NDA 21-038
`
`Table 253-1 :
`
`Mean Distribution of Metabolites after Incubation of [’HJMedetomidine,
`[’HJDexmedetomidine and [’H]Levomedetomidine with Human Liver Slices
`Wm
`
`‘-
`
`3‘”
`
`Metabolite
`
`G-Dex-l
`G-Dex-Z
`G-levo
`
`COOH
`OH
`G-OH
`
`’
`
`‘
`
`-
`
`Medetormidine Dexmedetomidine __Levomedetomidine
`(n=2>
`may
`man
`14.32
`22.39
`0.67
`9.32
`14.69
`2.06
`44.60
`t
`71.30
`
`0.40
`2.08
`0.61
`
`1.02
`_
`"10.81
`1.56
`
`0.27
`1.14
`0.29
`
`nd
`nd
`2.52
`0.57
`21.20 '
`83.02
`
`' —
`
`nd
`nd
`10.77
`1.54
`37.22
`54.43
`
`_
`
`._
`
`nd
`$0,011
`nd
`M-QH
`2.73
`N-Me'thyl
`1.05
`H-1
`24.91
`Other
`78.39
`Turnover (%)
`G-Dex-l == N-glucuronide of dexmedetomidine
`G-Dex-2 = N-glucuronide of dexmedetomidine
`G-Levo = N-glucuronide of levomedetomidine
`COOH = carboxylic acid metabolite (MPV-l306)
`OH = hydroxy metabolite (MPV-l305)
`G-OH=_ O-glucuronide of the hydroxy metabolite
`$0,011 = sulfate conjugate of the hydroxy metabolite
`M-OH = mercapturic acid conjugate of the hydroxy metabolite
`methyl N-methylated metabolite (MIN-1709)
`PM = glucuronide of the hydroxylated N-methyl metabolite
`Turnover = % Parent drug converted to metabolites
`t = trace nd = not detected
`
`Table 253-2:
`
`-
`
`_
`
`Variability in the Rate of [’HIDexmedetomidine Glucuronidation
`in a Panel of Twenty-One Human Liver Microsomes
`pmol/min/mg protein
`G-Dex-l
`5.82
`2,61
`‘ 38.00
`65.92
`
`Subject ID
`EGF426‘
`FAG771
`FBI779
`EFESS6
`
`‘.
`
`G-Dex- 2
`m
`6.11
`24.42
`40.17
`
`FGL852
`F1w309
`FRX710‘
`GC4476
`GDD565
`GEQS91
`GFE060
`615562
`
`HAK163
`
`27.00
`86.50
`45.58
`49.33
`11.08
`75.08
`93.25
`12.25
`
`27.83
`
`-
`
`_ 17.67
`56.17
`30.67
`30.00
`8.42
`45.33
`59.67
`8.67
`
`18.75
`
`G- l/G-Z
`1.46
`1.57
`1.56
`1.64
`
`1.53
`1.54
`1.49
`1.64
`1.32
`1.66
`1.56
`1.41
`
`1.48
`
`“ —
`
`
`
`

`

`NDA 21-038
`
`GLT656
`
`13.67
`
`_
`
`'
`
`'Z'
`
`1.1.5.18.
`HOD057‘
`17.42
`HIFl812
`125.11
`HF0125951
`36.75
`ICF119
`63.83
`IEG710
`71.08
`lENOlG
`46.25
`1154420
`49.38
`Mean .
`35.30
`SD.
`‘ received known inducers of UDPGT activity
`
`..
`
`..
`
`9.75
`
`11.25
`10.17
`18.25
`22.83
`40:25::
`43.92
`29.58
`31.34
`22.02
`
`-'-
`
`1.40
`
`1.59
`1.71
`1.59
`1.61
`1.59
`- 1.62
`1.56
`1.55
`0.10
`
`The underlined values in the above table are demonstration of the extremes in rates of
`glucurinidatioriamong human subjects 5.83 to 124.17 pmol/min/mg protein, >20 fold difference.
`
`Table 253-3:
`
`Summary of the Kinetic Parametersfor the Glucuronidation of
`Dexmedetomidine by Human Liver Microsomes
`glucuronidation
`Subject 1.D.
`Reaction
`ICF
`Dex-l
`3.83
`3
`1 826
`0.22
`
`Parameter'
`Km (mM)
`Vmax (pmol/min/mg)
`Vmax/Km (rnL/min/rng)
`
`._
`
`EFE
`2.64
`1937
`0.73
`
`.
`
`Dex-2
`
`Km(mM)
`Vmax (pmol/min/mg)
`Vmax/Km (rnL/min/rng)
`
`1.57
`
`2.15
`
`2.61
`
`592
`0.38
`
`334
`0.16
`
`‘units for Vmax and Vrnax/Km are expressed relative to mg of microsomal pretein
`
`GDD
`1.67
`268
`0.16
`
`Mean +SD
`2.71+ 1.08
`1010 + 849
`0.37 + 0.32
`
`2.11+0.52
`332
`0.13
`
`420 + 150
`0.22 +0.14
`
`Summary
`The metabolism of dexrnedetomidine by human liver slices and human liver microsomal
`preparations indicated that the direct N-glucuronidation was a significant route of metabolism.
`and the metabolic profile is qualitatively similar to in viva results from human plasma and urine.
`There is a 10 fold difference between subjects in the extent-ofN-glucuronidation, but the ratio of
`the metabolites for each nitrogen is relative constant and indicates the preferential
`glucuronidation at one ofthe irnidazole nitrogen versus the other but apparently both by the same
`enzyme. [Metabolic pathways: page 72 (rat) and page 100 (human)]
`
`—
`
`

`

`
`
`NDA 21-038
`
`[41]
`
`Abbott-85499 Drug Metabolism Report No.36 -
`Shim:
`Identification of cytochrome P450 isoforms involved in the oxidative metabolism of
`dexmedetomidine (Abbott-85499) and the effectmf dexmedetomidine on
`cytochrome P450-mediated monooxygenase activities
`
`Study No: 'Report No. R&D/97/7S7
`W.“
`W: Abbott Laboratories Division 46: Abbott Park, IL
`W' Janualy 1998..
`
`(#254)
`
`-
`
`. Methgds:
`Human Liver Microsomes: The human livers of transplant quality were obtained fiom
`M The liver tissue samples
`were received within 24 hrs of removal. The fact that CYP2D6 may have a role1n
`dexmedetomidine metabolism was addressed by preparing liver microsomes from an extensive
`metabolizer (1131211961, male) and a poor metabolizer (113415961, male). The tissue was
`homogenized, centrifuged and the microsomal pellets resuspended in phosphate buffer and stored
`at -7;O?C-unti1 use in incubations for studies. The microsome incubations with dexmedetomidine
`
`was stopped, centrifuged and the supematants analyzed '
`
`cDNA--Expressed CYP proteins: Microsomes prepared fi'om B--lymphoblastoid cells containing
`cDNA--expressed CYP1A2, CYP2A6, CYP2B6,CYP2C9,CYP2C19,CYP2D6,CYPE1,
`CYP3A4 and CPY4A11 were obtained fi’omW“ 1 .'he
`microsome incubations with dexmedetomidine was stopped, centrifuged and the supematants
`analyzed by 1 “CH.
`
`-
`
`Selective CYP2A6 Antibody: Inhibition of metabolism of [3H]-dexmedetomidine by a selective
`CYP2A6 monoclonal antibody to provide more evidence of this isozyme in the in vitro
`
`metabolism. The antibody was supplied by
`
`W113 Medetomidine, with tritium on the bridge methyl group,
`
`was synthesized by
`ad the dexmedetomidine (Lot #50498-ST-108; 66 Ci/mmol)
`was separated at Abbott by chiral chromatography. Unlabeled dexmedetomidine (Lot #031940-
`002) were added to the labeled compounds only to provide final incubation concentrations
`greater than 0.05uM. The radiochemical purity wasW.
`
`Results:
`
`This study was done to identify which P450 isozymes were involved in dexmedetomidine
`metabolism and to examine the effects of dexmedetomidine on the isofonn~specific cytochrome
`
`—<
`
`86
`
`

`

`NDA 21-038
`
`P450 mediated reactions.
`
`Oxidative metabolites: The chromatograph of dexmedetomidine metabolites, in the presence of
`NADPH, typically demonstrated two major metabolic peaks. One of these peaks was identified
`as MPV— 1305, the phenyl-3--hydroxymethyl metabolite ofthe parent and a late eluting peak was
`tentatively identified as the methylene bridge hydroxymethyl, identified as the probable H-3
`metabolite detected1n human plasma in viva.
`
`Inhibition studies: The inhibition of CYP2A6 by 8-methoxypsoralen inhibited the formation of
`both hydroxymethyl metabolites, MVP- 1305 and H-3 by 40 to 60%. However the inhibition of
`this enzyme by coumarin, inhibited the formation of MVP- 1305 by more than 30% but of H-3 by
`less than 10%. Selective inhibition of CYP3A decrease MVP-' 1305 formation by 34%1n one
`prep but only 3%1n the other microsomal preparation.
`
`Metabolism by cDNA--Expressed Proteins: CYP2D6 and 2A6 exhibited the highest rates of
`hydroxylation to the MVP-1305 metabolite of dexmedetomidine. The CYPZEI and CYP2D6
`were the most active P4505 for formation of H3 metabolite.
`
`The following tables present the results obtained (V45/pl324-5)
`
`Hydroxylation ofDexmedctormdme1n the Presence of Human
`Table 254-1
`B--Lymphoblastoid Cell Microsomes Containing cDNA-Expressed CYP Proteins
`
`12
`
`l
`
`'I'HI
`
`I'
`
`[511112
`
`!
`
`'l'fll
`
`'I'
`
`[MEN]
`
`CYP Form
`
`1A2
`2B6
`2C8
`2C9-arg
`2C19
`2D6-val
`2131
`3A4
`2A6
`4A1 1
`Control'
`2
`
`MPV-l305
`prnol/hr/pmol
`ND
`ND
`0.204
`ND
`0.295
`4.261
`0.467
`0.506
`1.770
`ND
`ND
`
`'
`H-3
`pmol/hr/pmol
`0.162
`0.044
`ND
`0.742
`ND
`1.7t1
`2.781
`0.955
`0.206
`0.306
`ND
`
`-
`
`‘
`
`MPV-l305
`pmol/hr/pmol
`0.002
`0.004
`0.008
`ND
`0.141 '
`0.664
`0.008
`0.079
`0.058
`ND
`ND
`
`,
`
`'
`
`-
`
`-.
`
`H-3“
`pmol/hr/pmol
`0.004
`0.060
`ND
`0.002
`ND
`0.002
`0.049
`0.054
`0.005
`ND
`ND_
`
`Microsomes prepared from cells devoid of CYP
`ND =No activity detected
`
`WWWHWWWM
`
`
`
`

`

`NDA 21-038
`
`Dexmedetomidine inhibition of Cytochrome P4505: The inhibition was most evident on
`CYP2C9, CYP2D6 and CYPBA, all less than luM. The ICso values are presented in Table 254-3
`below. The CYP2C9 has a major role in the metabolism of phenytoin, warfarin and NSAIDS.
`CYP2D6 is involved in metabolism of compounds like codeine and hydroxycodone and the type
`of dexmedetomidine inhibition appears to be mixed, competitive and non-competitive. It is a
`polymorphic enzyme and about 5% of caucasians, 2% of asians and africans are deficient in this
`enzyme. CYP3A, the major form of CYP3 in adults, is about 33% of the total P450 isozymes
`and it-playsa role in sex steroid metabolism, e.g. testosterone. Dexmedetomidine also potently
`inhibits the N-demethyl'ation of ketamine in human liver microsomes with a Ki of 0.4 uM. The
`CYP involved in this reaction has not been identified.
`
`Hydroxylation of Dexrnedetornidine in the Presence offiurnan
`Table 254-2
`‘
`B-Lymph’oblastoid Cell Mierosomes Containing cDNA-Expressed CYP Proteins
`
`11
`
`1.1.“!
`
`l‘
`
`:5”:
`
`1.1."!
`
`1'
`
`ICE:
`
`CYP Form
`
`MPV-1305
`
`H-3 -
`
`1A2
`2B6
`2C8
`2C9-arg -
`2Cl9
`2D6-val
`2131
`3A4
`2A6
`4A1 1
`Control'
`2
`
`pmol/hr/pmol
`ND
`ND
`0.204
`ND
`0.295
`4.26]
`0.467
`0.506
`- 1.770
`ND
`ND
`
`-
`
`pmol/hr/pmol
`0.162
`0.044
`ND
`' 0.742
`ND
`1.7tl
`2.78]
`0.955
`0.206
`0.306
`ND
`
`MPV-1305
`
`pmol/hr/pmol
`0.002
`0.004
`0.008
`2 ND
`0.141
`0.664
`0.008
`0.079
`0.058
`1 ND
`ND
`
`.
`
`H-3
`
`pmol/hr/pmol
`0.004
`0.060
`ND
`0.002
`ND
`0.002
`0.049
`0.054
`0.005
`ND 1
`ND
`
`Microsomes prepared from cells devoid of CYP
`
`ND = No activity detected
`
`WWWWWW—W
`
`Summary
`The CYP2A6 is apparently the largest contributor to dexmedetomidine hydroxylation in vitro in
`human microsomes to the metabolites MPV-1305 and H-3, the 3-hydroxymethyl and the bridge
`carbon hydroxylation, respectively. The CYP inhibition by dexmedetomidine affects several
`isozymes, most potently CYP2C9 (0.2uM ICSO), CYP3A4 (0.65uM 1C”), and CYP2D6 (0.4 uM
`1C50). The sponsor cites clinical data indicating the therapeutic blood level are 0.04 uM or less
`and claims this precludes any role of dexmedetomidine in metabolism of concomitant drugs.
`However, the ADME study with labeled dexmedetomidine demonstrated that, upon a single
`administration, the liver concentrations were nearly 100X the peak plasma concentrations. Since
`
`
`
`

`

`NDA 21-038
`
`the metabolising P4505 are mainly in the liver, there remains the possibility that
`dexmedetomidine can interfere with the metabolism of concomitant medications, especially afier
`prolonged administration. The latter situation has not been studied, although it has been -
`proposed in clinical protocols. Studies to address this concern have been proposed by the
`sponsor, approved by the division and are to be done in thenear future.
`
`
`
`_
`
`M15:
`
`Abbott-85499 Drug Metabolism Report No.13 -
`“ The1n vitro interaction of dexmedetomidine with human liver
`
`microsomal cytochrome P450 2D6 (CYP2D6)
`
`Study N91 Report No. R&D/96/557
`_
`VQI £515, pggg £1 22:
`WW: Abbott Laboratories Division 46: Abbott Park, IL
`Wagon: August 1996
`
`(#258)
`,
`
`Mghgds: The human livers of transplant quality were obtained
`—- m t..The liver tissue samples were received within 24 hrs
`of removal. The tissue was homogenized, centrifuged and the microsomal pellets resuspendedin
`phOsphate buffer and stored at -70°C until use in incubations for studies. The microsome
`incubations with dexmedetomidine was stopped, centrifuged and the supematants analyzed by
`‘\-— '.[0--methyl l‘C] dextromethorphan was also used~as a substrate.
`W: Microsomes prepared from B--lyrnphoblastoid cells’containing
`
`
`
`cDNA-expressed CYP2D6-Val were obtained fromM The
`microsome incubations with dexmedetomidine was stopped, centrifuged and the supematants
`analyzed by /____________\
`WWW: [O-methyl l‘C] dextromethorphan was synthesized by
`. _.w '
`The unlabeled dexmedetomidine, Lot
`#295260-0-AX “A -'y and the quinidine, Lot #01831KW fromku- ~-—-——-
`
`~A'\m WC]HCHO, 30.1 mCi/mmol, was purchased from
`
`mm:
`
`The effects of dexmedetomidine on the Dextromethorphan O-demethylase, CYP21_)6, was
`studied in vitro. The Table 258-1 presents the IC,0 values for dexmedetomidine and quinidine.
`Although quinidine is about 7-times more potent, dexmedetomidine's K. was still in range of 1
`uM.
`
`

`

`NDA 21-03::
`
`Table 258-1:
`
`:
`i
`
`Inhibition of Dextromethorphan O-Demethylase Activity in the
`Presence of Dexmedetomidine or Quinidine
`__ICm.i.uMl'_
`I
`.l.
`
`II:
`S 1'
`Human Liver Microsomes
`HFO
`GC4
`FRX
`HAK
`ICF
`Mean :t SD‘
`Projected K, (uM)d
`cDNA-Expressed CYP2D6‘
`
`;
`
`'
`
`;
`
`E
`
`,
`'
`
`.
`
`1.3
`1.2
`1.5
`1.5
`11.2
`1.3 i 0.25
`0.70
`2.0
`
`1 ~13
`
`_
`
`i
`
`’. '
`
`C
`
`.
`
`.1.
`
`0.18
`b
`b
`0.16
`m
`0.18 :t 0.02
`0.09
`0.15
`
`;
`b
`
`1C”: Concentration of quinidine or dexmedetomidine required to inhibit activity by 50%.
`The final concentration of DEXTRO approximated apparent Km.
`Not determined.
`c Mean :e standard deviation.
`‘ Assuming competitive inhibition. When substrate concentration = Km, [Cg/2 = K,.
`e Human B-lymphoblastoid cell microsomes containing cDNA-expressed wild type CYP2D6.
`WWWWWWW
`
`Table 2582
`
`._
`
`I. Inhibition Constants Characterizing the Inhibition of Human Liver Microsomal Dextromethorphan 0~
`Demethylase Activity in the Presence of Dexmedetomidine or Quinidine
`W
`HE
`
`Hammers:
`Dexmedetomidine
`
`lCE
`
`514.
`
`Mean 1 512b
`
`'
`
`0.2
`3.2
`16
`
`K;(uM)
`K.“ (uM)
`Alpha
`Quinidine
`Ki (uM)
`0.05
`0.08
`C
`0.07‘
`'
`l(,-. Km and a (Kies/Ki) were determined using Dixon and Cornish-Bowden plots. Dexmedetomidine behaved as
`a mixed (competitive/noncompetitive) inhibitor (Kt? Kigalpha >1) and quinidine exhibited competitive
`inhibition.
`" Mean + SD of three livers.
`‘ Not determined.
`
`0.5
`2.2
`4.4
`
`:
`
`0.4
`1.5
`3.9
`
`'
`
`_
`
`0.4 i 0.2
`2.3 :t 09
`8.1 i 6.8
`
`Summary
`The potent inhibition of CYP2D6 by dexmedetomidine was as a reversible mixed
`(competitive/non-competitive) inhibitor and quinidine, a competitive inhibitor, was 6-7 times
`more potent. The sponsor again cites that the expected plasma levels of dexmedetomidine
`(0.04uM) is much lower than the IC,0 (1.3uM). However, upon single administration of labeled
`dexmedetomidine to the rat, the liver concentration eitceeded the peak plasma level by nearly two
`orders of magnitude. There has been no study to evaluate possible liver accumulation and yet the
`sponsor has proposed 5 consecutive days of dexmedetomidine infusion. The CYP inhibition by
`dexmedetomidine could produce significant changes in metabolism of concomitant medications
`if there is any liver accumulation of the parent compound or active metabolites.
`W' .......................................
`........................................
`..................
`
`
`
`

`

`
`
`NDA 21-038
`
`[43]
`
`-
`
`We:
`
`Abbott-85499 Drug Metabolism Report No.8 -
`In vitro protein binding of [3H]Abbott-854991dexmedetomidine) in
`mouse, rat, dog, monkey, and human plasma (Protocol V96-004)
`
`(#242)
`
`Sim: : V96-004; Report No. R&D/96/320
`W:
`W: Abbott Laboratories Division 46: Abbott Park, IL
`MW: July 1996
`Methods: Blood samples were obtained fi'om both sexes of mice (CD, Charles Rivers); rats
`1(Sprague-Dawl'ey, Sasco), beagle dogs (Marshall Research Farms), cynomolgus monkeys
`(Charles Rivers), and human volunteers. The heparinized blood was centifuged to separate the
`plasma and appropriate drug solutions were added to the plasma. The solutions Were incubated
`at 37°C in shaking water baths and placed in a centrifuge devise that provided ultrafiltration
`during centrifugation. The filtrates were extracted with acetonitrile and analyzed
`chromatographically.
`WW: Medetomidine HCl, with tritium on the bridge methyl
`group, was synthesized by. C-.\« l and the dexmedetomidineisomer was separated at Abbott
`by Chiral chromatography. (Lot #53863MK-085 (80 Ci/mmol; 331 uCi/ug, 1.1 ug/ml).
`Unlabeled dexmedetomidine (Lot #295260--0-AX), was added to the labeled dexmedetomidine
`HCl to provide a solution of 10, 5, 2.5 and 1.0 ug salt/ml dose solution. The radiochemical
`lM.
`
`Results:
`The protein binding results are presented in the following table copied from the submission
`(V43/p146):
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`Table 242-1 :
`
`Summary of the In Vitro Protein Binding of [’H]Abbott—85499 in
`Mouse, Rat, Dog, Monkey and Human Plasma
`
`91‘
`
`
`
`

`

`
`
`NDA21-038
`
`.
`
`Mouse
`
`Rat
`
`Dog
`
`.
`
`Monkey
`
`-
`
`5'
`
`-
`
`-.
`
`'
`
`Human
`
`-.
`
`'
`
`Saline
`
`Sex
`
`Mean‘
`SD
`
`Mean'
`SD
`
`Mean'
`SD
`
`Meanl
`
`SD
`
`Mean‘
`SD
`
`0
`
`E
`
`. E‘
`
`1‘
`
`94.89
`0.18
`
`88.16:
`0.31
`
`92.58
`0.28
`
`84.59
`
`0.48
`
`J
`
`93.72
`0.40
`
`—
`
`4 Day Mean
`SD
`
`3.20
`3.10
`
`SD = Standard Deviation
`‘ Means are calculated from the male and female results of each concentration tested.
`
`Summary:
`Theibi’nding in males and females was similar in all‘ species and the percent plasma protein
`binding ranged from a mean of 84.6% in monkeys to 94.9% in mice and in humans the mean
`binding was 93.7%.
`
`
`
`Study;
`
`_ Abbott-85499 Drug Metabolism Report No.20 -
`In vitro binding of [’H]Abbott-85499 (dexmedetomidine) to human serum albumin
`and “1° glycoprotein (Protocol V96-0 11)
`
`(#243)
`
`Study N9: Report No.R&D/97/338
`V9! M3, page filfil:
`WW: Abbott Laboratories Division 46. Abbott Park, IL
`MM: June 1997
`Methods: Human serum albumin and alphal-acid glycoproteins were obtained flowa V
`\-\__ and dissolvedin phosphate buffer. The protein binding was determined by an
`ultrafiltration technique. The solutions were incubated at 37°Cin shaking water baths and
`placed in a centrifuge devise that provided ultrafiltration during centrifugation. The filtrates were
`extracted with acetonitrile and analyzed chromatographically. The radioassay of the proteins was
`in a liquid scintillation analyzer.
`
`92
`
`
`
`

`

`
`
`NDA 21-038
`
`W: Medetomidine HCI, with tritium on the bridge methyl
`group, was synthesized it? .1 and the dexmedetomidine isomer was separated at Abbott
`by chiral chromatography. (Lot #53863-MK-085; 80 mcCi/rnmol) Unlabeled dexmedetomidine,
`Lot #295260-0-AX, was added to the labeled dexmedetomidine HCl
`to provide a solution of
`8.5, 4.25, 2.125 and 0.85 ug free base/m1. The radiochemical fl' /o.
`
`:
`
`Results:
`
`The-resultsare presented in the following tables from the submission (V43/p173-177):’-
`Table 243-2:
`2
`-'
`
`In Vitro Binding of [’H]Abbott-85499
`,
`(Dcxmedetomidine) to Human Serum Albumin (BSA) and
`a,-Acid Glycoprotein (AAG) at Normal Physiological Concentrations ‘ '
`
`Dexmedetomidine
`Maxim]!
`
`Sample
`
`Percent [3HJA-85499 Bound‘
`HSA"
`AAQC
`HSAZAAQ‘
`
`0.85
`
`8.5
`
`:
`
`.-
`
`21.25
`
`42.5
`
`85
`
`1
`2
`Mean
`
`l
`2
`Mean
`
`1
`
`Mean
`
`1
`
`Mean
`
`1
`2
`
`0.85 - 85
`
`Mean
`
`Mean
`
`80.65
`8.0.61
`80.64
`
`80.83
`8.1.92
`80.96
`
`80.39
`82.12
`80.48
`
`81.24
`
`89.29
`81.07
`
`80.47
`8.0.70
`80.59
`
`65.22
`65.52
`65.39
`
`63.97
`m2
`64.33
`
`63.85
`$.92
`63:97
`
`62.48
`
`'
`
`' 63.53
`63.00
`
`. 62.97
`__§3..2§
`63.12
`
`‘
`
`81.94
`81.15
`81.85
`
`~
`
`82.49
`82.5.2
`82.46
`
`82.01
`82.12
`82.10
`
`82.24
`
`82.32
`82.32
`
`82.34
`82.59
`82.37
`
`63.96
`80.75
`‘EAs determined by an ultrafiltration technique.
`5 Buffer solution (0.067 M phosphate, pH 7.4) containing 40 ngml human serum albumin.
`cBuffer solution (0.067 M phosphate. pH 7.4) containing 0.8 mg/ml a,-acid glycoprotein.
`‘Buffer solution (0.067 M phosphate. pH 7.4) containing 40 mg/ml human serum albumin
`and 0.8 myml a,-acid glycoprotein.
`
`82.22
`
`WWW-WWW
`
`93
`
`

`

`
`
`NDA 21-038
`
`Summary:
`.[3H] Dexmedetomidine wasexamined in vitro for binding to serum albumin and a-acid
`glycoproteins by an ultrafiltration technique. The concentation of dexmedetomidine was
`evaluated between 0.85 and 85 ng/ml and the concentrations of albumin and ail-acid
`glycoproteins were varied to approximate clinical disease state conditions. The results indicate
`that dexmedetomidine may have slightly higher unbound levels in the disease states which
`substantially lower serum albumin levels. An elevated capacid glycoprotein level can ameliorate
`this reduced binding and if these levels are reduced, the unbound fraction would be expected to‘
`furtherincrease.
`
`
`
`Abbott-85499 Drug Metabolism Report No.29 -
`W3
`Protein binding interactions betw_een Abbott-85499-3H (dexmedetomidine) and selected
`other drugs in human plasma (Protocol V97-034)
`
`(#244)
`
`Study No: Report No. R&Dl971525
`.‘
`Vgl £3, and page #182:
`WWW: Abbott Laboratories Division 46: Abbott Park, IL
`MW: Report No. R&Dl971525
`
`Mflhgdii Blood was obtained from male and female voluteers who had fasted for at least 8 hours
`and had taken no medicine other than aspirin in the last week and no salicylates within the last 48
`hours. The heparinized samples were centrifuged and the plasma frozen until use.
`
`The protein binding was determined by an ultrafiltration technique. The solutions (as specified
`under Results:) were incubated at 37°C in shaking water baths and placed in a centrifuge devise
`that provided ultrafiltration during centrifugation. The filtrates were extracted with acetonitrile
`and analyzed chromatographically. The radioassay of the proteins was in a liquid scintillation
`analyzer.
`
`WWW: Mcdetomidine HCl with tritium on the
`bridge methyl group, was synthesized '*
`nd the dexmedetomidineisomer was
`separated at Abbott by chiral chromatography. (Lot #55585-st-108; 66 Ci/mmol). The
`W.
`
`Resins:
`
`The results are presented on the following table from the submission (v43/p184):
`
`94
`
`

`

`
`
`NDA 21-038
`
`mm
`Control‘
`+ Fenianyl
`+ Ketorolac
`+ Theophylline
`+ Digoxin
`+ Lidocaine ,
`‘ = f 50% Ethanol
`
`-."
`
`,_
`
`Bgund
`92.71
`92.61
`92.50
`92.58
`92.66
`91.79
`
`% A85499-’H
`
`,. Communion
`0.6 ng/ml
`3.0 ng/ml
`3.0 ug/ml -. _-.-.
`20.0 ug/ml
`3.0 ug/ml
`6.0 uglm]
`
`Snmmamt
`The effects of fentanyl, ketorolac, theophylline, digoxin and lidocane on the in vitro protein
`:binding of dexmedetomidine was minimal. There were no differences1n binding as great as 1%.
`
`
`[46]
`
`Abbott-85499 Drug Metabolism Report No.30 -
`m:
`Effect of Abbott-85499 (dexmedetomidine) on the protein binding of selected other
`drugs in human plasma (Protocol V97-027)
`
`Stud3; No: Report No. R&D/971526
`Vglfii, page12:32!”
`Wm: Abbott Laboratories Division 46: Abbott Park, IL
`mm: September 1997
`
`~
`
`2
`
`(#245)
`
`Methods: Unlabeled dexmedetomidine, 0.06 ug base/m1 saline was the test concentration. Blood
`was obtained from male and female volunteers who had fasted for at least 8 hours and had taken
`no medicine other than aspirin in the last week and no salicylates within the last 48 hours. The
`heparinized samples were centrifuged and the plasma frozen until use.
`
`The protein binding was determined by an
`. The solutions of plasma and
`test drugs were incubated at 37°Cin shaking water baths for 15 minutes. The samples were then
`divided in two portions and one recieved an aliquot of normal saline and the other the unlabed
`dexmedetomidine. After an hour of additional agitation at 37°C, the samples were placed1n a
`centrifuge devise thatprovided ultrafiltration. The filtrates were extracted with acetonitrile and
`analyzed chromatographically. The radioassay of the proteins was in a liquid scintillation
`analyzer.
`—
`
`Wm: Tritium labeled ibuprofen (lOug/ml), theophylline
`(ZOug/ml), propanolol (0.0211g/ml), and digoxin (3ng/ml) were used and I‘C-labeled phenytoin
`(1611 g/ml) and warfarin (1011g/ml)were also test solutions. Unlabeled dexmedetomidine
`(0.6ng/ml) (lot #2952609-0-AX). Radiochemical purity was -m-
`
`95
`
`
`
`

`

`NDA 21-038
`
`Results:
`-
`None of the tested compounds appeared to be significantly displaced by dexmedetomidine (0.6
`ng/ml). There was no significant differences between the sexes. The combined results are
`presented on the following table from the submission (v43/p203).
`Table 245-1:
`
`Radiolabeled
`Drug
`._
`Phenytoin
`Warfarin
`Ibuprofen
`Propranolol
`Theophylline
`.Digoxin
`" 0.6 ng/ml
`
`-.
`
`.
`
`__%_B_Qund___
`Control’
`+ Abbott-85499
`93 .55
`93.53
`99.38
`99.37
`99.55
`99.55
`75.47
`75.36
`60.99
`60.69
`33.75
`34.46
`‘ + 50% ethanol
`
`»‘-
`
`% of
`Control
`100
`100
`100
`99.9
`99.5
`102
`
`~
`Summary:
`Dexmedetomidine, at 0.6 ng/ml, did not displace any of the concomitant drugs from the plasma
`protein binding, in vitro. The mean Cmax, in viva, during the use of the MRHID was 2.4 ng/ml,
`exceeding the test dose by 4-fold. This test may not be predictive of clinical effects.
`
`
`
`Abbott-85499 Drug Metabolism Report No.22 -
`We:
`In vitro determination of human red cell binding of Abbott-85499-3H (dexmedetomidine)
`(Protocol—V97-026)
`‘~
`(#246)
`
`mm: Report No. R&D/97/371
`191mm:
`Wimp Abbott Laboratories Division 46: Abbott Park, IL
`W3 September 1997
`Methods: Blood was obtained from 2 male and 2 female volunteers who had fasted for at least 8
`hours and had taken no medicine other than aspirin in the last week and no salicylates within the
`last 48 hours. The hemocrit was determined for each subject; M1=41.7%, M2=42.9%,
`F 1=39.2% and F2=40_%. The heparinized samples were spiked with labeled dexmedetomidine,
`0.5 to 5ng base/ml, and incubated for 1 hour at 37°C. An aliquot of the samples was centrifuged
`at 4°C and 1 ml of plasma was extracted with acetonitrile and characterized 5e»
`WWW: Medetomidine HCl, with tritium on the bridge methyl
`
`group, was synthesized
`the dexmedetomidine isomer was separated at Abbott
`by chiral chromatography. (Lot #55585-ST-108; 72.6 Ci/mmol, 278.3 mCi/mg) The
`W
`
`96
`
`

`

`NDA 21-038
`
`Results:
`
`'
`
`_
`
`There was no metabolism of dexmedetomidine or degradation in the whole blood. There were
`minor concentration dependent differences in binding but the binding was low to the RBCs.
`There were no sex differences evident and the fraction bound to the red blood cells over the
`
`entire concentration range, 0.5 - 5 ng base/ml, averaged 0.153, the RBC to plasma concentration
`ratio was 0.325 and the whole blood to plasma ratio was 0.723. Thefollowing table was copied
`from the submission:
`Mean
`Female
`Male
`Parameter
`0.183
`0.186
`O.-180
`{m -.
`0.325
`0.348
`0.302
`Cdpr
`0.723
`0.742
`0.704
`Cbm/Cp
`{m = fraction bound; Cm= concentration in RBC; Cuwfi concentration in.whole blood
`Cp= concentration in plasma
`A -
`
`The binding for dexmedetomidine to human red blood cells was low, only about 18% and this
`represented about 32% of the plasma concentrations.
`
` ####
`
`[431[451
`
`Abbott-85499 Drug Metabolism Report No.27 -
`51ml;
`Conversion of [3H]dexmedetomidine to [H] levomedetomidine in male subjects
`following a 2 jig/kg infusion of [3H]dexmedetomidine'HCl
`
`_
`Study No: Report No. R&D/97/458
`V9] #55. page £|§3z
`WWW: Abbott Laboratories Division 46: Abbott Park, IL
`W August 1997
`
`(#256)
`.
`
`: .
`
`Methods: Plasma samples were obtained from human subjects (from study DEX-96-018), 10
`_
`minutes, 1, 2, and 4, 5 or 6 hours post administration of labeled dexmedetomidine, 2 ug/kg
`infusion. The samples were analyzed by ___.._’———— Some samples were spiked with labeled
`levomedetomidine to.establish the minimum level of detection. The urine of the subjects was
`also analyzed for levomedetomidine was previously found in vitro to be rapidly glucuronidated.
`
`
`
`Wm: Medetomidine HCl, with tritium on the bridge methyl
`group, was synthesized.
`ind the dexmedetomidineisomer was separated at Abbott
`by chiral chromatography. (Lot #55585-ST-37 360 mcCi/ug) Unlabeled dexmedetomidine, Lot
`#295260-O-AX, was added to the labeled dexmedetomidine HCl and levomedetomidine (Batch
`PT0202). The radiochemical purity of ’M
`
`97
`
`
`
`

`

`NDA 21-038
`
`Results:
`
`Chiral conversion of dexmedetomidine to levomedetomidine was not detected in chiral
`
`chromatography of plasma samples from human receiving 2 ug/kg infusions. The limit of
`detection was 0.02 ng/ml. Reevaluation of data from study DEX-96-018 did reveal a possible
`exposure to the glucuron‘idated levo isomer. The possible exposure was slight, less than 0.5% of
`the AUQm for total plasma radioactivity. The possible amount of glucuronidated
`levomedetomidine was less than 1.5% of the dose, in the 0-72 hour urine samples and it was
`present as an impurity of about 0.3% in the labeled dexmedetomidine administered.
`‘
`..
`
`If there is any chiral conversion of dexmedetomidine into the leyo isomer, it is very slight and
`the levo isomer has been shown to be inactive and non-toxic at-any feasable dose (see
`Toxicology, impurities).
`
` W
`
`ADME - Pharmacokinetic Summary
`
`Was:
`The in vitro study ofplasma protein binding of dexmedetomidinc in different species did not find
`any significant sex differences and monkey plasma had the least binding at about 85% with rats
`at 88% [34]. The dexmedetomidine binding was similar in dog, mouse and man, 93%, 95% and
`94%, respectively. Dexmedetomidine was not extensively bound to human red blood cells over
`a range of concentrations. The fraction of dexmedetomidine bound averaged 0.183. The ratio of
`RBC concentration / plasma concentration averaged 0.325 [38]. The binding to alpha,-
`glycoproteins was studied also. The concentration of dexmedetomidine was evaluated between
`0.85 and 85 ng/ml and the concentrations of albumin and a.-acid glycoproteins were varied to
`approximate clinical disease state conditions. The results indicate that dexmedetomidine may
`have slightly higher unbound levels in the disease states which substantially lower serum
`albumin levels [35].
`
`The in vitro effects of other therapeutic agents on the plasma binding of dexmedetomidine was
`examined with fentanyl, theophylline, digoxin and other compounds and found to be minimal
`[36]. In the converse, dexmedetomidine did not affect the plasma protein binding of phenytoin,
`warfarin, theophylline or ibuprofen [37].
`
`98
`
`

`

`NDA 21-038
`
`Absorption:
`The absorption of dexmedetomidine fi'om subcutaneous injection in the rat was rapid, the t m,
`was 0.6 to 0.7 hours [22], and the t m, in the rat afier im injection was 0.33 hrs[47]. In the dog
`the intramuscular absorption was also rapid, t m = 0.6 hours [23].
`
`L .
`.1
`.
`:
`.
`Tissue distribution in the rat was examined in one study the sponsor considered questionable, due
`to a specific activity too low to reliably measure the parent compound by HPLC [47]. However,
`the exposures of the adrenals, liver and kidneys afieriv administration relative to plasma
`exposures (AUC values compared) was 51x, 34x and 15x, respectively.
`
`Another study was submitted with the IND and previously reviewed (see attached Addendum 1,
`#239). In that‘s'tudy the sc dose of labeled dexmedetomidine (40 ug/kg) accumulated in the
`adrenals 72x plasma concentrations and 36139x in the kidneys. The 20 ug/kg iv study [29] found
`that the labeled dexmedetomidine accumulated in the pigmented eyes of the Long Evans rats, but
`not the eye of the albino Sprague Dawley rats. However, the pigmented skin of the Long Evans
`rats did not accumulate the compounds. The exposure of various tissues to labeled compound
`exceeded the plasma exposure, as determined by AUC ratios. In the males, the exposure ratios
`were 185x, 54x and 11x, for adrenals, liver and kidneys, respectively. The tissue concentrations
`all exceeded the plasma concentrations at least at one time point. The mean peak concentrations
`in the brain were 6x greater than in plasma. The tissue levels of labeled compounds decreased
`significantly and after 72 hours the concentrations were only 0.1% to 5% of the peak levels.
`
`Metabolism;
`Dexmedetomidine isextensively metabolized in rats, dogs and humans as the parent compound
`is present as less than 1% of the administered dose in either feces or urine. The following
`discussion of primary metabolic pathways must be regarded as preliminary as the “other” in the
`metabolic tables represents 55% to 64% of metabolites in rats, 60+% in dogs and 30% of the
`urine metabolites in humans. The metabolism is similar in the different species as the first step
`involves N-methylation, bridge methyl hydroxylation, 3-methyl hydroxylation or N-
`glucuronidation. However, the N-glucuronidation is observed as a primary metabolite only in-
`humans. The 3-methyl hydroxylation is favored in the rats and dogs but is also present in man.
`The glucuronidation of the 3-hydroxyl metabolite is a major pathway in rats and the oxidation of
`3-methyl hydroxyl to the carboxy is a major pathway in rats and dogs, but minor in humans. The
`sulfate of the 3-hydroxy is a major plasma metabolite. in rats and dogs but not in humans. While
`these metabolites have not been shown to be in active 'in viva, they have been found weakly
`active in in vitro studies[3] and they represent 34% ofthe dexmedetomidine excretion[33]. The
`human plasma AUC for dexmedetomidine, 2 ug/kg i.v.,
`is 3.26 and the AUCs' for the N-
`glucuronides are 7.8 and 1.37 [33]. This exposure of humans to the N-glucuronides is not seen in
`animals as the dog and rat do not make these metabolites except possibly in trace amounts. The
`proposed human metabolism is presented as a flow diagram on the following page.
`
`99
`
`
`
`

`

`NDA 21-038
`
`Table of the proposed metabolic pathway in humans was copied from the submission
`(Vol43/pg07 l ):
`
`Figure 8. Proposed Dexmedetomidine Metabolic-fathway in
`Humans
`
`
`
`1
`1
`a
`
`<
`”,4
`
`- .,.
`
`com
`
`as
`
`3. “r;
`
`2......
`
`<
`«c’
`
`goon N-Meom
`
`N-Meuui O-Ghumidc '
`
`1 W |
`
`_
`
`I Coup.-
`
`' Os
`
`'w
`
`‘
`<
`.4 l
`as 9.,
`
`«ya-am
`
`mum N-Methyl
`
`
`
`100 ’
`
`
`
`

`

`
`
`NDA 21-038
`
`The Pk parameters and the metabolites of rats, dogs and humans are presented in the following
`table from the submission (Vol 23/pg 299) :
`2
`
`Table Pk sum 1:
`Summary of [’HJDexmedetomidine Metabolism in Animals and Humans -Plasma Data
`Human
`1381
`821
`1208
`1202
`2.+»
`
`1342mm
`Elamlmaljfl
`
`Cmax (ng Eq/mi) _
`_
`_
`Tmax (hr)
`_
`
`2.48
`2.13
`
`8.98
`‘ - 6.0
`
`m'mm 11.0.3.8
`
`22.11
`
`E
`
`. l.
`l
`Cmax (ng/mi)
`Tmax(hr)
`W
`Msialmlms
`AUC (ng Eq.hr/ml)
`Total 3H
`011‘-
`COOH
`G-OH
`
`S0,0l-l
`
`GS-OH
`M-OH
`G-Dex-l
`G-Dex~2
`
`,
`N-Me.
`G-N-Me-OH
`N-MeCOOH
`
`H-3/D-7@
`chers
`
`Reference
`
`,
`
`2.03
`0.50
`
`5.23.
`
`30.48
`0.46
`1.67
`1.96
`2.28
`
`15.15
`
`101.81
`1.01‘
`5.0
`8.37
`7.20
`
`nd
`nd
`nd
`nd
`nd
`nd
`nd
`
`nd
`nd
`nd
`‘ nd
`nd
`nd
`nd
`
`2.521
`
`32.63
`0.62
`3.04
`3.05
`3.63
`
`nd
`nd