`TRA‘
`Lsc‘
`
`Rats
`5?
`Pastel
`Aqua bids! i Solution
`6312:;
`is!)
`IRA“
`LSC‘
`
`Dogs
`3M
`Paved
`Aqua bidst ! Solution
`6:;ng
`20
`"my
`LSC'
`
`Humans
`4M
`F
`Capsule
`01:1
`100 mg‘
`TIL-1‘
`LSC‘
`
`magmm'Fec—sm MMM me m Beam
`32
`7
`89
`69
`16
`95
`94
`5
`99
`81
`18
`99
`99
`!
`100
`12:1
`3:!
`PKSEGIA
`1711583
`
`46:1
`P843025.
`
`76:1
`EPSSDSNM
`
`EmeIInmme
`Tim: 0 — 48 h:
`Mean excretion balance of
`mimi’zxu
`Study umber
`Locafinn in CH!
`5) 5 ms ofS each
`b) total dose
`c) total radiuclixiry;patent of51152012243 values)
`a) liquid schnllan‘nn counting
`enheammmlofmdimrfifityfmndinfinsingwmubeingaddedmmm.
`
`l9:l
`K585
`
`Excretion in milk was demonstrated in the pre— and post-natal development study in rats
`(Study TP2772) by plasma levels measured in the pups of lactating dams.
`
`3.3.7 Pharmacokinetic drug interactions
`
`The potential for drug-drug interactions with tapentadol was investigated in vitro and in
`vivo, with additional information provided by the results of the primary and secondary
`pharmacology, pharmacokinetics and toxicology studies. In vitro evaluations of
`tapentadol metabolism revealed that conjugation by uridine diphosphate (UDP)
`glucuronyl transferase is primarily responsible for clearance of the parent drug from
`plasma. The high capacity of the UGT system reduces the likelihood of saturation in the
`presence of other drugs also cleared by glucuronidation. Drugs that inhibit the UGT
`enzymes, particularly subtypes involved in tapentadol glucuronidation (UGT1A9 and
`UGT2B7) such as‘probenecid, chloramphenicol and naproxen, and thus could potentially
`increase exposure to parent drug, the were examined in a study in liver microsomes
`(Study PK681). The results of that study showed only slight inhibition of tapentadol
`glucuronidation, with highest inhibition of 27% identified by naproxen and 45% by
`probenecid. The results of the assessment of glucuronidation by UGT in pooled human
`liver microsomes are presented in the following table (provided from the original NDA
`submission):
`'
`'
`
`APPEARS THlS WAY
`0N ORIGll‘iAL
`
`64
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`111mm;
`minimum
`Nomiptyline
`Imipnuniue
`Dedpmnine
`Codeine
`Morphine
`Naproxen
`Diclophenac
`Ketamlac
`Feuopmfen
`Ketoptofen
`Ibuprofen
`Niflnmic acid
`Meclofienamate
`Salicylic acid
`Valpmie. acid
`
`Paracetamol
`[ndumethacin
`Lidocaine
`Verapiamil
`Chlommphenicol
`Ketoconamle
`Miconuzole
`Zidovudine
`Pmbenecid
`
`931$?
`1
`0.5
`1.5
`0.5
`0.3
`0.4
`217
`4
`1.2
`‘03
`1.2
`48
`0.5
`16
`2000
`500
`
`,
`
`2000
`10
`20
`2
`so
`10
`10
`5
`700
`
`:11
`c
`G
`G
`G
`G
`G
`V
`V
`V
`v
`v
`V
`v
`v
`v
`o
`
`P
`v
`G
`c
`(3
`G
`n
`R
`R
`
`Te§1 cones [11m
`1, no, so, 100
`1, 10. so. 100
`1.10, so, 100
`1, 10, so, 100
`t. 10, so, 100
`1, IO, so, 100
`0.1, 0.5, 1. 2 mM
`50. 100. 250, 400
`I, 10, 50. 100
`1, 10, 50, 1110
`1, 10, so, too
`500
`1, 10. so, 100
`1, 50, 100, 250
`0.1, 0.5, 1, 2 mM
`1 mM
`
`'
`
`0.1, 0.5, 1, 2 mM
`10, so, 200. 500
`10. so. 200, 500
`1. 10, so. 100
`10, so, 200, 500
`1, 10, so, 100
`10, 50,200. son
`1, 10, so, 100
`025, 0.75. 1, 2 mM
`
`imp/1:1"
`38
`o
`40
`10
`s
`0
`65
`90
`2
`30
`12
`' me.
`10
`90
`'10
`30
`
`Activation
`40
`16
`37
`33
`53
`70
`11
`67
`
`Ki {11311
`so
`u.
`30
`u.
`11.2.
`me.
`600
`56
`me.
`20
`me.
`980
`me.
`29
`m,
`4400
`
`me.
`so
`11:.
`so
`so
`25
`so
`840
`340
`
`'
`
`in, (941‘
`3
`o
`7
`o
`o
`0
`27
`6
`0
`1
`o
`3
`o
`35
`12
`10
`
`‘
`
`‘E
`9
`o
`8
`15
`21
`2;
`1
`45
`
`a) maximal clinical concentrations (Cum) were derived from either Goodman 11nd Gilman (refG), Prucon (zefP), Rajaonarison et :11. (refR), or Vietri at 111. (rer)
`b) apparent maximal extent of inhibition (15“) is estimated. as is the ICSOIK;
`t) approximated maxim-ii extent ofinlnbition in the clinic (135,.) is the best estimate from the available data. but does not tube any 1mm protein binding into account.
`
`Additional in vitro investigations demonstrated potentiation of the UGT metabolic rate by
`acetaminophen by 20%, suggesting a potential decrease in tapentadol exposure with co-
`administration. The potential for metabolic interactions of tapentadol with drugs that
`inhibit or potentiate UGT metabolism was also addressed in the clinical studies (see
`Studies PAI-l 01 1 and PAI-1013) in the dose ranges relevant to those indicated for
`treatment. Increased tapentadol exposure of approximately 17% by naproxen and 57%
`by probenecid were found in those studies, but there were no effects on tapentadol
`exposure by co-treatment with acetaminophen.
`In vitro studies conducted to investigate
`tapentadol inhibition and induction of the cytochrome P450 metabolic enzymes found
`inhibition of the isoenzyme, CYP2D6 only (Ki = 181 mcM for competitive inhibition and
`1410 mcM for noncompetitive inhibition), at concentrations that were 180 to 1400 times
`the Cmax for tapentadol in clinical treatment (studies PK680 and PK679). There was no
`effect of co-incubation of tapentadol with dextromethorphan in the presence of the
`NADPH regenerating system in vitro. No induction of the cytochrome P450 isoenzymes
`CYP1A2, CYP2C9, and CYP3A4 were found in human hepatocytes (Study PK679),
`except for a 1.5X induction at a concentration of 200 times the highest plasma
`concentration (Cmax) in clinical treatment in the indicated dose range.
`_
`
`Potential metabolic drug interactions with tapentadol was examined in vivo in rats and
`dogs using assessments of metabolic enzyme activities in microsomes from liver samples
`taken at necropsy to measure several of the markers for induction of CYP isoenzymes
`and Phase II glucuronidation (see studies TP2397, TP2415, TP2441, TP1968/A, and
`TP2593 [PK268], below under Toxicology). Thyroxine UDP glucuronosyltransferase
`
`65
`
`

`

`51(4)
`
`Reviewer: Kathleen Young, PhD.
`
`NDA No. 22-304
`
`may be involved in thyroid tumor formation by non-genotoxic CYP enzyme induction,
`via stimulation ofthyroxine glucuronidation and biliary excretion, resulting in decreased
`serum thyroxine and triiodothyronine, with increased serum thyroid stimulating hormone,
`which during chronic stimulation results in thyroid follicular cell hyperplasia that may
`progress to follicular cell tumors. Cytochrome P450 and thyroxine UDP
`glucuronosyltransferase activities were measured in Wistar rats (Study TP2593 fj
`report 5335]) administered oral gavage tapentadol doses of 75-300 mg/kg/day fof4'
`weeks. There were significant dose-related increases in hepatic microsomal total CYP
`content (+143% in the males at 300 mg/kg/day and 11%-117% in the females at 150-300
`mg/kg/day), predominantly on CYPZB-dependent activity‘by 7-pentoxyresoruf1n O-
`depentylase (429%—3219% in the males given 75-300 mg/kg/day, and 542%-3159% in
`the females given 150-300 mg/kg/day), compared to'control values. Additionally, there
`were dose-related, statistically significant increases in hepatic microsomal 7-
`ethosyresorufin O-deethylase activity (l76%—362% all doses in the males, 188% in the
`females at 300 mg/kg/day), 7-pentoxyresorufin O-depentylase activity (429%-3219% at
`all doses in the males, 54.2%—3159% at 150-3 00 mg/kg/day in the females), and 4-
`.
`nitrophenol hydroxylase activity (143%-179% at 150-300 mg/kg/day in the males, 131%
`at 300 mg/kg/day in the females). There were no tapentadol treatment-related changes in
`microsomal activities of testosterone 6B-hydroxylase, lauric acid ll—hydroxylase, lauric
`acid lZ-hydroxylase, and thyroxine UDP—glucuronosyltransferase. These results suggest
`tapentadol-related induction of CYP2B isoforms in male and female rats, and similarity
`to other CYPZB inducers including phenobarbital, and therefore potential interactions
`with drugs that are metabolized by CYP2B—dependent 70-pentoxyresorufin O-
`depentylase, but not CYPlA, CYPZE, CYPSA and CYP4A forms. The effects on the
`other CYP isoenzymes were relatively minor in comparison. The results of liver
`metabolic enzyme activity in the 4-week oral gavage study in rats are presented in the
`following tables (provided from the original NDA submission, means i SD, *p<0.05,
`**p<0.01, ***p<0.001):
`
`
`
`
`
`
`
`
`
`*
`
`,
`Treatment
`
`
`
`Cytochrome P450 cunteul
`(nmol/mg protein)
`
`'
`
`
`
`— C
`
`0.46:0.015
`0.54t0.061"
`ontrol
`(100)
`(my
`.
`(vehicle onh )
`
`0.51; 0.068
`0.51 :': 0.013
`(113)
`(111)
`
`
`
`ccssos
`.- .'
`
`
`
`CG5503
`150 mg’kg/dny
`
`
`
`
`.
`CG5503
`300 mgikgirlny
`
`
`g
`
`0.60 _ 0 063
`0.51 t 0.057‘
`(1] l)
`(l l l)
`
`0.54 i 0.030”
`0. 7 i 0.104‘“
`(117)
`(143)
`
`
`
`66
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Treatment
`
`,
`
`Contra!
`(vehicle only)
`
`I
`
`711:2 1"
`
`171-26
`
`‘
`7-Elhoxyresorufin O-deethyhse ntlifity
`
`(pmollminlmg protein)
`
`_ Malena
`
`
`
`_
`
`17 i 4.7
`(100)
`
`76 i 15.3"3
`(352)
`
`32 i 41‘”
`(188)
`
`
`C95503
`300 mg/kg/dny
`
`Trentmen!’
`
`
`
`
`.
`
`7-Pentoxyresornfiu 0-depentyhse activity
`(pmol/minlmg protein)
`——
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`44 t 9.9"
`
`(210)
`
`
`
`
`
`
`
`
`CGS‘03
`
`300 mg/Lgldm
`
`
`
`Contra!
`(vehicle onlv)
`
`CGSSD3
`75 mglkgldm
`
`CGS§03
`150 mg/kglflay
`
`21 i 5.0”
`(100)‘
`
`90 i 39.4":
`(429)
`
`242 i 62.1‘"
`(1152)
`
`6.5 A: 2.00
`(100)
`
`8.9 :i: 3.65
`(137)
`
`35.2 :h 9.85‘“
`(542)
`~
`
`
`
`
`
`
`
`
`
`676 $191,8“*
`(3219)
`
`,
`4-Nitmphenol llydmxyhse activity
`Treatment
`(ulnollmiulmg protein)
`
`
`
`205.3 d: 71.79m
`(3159)
`
`— Male-m:
`
`Control
`(vehicle 0111))
`
`ccssos
`75 ms/kydny
`
`0.56 i 0.036“
`(100)‘
`
`0.67 i 0.059
`(120)
`
`0.55 :1: 0.080
`(100)
`
`0.57 i 0.063
`(104)
`
`
`
`(255503
`150 Iflglkg/dny
`
`'
`
`0.30 : 0.181’
`(143)
`
`
`
`
`
`
`
`
`
`0.72:0.071”
`1.00:0.159m
`035503
`
`(131)
`(179)
`300 meme-"day
`
`0.56 :E 0068
`(102) _
`
`67
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Trentmem'
`
`
`— Mama's
`
`Testostemne (SB-hydroxylase activity
`(nmoI/minlmg profein)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`CG5503
`1.14i 0.168
`0.10: 0.015
`
`
`(114)
`(125)
`
`>
`Lmnnc and ll—lmlroxylase arm-fly
`
`‘
`(nmol/min/mg protein)
`——_
`
`
`0.35am:
`0.34:0.084’
`
`(way (100)
`
`
`
`CG5503
`0.43 i 0.096
`
`
`300 mglkg/day
`(127)
`Laurie arid ll—hytlmxyhse activity
`
`
`
`_
`Treatmeni’
`(mnol/minlmg protein)
`——
`
`
`Conh‘ol
`0.44 i— 0.150"
`0.50 2 0.032
`
`
`
`(vehicle only)
`
`
`
`CG5503
`0.42 i 0.122
`0.46 i 0.105
`
`
`
`
`75 mgfkg/day
`
`
`
`
`CGSSU3
`0.36 a 0.029
`0.56 i 0.161
`
`
`
`
`(82)
`150 mg/kg/dny
`(112)
`
`
`0.53 i 0.068
`(106)
`
`Control
`(vehicle only)
`
`CGSSO3
`75 Ing/kg/da."
`
`CG5503
`150 mg/kg/dny
`
`
`
`Control
`(vehicle 010,)
`
`CG5503
`75 lug/kgldny
`
`ccssoa
`150 mu a day
`
`1.00: 0.315“
`(100)(
`
`1.06 i 0.252
`(106)
`
`1.14 i- 0.377
`(114)
`
`0.08:0.034
`(100)
`
`0.07 i 0.039
`(88)
`
`0.08 i 0.011
`(100)
`
`0.36 i 0.066
`(106)
`
`0.37 :': 0.064
`(109)
`
`0.31 i 0.066
`(89)
`
`0.34 i 0.077
`(97)
`
`0.37 :1: 0.048
`(105)
`
`.
`
`
`
`
`CG5503
`300 mg/kgldny
`
`0.37 i 0.111
`(84)
`
`
`
`68
`
`
`
`
`
`
`
`
`
`
`
`

`

`Reviewer: Kathleen Young, PhD.
`
`NDA No. 22-304
`
`
`
`
`Thymxine UDPglucumnosyltmnsferase activity
`Tre-ntment’
`(pmollmin/mg protein)
`I
`_—
`
`
`
`
`
`
`
`
`
`
`CG5503
`6.8 11.12’
`151) mglkg/day
`(126)
`
`
` _—_
`
`CGSSOB
`5.0 =' 0.55
`5.4 + 0 28
`300 mglkg/day
`(95)
`(100)
`
`
`
`
`*p<0.05, **p<p.o1, ***p<0.001
`
`Control
`(vehicle only)
`
`‘
`
`_
`
`.
`
`cessos
`75 mglkg/day
`
`,
`
`5.2 .—'. 1.20“
`(100)‘
`
`6.0 1 1.59
`(115)
`
`4.3 1 1.35
`
`5.4 :1 1.15
`(100)
`
`‘
`
`5.6 1 0.71
`(104)
`
`'
`
`P450 content and enzyme induction of N—dealkylation (aminopyrine N—demethylase), O-
`dealkylation (7-ethoxycoumarin O-deethylase) and UDP glucuronyltransferase (2-
`aminophenol-g1ucuronyltransferase) activity, was assessed in the 26-week oral gavage
`toxicity study in the male and female Wistar rats given Control vehicle and tapentadol at
`75 mg/kg/day (Study TP2397 [Study‘BKIgI253D to explore the potential for interactive
`effects with other drugs that induce or inhibit these enzyme systems. The measurements
`were made in microsomes isolated from the rat livers at necropsy. The results, presented
`in the following tables from the Sponsor, showed statistically significant increases in 2-
`aminophenol glucuronyltransferase activity in the tapentadol-treated female rats, but not
`in the male rats. There were no tapentadol-related effects on the other metabolic enzyme
`systems tested.
`
`
`
`
`
`
`
`
`[mg/kg]
`Control
`
`
`
`lpmol/mg]
`1283 1 91
`1368 1178
`
`lpkat/mgl
`24.7 1 3.1
`30.1 1 6.7
`
`lpkaf/mg]
`40.9 11.9
`48.1 1 12.9
`
`lpkat/mg]
`16.2 1 3.7
`15.2 1 3.9
`
`
`
`not significant not significant not significant not significant
`ANOVA p—values
`Induction is expressed as 75 mgIkg vs. control ratio
`
`Table 3.2: Mean (1 SD.) P450 contents and enzyme activities in female rats
`
`
`
`
`
`
`[mg/kg]
`Control
`
`[pmol/mg]
`1024 1 200
`
`[pkat/mgl
`11.4 1 1.7
`
`[pkailmgl
`22.1 1 2.9
`
`lpkat/mg]
`8.3 1 2.2
`
`
`
`
`
`ANOVA -values not significant not significant not sinificant
`Induction is expressed as 75 mglkg vs. control ratio
`
`0.021
`
`
`
`
`
`
`
`
`
`
`
`
`
`69
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`.
`
`NDA No. 22-304
`
`Liver metabolic enzyme activities by cytochrome P450, N-dealkylation (aminopyrine N-
`demethylase), O-dealkylation (O-ethoxycoumarin O-deethylase) and
`glucuronyltransferase (2-aminophenol-glucuronyltransferase) activity were also tested in
`microsomes isolated at necropsy from the livers in male and female Beagle (degs
`administered tapentadol by oral gavage at doses of 10-120 (highest dose reduced to 80
`mg/kg/day on Day 22 of treatment) mg/kg/day for 13 weeks (Study TP2593) and 10-80
`mg/kg/day by gavage for 52 weeks (Study TP2441 [PKN309]), and by intravenous
`injection at doses of 1-7.5 mg/kg/day for 4 weeks (Study TPl968). The results of the 13-
`week oral gavage study found significant induction of aminopyrine N-demethylase
`activity in the male dogs, and glucuronyltransferase activity in the male and female dogs,
`but no effects on P450 content and O—deethylase activity by tapentadol treatment under
`the conditions of this study. Therefore, there may be a potential for interactions with
`tapentadol by drugs metabolized by N-demethylase. Also, as demonstrated in the in vitro
`and clinical studies discussed above, tapentadol may potentially decrease plasma
`concentrations of drugs that undergo glucuronidation. Conversely, drugs that inhibit or
`activate these metabolic enzymes may increase or decrease, respectively, the plasma
`concentrations oftapentadol with co-administration. The findings are presented below
`(table provided from the original NDA submission):
`
`The mean (3: SD.) P450 contents and enzyme activities in male dogs were:
`
`.
`
`Dose
`
`[mgfkg]
`Control
`120
`
`P450
`
`
`
`[pmollmg]
`564 i 39
`475 1- 87
`
`ECOD
`
`[pkat/mg]
`32.4 1 5.4
`25.0 i 3.3
`
`
`
`
`
`not significant not significant
`ANOVA p-values
`Induction is expressed as 120 mglkg vs. control ratio
`
`induction [%]
`
`84
`
`77
`
`.
`
`AND
`
`'
`
`[pkat/mg]
`31.1 i 1.5
`40.2 i 1.4
`
`129
`
`0.001
`
`
`
`
`
`GT
`
`[pkat/mg]
`17.5 i 0.4
`13.2 i 1.7
`
`75
`
`0.012
`
`
`
`
`
`
`The mean P450 contents and enzyme activities in female dogs were:
`
`Dose
`
`[mg/kg]
`Control
`120
`
`
`
`
`
`P450
`
`ECOD
`
`AND
`
`GT
`
`lpmollmg]
`443 i 47
`566 i 81
`
`lpkat/mg]
`32.8 i 11.0
`51.8 i 14.1
`
`lpkaflmgl
`33.7 i 6.9
`55.7 1 10.9
`
`[pkatlmgl
`15.7 i 1.6
`14.9 i 3.3
`
`
`
`
`
`
`165
`0.042
`
`. 95
`not significant
`
`128
`158
`induction [%]
`not significant not significant
`ANOVA p-values
`Induction is expressed as 120 mglkg vs. control ratio
`
`Oral gavage treatment for 52 weeks in the dogs produced the following results (table
`provided from the original NDA submission):
`
`70
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Table 3.1: Mean (:1: SD.) P450 contents and enzyme activities in male dogs
`
`
`
`
`
`[pkat/mg]
`67.9 i 14.5
`38.4 i 6.0
`
`[mg/kg]
`Control
`30
`
`80
`
`[pmoifmg]
`[pkatfmg]
`[pkatlmg]
`
`1008 :2 224
`44.5 a: 7.8'
`55.9 i 11.1
`994 i 130
`.
`.
`’
`. i .
`
`
`
`55.63.: 16.6
`65.4i11-1 95.9i21.3
`1133i: 188
`
`
`Induction [9’0] 30 mg/kg
`Induction {9/0} 30 mg/kg
`
`ANOVA
`30 mgfkg
`p-values
`80 mg/kg
`
`
`
`Induction is expressed as 30 mg/kgfday or 80 mgrkg/day vs. control ratio
`
`Table 3. 2. Mean (:1: S.D. ) P450 contents and enzyme activities in female dogs
`
`[ngcg]
`
`P450
`
`[pmolfmg]
`
`ECOD
`
`[pkat/mg]
`
`[pkafz’mg]
`
`GT
`
`[pkat’mg]
`
`56.7...-‘- 15.5
`83.1 i 25-9
`
`55.3 :1: 3.6
`86.9 :i: 22.2
`
`894i 8’]
`Control
`‘
`1108 :l: 115
`
`
`
`113 :|:13_4
`913 i 242
`107 i- 30
`40.2 :1: 5-0
`
`
`
`
`124
`
`
`
`Induction [%] 30 mg/kg
`102
`Induction [9/0] 80 mg/kg
`
`
`
`ANOVA
`30 mgfkg
`not sign
`
`
`
`p-values
`80 mg/kg
`not Sign.
`
`Induction is expressed as 30 mg/kgfda}' or 80 mgfkgiday vs. control ratio
`
`64.1 i: 3.0
`46-9 :1: 4.6
`
`There. were dose-related increases in ethoxycoumarin O-deethylase activity t0145%-
`200% control values and N-demethylase activity to 138%—193% control values at 30—80
`mg/kg/day in the male and female dogs at the 52-week assessment. There were no
`changes in cytochrome P450 content, and glucuronyltransferase activity was decreased in
`the male and female dogs to 5 8%-82% of control values (decrease of 20%—40%) in the
`dose range studied. '
`
`Enzyme activity analysis in microsomes fi'om the livers in dogs given IV tapentadol
`injections at doses of l-‘7.5 mg/kg/day for 4 weeks (Study TP1968) showed no effects on
`cytochrome P450 content and N-dealkylation (aminopyrine N-demethylase), O-
`'dealkylation (O—ethoxycoumarin O-deethylase), and aminophenol glucuronyltransferase
`activities. There was greater activity by tapentadol on glucuronyltransferase activity by
`the oral route in the previous study.
`
`71
`
`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`3.3.10 Clinical Exposure for Comparison in the Toxicology Studies .
`
`Clinical tapentadol pharmacokinetic assessments showed rapid and complete absorption
`by the oral route, with a mean bioavailability of approximately 32%. There were dose—
`proportional increases in systemic exposure (Cmax and AUC). Slight accumulation was
`found in the comparison of single and repeated dose exposure; AUC values for the parent ,
`drug were 1.6 times the single dose values, and for the main glucuronide metabolite of
`approximately 1.8 times the single dose values when given q.i.d. Steady state is observed
`after 3 or 4 doses. Peak plasma levels were found at approximately 1% hours after
`administration. The clinical half-life is 4 hours and clearance is approximately 1530
`ml/min following oral treatment. In the clinical evaluation of food effect, exposure
`(AUC values) increased 25% and Cmax increased 16% in the fed state, compared to
`fasting exposure values. Tapentadol is approximately 20% protein bound in human
`plasma, and the high volume of distribution (540 L) indicates wide tissue distribution.
`Oral tapentadol is subject to rapid and extensive metabolism of nearly all ofthe parent
`drug dose. The main pathway of tapentadol metabolism in humans is by glucuronidation
`by uridine diphosphate glucuronyl transferase to tapentadol—O-glucuronide.
`Additionally, there is minor metabolism of approximately 3% by CYP2C9 and CYP
`2C19, and approximately 2% by CYP2D6 to metabolites that subsequently undergo
`conjugation. Excretion is predominantly by the urinary route, with approximately 3% of
`the dose excreted as parent drug, 55% excreted as the glucuronide metabolite, and
`approximately 15% excreted as a sulfate conjugated metabolite. The minor role of the
`cytochrome P450 metabolism of tapentadol in humans suggests a low risk of
`pharmacokinetic interactions with drugs that undergo Phase I oxidative metabolism,
`which is supported by the results of the clinical and in vitro drug interaction studies.
`
`The cross study means for clinical PK parameters after single dose immediate-release
`tapentadol are provided in the following table provided by the Sponsor, for comparison
`with the nonclinical pharmacokinetics results:
`
`Table 32: A cross Study Mean Pharmacokinetic Parameters After a Single Dose ofTapentadol [EL
`Dose —Ncimal.ized to 100 mg Tapentadol
`(Dataset for cross—stud: comparison)
`11
`Mean :i: SD
`Parameter
`631
`1.25 (0.50-6.27)
`tn“, h
`39
`631
`90.1 i 36.2
`Cmax, ngImL
`34
`576
`417 i 143
`AUG”, ng-h/mi.
`16
`576
`4.3 .L— 03
`tm, 11
`38
`78
`99.0 i 373
`Gig, mLI'mjn
`Data expressed as mean i SD, except for tn“ where median (range) is provided; 11: number ofobservations.
`* more than 90% ofobservations was below or equal to 3 hrs.
`Cross-reference: post-hoe analysis, data on file-
`
`.
`
`.
`
`%CV
`
`.
`
`The results of pharmacokinetic assessments in several multiple dose studies in human
`volunteers, at doses relevant to the proposed indication are presented in the following
`table from the Sponsor, for comparison of exposure in the nonclinical studies: