Table 4. Comparison between ESRD and Healthy Control Subjects for AUC and Cm,
`Parameter
`Status
`Least-Squares
`Ratio of Geometric
`
`Atomoxetine
`Geometric Mean
`Mean (90% CI)
`
`CM (ng/ml)
`
`AUCOM (ughr/ml)
`
`Crm (ng/rnl)
`
`AUCM (ughr/ml)
`
`Cm (ng/ml)
`
`AUCM (ughr/ml)
`
`Cm (ng/ml)
`
`AUC‘(ug.hr/ml)
`
`Healthy
`ESRD
`Healthy
`ESRD
`
`Healthy
`ESRD
`Healthy
`ESRD
`
`86.0
`92.2
`0.469
`0.769
`4-Hvdroxvatomoxetine
`
`1.81
`1.45
`0.00714
`0.02095
`
`1.07 (0.68, 1.68)
`
`1.64 (0.86, 3.13)
`
`0.80 (0.64, 1.00)
`
`2.93 1.30, 6.60
`
`3.09 (l .65, 5.79)
`
`'-Desmethylatomoxetine
`2.00
`Healthy
`6.19
`ESRD
`0.00513
`Healthy
`15.73 (3.13, 79.15)
`0.09073
`ESRD
`4-Hydroxyatomoxetine —0-glucuronide
`Healthy
`307.7
`ESRD
`651.4
`Healthy
`2.39
`ESRD
`20.34
`
`2.12(1.71,2.63)
`
`8.51 (7.22, 10.02)
`
`'4-hydroxyatomoxetine glucuronide ADC is AUCM for ESRD subjects and AUCrt-m; for healthy subjects.
`
`Summary
`
`Atomoxetine can be administered to ADHD patients with ESRD or lesser degrees of
`renal insufficiency without changing the normal dose-escalation sequence.
`Changes in the plasma concentrations of atomoxetine, 4-hydroxyatomoxetine , and N-
`desmethylatomoxetine in ESRD subjects are not sufficient to warrant a change in
`dose in ESRD patients.
`'
`The plasma concentrations of 4-hydroxyatomoxetine-O-glucuronide, a renal excreted
`metabolite with no knowu pharmacologic action,
`increased as expected with a
`decreased in renal function.
`
`Plasma protein binding of atomoxetine is independent of renal fimction.
`The single 20-mg oral dose of atomoxetine was very well tolerated by ESRD and
`healthy subjects.
`
`B4Z-LC-HFBN (Vol. 70-71): Single Dose Pharmacokinetics of Atomoxetine
`Hydrochloride in Patients with Liver Disease
`
`The objectives of this study were to evaluate
`(1)
`the influence of moderate and severe liver disease on the pharmacokinetics of
`atomoxetine and on the plasma profile of the 2 main metabolites of atomoxetine (4-
`hydroxyatomoxetine and N—desmethylatomoxetine),
`the safety of a ZO-mg single oral dose of atomoxetine in patients with moderate and
`severe liver disease,
`plasma protein binding of atomoxetine in subjects with moderate and severe liver
`disease, and
`
`(3)
`
`(2)
`
`122
`
`

`

`(4)
`
`the correlation of CYP2D6 activity (Debrisoquine Metabolic Ratio) and liver blood
`flow (sorbitol clearance) with the clearance of atomoxetine in patients with
`moderate and severe liver disease and controls.
`
`This study was an open-label, 2-period (Period 1 = Sorbitol and Debrisoquine tests;
`Period 2 = Atomoxetine 20~mg dose — capsule CT10230), parallel groups design. Ten
`patients with liver disease and 10 healthy subjects participated in this study. Debrisoquine
`(Delinax) was given as lO-mg tablets and Sorbitol was provided in 40% sterile solution
`for intravenous use.
`
`Plasma samples for the measurement of sorbitol wge taken at Period 1 at predose, and
`then at 165, 170, 175 and 180 minutes. Before and 30 minutes after termination of the 3-
`hour infusion of sorbitol, subjects were asked to completely empty their bladder, and
`urine samples were obtained. Urine samples for debrisoquine were collected during the
`interval 0-8 hours after drug intake.
`
`Plasma samples for the measurement of atomoxetine and its metabolites were taken for
`healthy controls and HI patients at: predose, and then at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24,
`and 48 hours postdose. Additional samples were collected in patients at 72, 96, and 120
`hours. Urine samples were collected at period 2 over the following intervals after dosing:
`0-6 hours, 6-12 hours, and 12-24 hours. One plasma sample for the measurement of
`plasma protein binding of atomoxetine was taken at Period 2 at predose.
`
`Table 1. Child-Pugh Classification
`
`Albumin (
`
`)
`
`Total Bilimbin (umol/l)
`-patients without PBC
`-patients with PBC
`Prothrombin Time (%)
`(or INR)
`
`1 point
`>35
`
`<34
`<68
`570%
`
`2 points
`28-35
`
`34-51
`68-170
`40-70°/n
`
`3 points
`<28
`
`>51
`>170
`<40%
`
`Child A: 5-6 points
`Child B: 7-9 points
`Child C: 10-15 points
`
`Moderate
`Slight
`Absent
`Ascites
`3-4
`1-2
`None
`Pncephalopathy
`PBC: Primary biliary cirrhosis, lNR=Intemational Normalized Ratio®patient prothrombin time/normal plasma pool
`prothrombin time)m. lSI=International Sensitivity Index (provided by the laboratory).
`
`CYP2D6 Genotyping
`
`Procedure - A lO-ml whole blood sample was collected from each subject at screening for
`CYP2D6 genotyping. CYP2D6 genotype was determined by allele-specific polymerase chain
`reaction (PCR) amplification using a method derived from the method (Heim and Meyer 1991).
`Two laboratories were successively used to perform this analysis, Regipharm S.A., Belgium, and
`PPGX, UK. The wild type (wt) and the mutant alleles A (*3), B (’4), D (*5) and E (*7) were
`identified in genomic DNA of human peripheral lymphocytes by both laboratories. Additionally,
`the mutant alleles T (‘6) and G (*8) were also identified by PPGX (Daly et al. 1996).
`
`123
`
`

`

`_
`
`. _._.‘.2--2-4---‘ ..-A.‘_,_.....-4......,- . a-
`
`.
`
`.
`
`.
`
`.
`
`.
`
`_
`
`_
`
`.7
`
`-
`
`.—.
`
`-— -.
`
`.
`
`-. I-.-
`
`Table 2. Individual Mean Atomoxetine Plasma Protein Binding Results
`
`Subject Age
`ID
`(yrs)
`011 '
`47
`012
`57
`013
`55
`014
`48
`015
`59
`016
`34
`017
`52
`018
`62
`020
`49
`906
`52
`MeaniSD
`
`M
`M
`F
`M
`M
`M
`M
`M
`F
`F
`
`Healthy Controls
`Gender Origin % Protein
`Binding (SEM)
`
`Hepatic patients
`Subject Age
`Gender Origin % Protein
`11)
`(yrs)
`Binding (SEM)
`001
`62
`98.1 (0.09)
`M
`Caucasian
`”MW 002
`43
`M Kym“ 97.4 (0.03)
`Caucasian
`Caucasian M 003
`58
`F .
`97.3 (0.00)
`Caucasian
`'
`004
`59
`M
`93.0 (0.06)
`Caucasian
`006
`63
`M
`95.8 (0.03)
`Caucasian
`007
`53
`M WW...-----
`95.7 (0.06)
`Caucasian
`008
`48
`M
`97.4 (0.06)
`Caucasian M 009
`52
`F
`“MW“ 96.2 (0.17)
`Caucasian
`010
`54
`F
`95.3 (0.10)
`Caucasian
`an...“ 901
`35
`M
`"W“jjm-ww 98.0 (0.07)
`98.710.07
`p-Value 0.0008
`96.4i1.56
`
`MW.
`
`‘Mmmm-..
`
`Table 3. Values of Atomoxetine Pharmacokinetic Parameters (Mean with CV°/-)
`
`Group
`
`Healthy Controls (n=10)
`Child—Pugh B (n=6)
`Child—Pugh C (n=4)
`
`Cm
`(ng/mI)/(mg/kg)
`(fig/ml)
`560.4 (35)
`142.2 (36)
`431.9 (48)
`115.8 (55)
`431.9 (48)
`125.8 (45)
`tn (hr)
`Tm (hr)
`4.3 (2.4-8.0)
`1.0 (0.5-1.6)
`Healthy Controls (n=10)
`11.0 (7.9-17.9)
`3.3 (0.56.0)
`Chi1d~Pugh B (n=6)
`16.0 (72—263)
`6.0 (05-120)
`Child-Pugh C (n=4)
`Median with range for Tm and mean with range for tm,
`
`VZ/F
`AUCMH;
`AUCCH
`(ng)
`(tight/ml)
`(ugh/ml)
`2.66 (41)
`0.706 (68)
`0.692 (69)
`3.26 (35)
`1.17 (37)
`1.16 (37)
`2.72 (22)
`2.73 (63)
`2.54 (56)
`CL/F (L/hr)
`CL/F (L/hr/kg)
`41.5 (63)
`0.506 (54)
`20.0 (52)
`0.208 (28)
`10.8 (80)
`0.155 (79)
`
`Table 4. Values of Pharmacokinetic Parameters for Metabolites ofAtomoxetine (Mean with CV%)
`
`Parameter
`
`AUG;|
`(tight/ml)
`
`AUCo.
`(Hg-hr/ml)
`
`Tm
`(hr)
`
`2.28 (16)
`1.56 (38)
`2.94 (35)
`
`2.0 (1.2-4.1)
`3.0 (LO-8.0)
`9.0 (2.0-18.0)
`
`5.7 (3.8-8.8)
`9.4 (7.2-10.5)
`21.3 (9.7-38.6)
`
`,fl‘
`
`124
`
`Cm
`("g/ml)
`4-Hydroxyatomoxetine
`Healthy (n=9)
`1.9 (37)
`OF B (n=6)
`3.3 (33)
`C-P C (n=3)
`2.9 (41)
`N—Desmethylatomoxetine
`0.0385 (145)
`Healthy (n=10)
`4.1 (75)
`0.0124 (45)
`OF B (n=3)
`1.9 (18)
`0.0493 (109)
`G? C (n=3)
`1.7 (19)
`4-Hydroxyatomoxetine-O—Glucuronide
`Healthy (n=10)
`355.9 (45)
`2.20 (16)
`C-P B (n=6)
`104.5 (36)
`1.46 (41)
`OF C (n=4)
`92.2 (47)
`2.79 (40)
`Median with range for Tm and mean with range for tm.
`
`0.0046 (97)
`0.0263 (37)
`0.0334 (77)
`
`-
`-
`—
`
`—
`-
`—
`
`tm
`(hr)
`
`—
`-
`-
`
`1.2 (1 .0-2.1)
`1.8 (1 .0-8.0)
`2.0 (1 .0-1 2.0)
`
`-
`2.0 (1.0-8.0)
`—
`6.0 (0.581)
`12.0 (6.0-96.3) —
`
`

`

`Table 5. Parameter Comparison hem een Hepatic Impairment and Healthy Control Subjects
`
`Parameter
`Status
`Least-Squares
`Ratio of Geometric
`
`Alamoxefine
`Geometric Mean
`Mean (90% Cl)
`
`Cm (ng/ml)
`
`AUCQ'mf (pghr/ml)
`
`136.9
`Healthy
`107.1
`Hepatic
`0.849
`Healthy
`Hepatic
`1.585
`1.87 (1.17, 2.98)
`
`4-Hvdranvatomaxet‘ine
`.
`
`0.78 (0.54, 1.12)
`
`C,m (mg/ml)
`
`AUCM (ughr/ml)
`
`Healthy
`Hepatic
`Healthy
`he atic
`
`4-Hydroayatomoxetine-O-glucuronide
`Cm (rig/ml)
`Healthy
`Hepatic
`Healthy
`hepatic
`
`AUCGM (ughr/ml)
`
`1.681
`2.904
`0.003
`0.025
`
`276.2
`86.9
`3.034
`2.003
`
`1.73 (1.28, 2.34)
`
`7.88 (4.05, 15.3
`
`0.31 (0.22, 0.45)
`
`0.66 (0.54, 0.81)
`
`Table 6. Cumulative Amounts of Total (after Hydrolysis) Atomoxetine and Metabolites Excreted in
`Urine from 0-24 hours following a 20-mg Dose
`Compound (pg)
`Healthy (n=9)
`Child-Pugh B (n=5)
`Atomoxetine
`19.9 (1 12)
`45.8 (48)
`(”/0 of Dose)
`0.10
`0.23
`N-Desmethylatomoxetine 2.8 (143)
`0.31 (190)
`(% of Dose)
`0.015
`0.0017
`4-Hydroxyatomoxetine
`6830 (30)
`5430 (37)
`(% of D058)
`32.]
`25.6
`Total (°/o ofDose)
`32.3 (30)
`25.8 (37)
`
`Child-Pugh C (n=4)
`116 (64)
`0.58
`1.7 (76)
`0.009
`3750 (80)
`17.6
`18.2 (76)
`
`Table 7.1ndividual and Mean Clearance Values
`
`Group Subject
`Healthy
`
`0011
`
`Sorbilol
`CI.ss M,
`(ml/min)
`
`Debrisoquine
`Molar Metabolic
`Ratio in Urine
`
`Aiomoxetine
`CL/F
`(W)
`
`w. .
`001 2
`0013 W " “cm.
`0014
`
`0015
`0016
`0017
`
`0018
`0020
`0906
`
`Mean (%CV)
`Child-Pugh B
`0001
`0002
`0003
`
`0007
`0008
`0901
`
`W .
`uuwswfl'
`
`_
`
`M
`
`mm
`W “”7“” 7
`
`.
`
`....,
`
`.
`
`1380 (20)
`
`1.73 (188)
`
`41.5 (63)
`
`figfivimwvmamwwcw
`W“
`
`,
`
`wflcwwwm ,
`777' 7
`
`Mean (%CV)
`
`736 (36)
`
`7.68 (111)
`
`20.0 (52)
`
`125
`
`

`

`Sorbitol
`Debrisoquine
`A tomoxerine
`Group
`Subject
`Cl.“ M,
`Molar Metabolic
`CL/F
`
`Healthy
`(ml/min)
`Ratio in Urine
`(L/hr)
`
`Child—Pugh c
`0004
`0006
`
`WM V.r.ag~vum<wmwm‘ere=KW\—W .
`M ,
`“W“‘im" ‘
`‘-‘-~‘.._
`
`0009
`0010
`540 (32)
`Mean (°/oCV)
`' Debrisoquine PM phenotype (>12.6)
`
`"W
`
`WWWWW M _,
`
`18.7 (78)
`
`10.8 (80)
`
`Table 8. Relationships between Atomoxetine Parameters and Sorbitol or Debrisoquine Parameters
`
`Parameter
`Cmem and CL,”
`Clam” and Debrisoquine MR (Log-log)
`Atomoxetine Urine Ratio and Debrisoquine MR
`Atomoxetine MR and Debrisoquine MR
`
`Correlation
`0.8037
`-0.9248
`0.9435
`-0.l 164
`
`Population
`Hepatic
`All
`All
`All
`
`Su mmary
`
`a
`
`Single doses of 20-mg atomoxetine were well tolerated by healthy subjects and
`hepatic impairment (HI) patients with moderate-to severe liver disease (Child-Pugh B
`and C) and genotyped as CYP2D6 extensive metabolizers.
`
`0 Moderate to severe hepatic impairment (Child-Pugh Class B and C) is associated with
`a decrease in mean atomoxetine plasma protein binding (96.5 vs. 98.7% in healthy
`controls).
`
`0 Moderate to severe liver hepatic impairment (Child-Pugh B and C) results in a
`reduced atomoxetine clearance (41% and 31% of the normal, respectively), increased
`atomoxetine exposure (AUC, 166% and 387% of the normal, respectively), and a
`prolonged half-life of the parent drug (from 4.3 to 11 and 16 hours, respectively)
`compared to healthy controls with the same CYP2D6 EM genotype.
`0 Compared to healthy controls with the same CYP2D6 EM genotype, the following
`changes in the metabolites of atomoxetine were observed in H1 patients:
`N-desmethylatomoxetine mean Cm decreased, median Tm was delayed,
`4-hydroxyatomoxetine mean Cmax and mean AUCM increased,
`for the glucuronide conjugate of 4~hydroxyatomoxetine, the mean half-life was longer and mean
`AUCOM and Cm were lower.
`
`-
`-
`-
`
`0 The sponsor claims that the atomoxetine pharmacokinetic and cardiovascular changes
`noted in hepatic impairment (HI) patients are less than those exhibited by healthy
`subjects with poor metabolizer CYP2D6 genotypes; therefore, dosing with ADHD to
`those who also have identified liver disease of Child Pugh B or C is not likely to
`result in higher plasma concentrations of atomoxetine than PM subjects.
`
`B4Z-LE-LYAN (Vol. 72, Amendment Vol. 1-6): Phase I Study of LYI39603 in
`Healthy Adult Male Subjects: Single Dose Oral Administration Study (Dose
`Escalation), Multiple Oral Administration Study
`
`126
`
`

`

`Srudy Design
`
`The objectives of this study were to evaluate (1) the safety of atomoxetine administered
`as single oral doses (10, 40, 90 and 120 mg),
`the single dose pharmacokinetics of
`atomoxetine,
`4-hydroxyatomoxetine,
`and N-desmethylatomoxetine,
`and
`dose
`proportionality of atomoxetine in healthy Japanese adult men, and (2) the safety of
`atomoxetine administered as multiple oral doses (placebo, 40 mg or 60 mg, twice daily),
`and the multiple dose pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-
`desmethylatomoxetine in healthy Japanese adult men.
`
`Twenty-three male volunteers (CYP2D6 EM) in the Part A of the study (placebo-
`controlled, single-dose escalation) received a single doses of 10 mg, 30 mg 60 mg, 90 mg
`and 120 mg atomoxetine capsules with a minimum washout of 4 days between dosing.
`Twenty male subjects (all CYP2D6 BM) in the Part B of the study (multiple doses)
`received 40 mg or 60 mg of atomoxetine capsules, twice daily for up to 7 days. Placebo
`capsules
`(CT13981/CT17087),
`10-mg
`and
`20-mg
`atomoxetine
`capsules
`(CT15498/CT17086 and CT15499/CT17083) were used in this study. Blood and urine
`samples for drug concentration determination were collected after dosing and analyzed
`using a validated M"
`,
`‘ method.
`
`Pharmacokinetic Results
`
`Atomoxetine
`
`Table 1. Values of Single-Dose Atomoxetine Pharmacokinetic Parameters (Mean with CV%!
`Parameter
`10 mg (n=22)
`40 mg (n=21)
`90 mg (n=20)
`120 mg (n=l9)
`Cmax (mg/ml)
`110.5 (33)
`478.4 (34)
`920.0 (33)
`1086.2 (31)
`AUQH (pghr/ml)
`0.567 (71)
`2.50 (69)
`5.29 (54)
`6.42 (37)
`AUCO. (tight/ml)
`0.574 (70)
`2.51 (69)
`5.30 (54)
`6.43 (38)
`T,m (hr)
`1.25 (05-20)
`1.0 (0.54.0)
`1.75 (05-60)
`1.0 (0.54.0)
`Tm (hr)
`3.5 (1.9-6.6)
`4.1 (2.1-7.1)
`4.0 (2.2-7.0)
`4.3 (2.9-6.2)
`CL/F (Uhr/kg)
`0.377 (43)
`0.347 (47)
`0.337 (40)
`0.348 (39)
`V20: (L/kg)
`1.64 (26)
`1.83 (34)
`1.79 (31)
`2.06 (32)
`Median with range for Tm and mean with range for 11/2-
`
`Table 2. Dose Proporfionalitv Assessment from Power Model for Atomoxetine
`Parameter
`Dose
`Predicted
`Ratio of Dose
`90% C1
`
`DP‘
`
`DP
`
`Normalized GM
`
`ofRatio
`
`(10-120 mg)
`
`GM
`(mg)
`0.483
`10
`120 mg 0.677
`10 mg
`0.489
`120 mg 6.80
`10 mg
`105.5
`ll.l0 Unsure
`(0.75, 0.95)
`0.84
`120 mg 1067.2
`(mg/ml)
`' Dose propomonallty (DP) could be theoretically concluded for any dose rat1o less than this value.
`Since the
`clearances were similar in the single- and multiple-dose parts of the study, multiple dose information (AUCM was
`combined with the single-dose information (AUCo..).
`
`AUCM
`(ughr/ml)
`AUC"
`(tight/ml)
`
`Cm
`
`1.17
`
`1.16
`
`(1.22, 1.23)
`
`16.59 Yes
`
`(1.10, 1.22)
`
`19.33 Yes
`
`Cmax and AUC values in Table 1 generally increased proportionally with dose with CUF
`remaining relatively constant. Dose proportionality was concluded over the dosing range
`of 10 to 120 mg (lZ—fold range) for AUC but conclusion was uncertain for Cmax based on
`the results of the power model analysis. The proportional increase of AUC with dose as
`
`127
`
`

`

`well as remaining relative constant of clearance with dose in BM subjects supports the
`hypothesis of linear pharmacokinetics.
`
`lable 3. Comparison of *10/*10 Subjects versus Other EM Subiects for Cm, and AUC
`Parameter
`Dose
`Genotype
`Predicted
`Ratio
`90% Cl
`(mg)
`GM
`of Ratio
`10
`0.713
`(1.01, 2.57)
`0.442
`0.727
`0.448
`125.1
`101.6
`9.80
`5.26
`9.83
`5.27
`1270.8
`977.8
`
`AUCM
`(ugly/ml)
`AUG}.
`(ughr/ml)
`
`Cm
`
`(mg/ml)
`AUCM
`(ughr/ml)
`AUCo.
`(ughr/ml)
`
`Cm
`
`(ng/ml)
`
`120
`
`‘10/‘10(n=4)
`Other EMS (n=18)
`‘10/‘10(n=4)
`Other EMS (n=18)
`’10/‘10(n=4)
`Other EMS (n=18)
`’10/‘10(n=4)
`Other EMS (n=14)
`‘10/‘10(n=4)
`Other EMS (n=l4)
`‘10/‘10(n=4)
`Other EMS (n=14)
`
`1.61
`
`1.62
`
`1.23
`
`1.86
`
`1.87
`
`1.30
`
`(1.02, 2.58)
`
`(0.94, 1.62)
`
`(1.43, 2.44)
`
`(143, 2.44)
`
`(0.96, 1.76)
`
`p—Value
`‘
`
`0.092
`
`0.087
`
`0.205
`
`0.001
`
`0.001
`
`0.150
`
`The comparison of AUC and Cmax between *10/*10 homozygous and other EM subjects
`shows that there is evidence of a difference in mean concentrations between these two
`
`groups. It should be noted, however, that the concentration for *lO/*lO subjects falls in
`the range of concentrations for other EM subjects.
`
`Table 4. Values of Atomoxetine Pharmacokinetic Parameters after Multiple-Dose (Mean with CV%)
`Dose
`C,m
`Tm
`AUCM;
`AUCM
`Accumulation
`(mg)
`(ng/ml)
`(hr)
`(ughr/ml)
`(ughr/ml)
`Ratio
`First Dose
`Steady-Stale
`1.95 (38)
`1.25 (0.52.0)
`40 BID 427 (34)
`2.47 (42)
`3 14(42)
`1. 00 (1 .0-2.0)
`_6_0__BlD616 (32)
`3 73 (42)
`C55,.g
`1255......
`€55...“
`Flux
`(Hg/ml)
`(Hg/m1)
`(ng'ml)
`(%)
`205.9 (42)
`34.6 (95)
`40 BID 604 (35)
`292 (21)
`310.7 (42)
`59.1 (87)
`60 BID 874 (26)
`291 (38)
`Median with range for Tm and mean with range for tm.
`
`1.26 (9)
`____1_.»2§(8)
`CLSS/F
`(L/hr/kg)
`0.321 (50)
`0.292 (41)
`
`N—Desmethylatomoxetine
`Table 5. Values ofSingle—Dose N-Desmethflatomoxetine Pharmacokinetic Parameters
`Parameter
`,
`10 mg (n=16)
`40 mg (n=2l)
`90 mg (n=20)
`120 mg (n=19)
`Cm (mg/ml)
`3.9 (57)
`12.9 (86)
`24.2 (76)
`28.0 (72)
`AUC.)4 (ughr/ml)
`0.046 (141)
`0.182 (155)
`0.334 (130)
`0.345 (118)
`AUCo.(1lg.hr/ml)
`0.063 (1 16)
`0.197 (147)
`0.350 (126)
`0.360 (114)
`Tm (hr)
`2.0 (1 .0-8.0)
`2.0 (1 .0-12.0)
`2.0 (1.0-8.0)
`2.0 (1 06.0)
`Tm (hr)
`7.6 (22-154)
`6.3 (2.4-13.4)
`5.8 (2.7-10.8)
`5.8 (2.8-10.4)£é.f
`Data presented as Arithmetic Mean (CV%), Tm: Median (range), t. r21 Arithmetic Mean (range).
`
`128
`
`

`

`Table 6. Values of Desmethvlatomoxefine Pharmacokinetic Parameters after MultiEle-Dose
`Dose
`Cm
`Tm
`AUCm;
`AUCM
`Tm
`(mg)
`(Hg/ml)
`(hf)
`(fig-Wm!)
`(ugh/ml)
`(hr)
`First Dose
`Steady-State
`11.6 (85)
`0.194 (80)
`13.4 (60
`0.227 83
`Cssm
`Flux
`(fig/ml)
`(W
`20.2 (87)
`119 (29)
`27.3 (75)
`132 (40)
`
`40 BID (n=10)
`60 BID n=10
`
`40 BID
`60 BID
`
`3.0 (1.060)
`4.0 (1.5-12.0
`Cssmill
`(Hg/ml)
`6.4 (123)
`9.0 (115)
`
`0.108 (74)
`0.128 (64
`Css“g
`(fig/m1)
`16.2 (80)
`18.9 (83)
`
`1.5 (1.0-4.0)
`1.5 (1.0-4.0
`
`Data presented as Arithmetic Mean (CV%), Tm: Median (range), tm:.An‘thmetic Mean (range)
`
`4-Hydroxyatomoxetine
`Table 7. Values of Single-Dose 4-Hvdroxvatomoxetine Pharmacokinetic Parameters
`Parameter
`10 mg (n=18)
`40 mg (n=21)
`90 mg (n=20)
`120 mg (n=19)
`Cm (ng/ml)
`1.5 (28)
`4.7 (36)
`9.1 (38)
`11.2 (35)
`AUCm(ttg.hr/m1)
`0.002 (131)
`0.025 (52)
`0.065 (35)
`0.921 (37)
`AUCO. (pghr/ml)
`-
`0.036 (45)
`0.076 (30)
`0.103 (34)
`Tmu (hr)
`1.5 (1.0-2.0)
`1.5 (1.0-4.0)
`2.0 (1 .0—6.0)
`2.0 (1.0-6.0)
`Tn (hr)
`—
`5.1 (1.7-13.0)
`4.7 (3.1-8.0)
`4.7 (3.3-6.6)
`Data presented as Arithmetic Mean (CV%), Tm: Median (range), that Arithmetic Mean (range)
`
`Table 8. Values of 4oHVdroxyatomoxetine Pharmacokinetic Parameters after MultiEle-Dose
`D058
`C
`T
`AUCQ];
`AUCoq
`T
`
`(mg)
`
`(hr)
`
`(ugh/ml)
`
`(Hg-hr/ml)
`(neJml)
`Steady-State
`First Dose
`0.037 (27)
`-
`1.5 (1.0-4.0)
`40 BID (n=10) 4.5 (44)
`0.057 (23)
`0.037 (24)
`1.5 (1.0-4.0)
`60 BID (n=10) 5.6 (37)
`Flux
`Css"g
`Cssmin
`Cssm
`(W
`(mg/ml)
`(rig/ml)
`(rig/ml)
`152 (27)
`3.1 (27)
`1.3 (23)
`6.1 (37)
`40 BID
`171 (29)
`4.7 (23)
`1.9 (29)
`10.1 (35)
`60 BID
`Data presented as Arithmetic Mean (CV%), Tm: Median (range), tm: Arithmetic Mean (range)
`
`(hr)
`
`1.5 (1.0-4.0)
`1.5 (1 04.0)
`
`Urine Excretion
`Table 9. Cumulative Amounts of Atomoxetine and Metabolites Excreted in Urine in 24 Hours
`
`(Single-Dose)
`Compound
`Atomoxeline (ug)
`% ofDose
`
`10 mg (n=22)
`27.2 (83)
`0.27 (83)
`
`40 mg (n=21)
`78.3 (87)
`0.20 (88)
`
`90 mg (n=20)
`153 (143)
`0.17 143)
`
`120 mg (n=19)
`178 (92)
`0.15 (92)
`
`N-Desmelhylalomoxetine (pg)
`% ofDose
`
`0.85 (187)
`0.009 (187)
`
`4—Hydroxyallomoxerine ((ttg)
`% of Dose
`
`196 (36)
`1.84 (36)
`
`4—Hydroxyallomoxetine-O-Gluc (pg) 3904 (27)
`%ofDose
`36.7 (27)
`Total (% of Dose)
`38.9 (26)
`
`3.43 (148)
`0.009 (148)
`
`801 (28)
`1.88 (28)
`
`17072 (29)
`40.2 (29)
`42.3 (28)
`
`7.43 (195)
`0.009 (195)
`
`1609 (20)
`1.68 (20
`
`40021 (21)
`41.8 (21)
`43.7 (20)
`
`5.68 (89)
`0.005 (89)
`
`2274 (18)
`1.78 (18
`
`49757 (28)
`39.0 (28)
`41.0 (27)
`
`129
`
`

`

`Pharmacodynamic Evaluation
`CYP2D6 EM subjects experienced atomoxetine dose—related increases in their mean
`standing heart rate (HR) following single doses of atomoxetine, 10- to lZO-mg. A
`maximum mean HR increase to about 115 bpm was associated with the 90-mg dose. This
`represents a maximum increase of approximately 23 bpm above the placebo mean HR at
`the same time of day. A rise in HR began at 3 hours following a 10-mg dose, at 1 hour
`following a 40-mg dose and at 0.5 hour following a 90- or 120-mg dose.
`
`Table 10. Effects of Single Doses of Atomoxefine on Pharmacodvnamics
`Variable
`10 mg
`40 mg
`90 mg
`Standing HR (bpm)
`91.4
`100.1
`104.6
`Orthostatic HR Change (bpm)
`29.9
`35.4
`36.6
`Orthostatic SBP Change (mm Hg)
`-3.7
`—6.7
`-l 1.9
`Data represent Least Squares Means
`
`120 mg
`104.9
`34.6
`-13.3
`
`After multiple doses, statistical increases in mean standing HR were first seen in the 40-
`and 60-mg dose group 1 hour after on the 1" dosing day. For the remaining days,
`increases in mean standing HRS compared to placebo group were significant for all
`subjects in the 40 mg dose group but not for 60 mg dose group. EM subject mean
`standing HR increases appeared to reach a plateau at 47.5 hrs post first dose at about 90
`bpm in the 40-mg dose group, and at 23.5 hrs post first dose at about 81 bpm in the 60-
`mg dose group through to 143.5 hrs post first dose. Similarly, statistically significant
`increases in mean onhostatic HR were first seen in the 40- and 60-mg dose groups 1 hr
`after dosing, but were insignificant by the 2nd and 3rd hr following dosing. There were no
`significant changes in the mean orthostatic systolic blood pressure over the observation
`period.
`
`Summary
`‘
`
`Plrarmacokinetics
`Cmax and AUC generally increased proportionally with dose with clearance remaining
`relatively constant over the dose range studied.
`0 Accumulation at steady state in EM subjects was minimal and averaged 13-fold
`increase. There was no difference in apparent clearance between multiple dosing and
`single doses.
`substantially
`are
`atomoxetine
`0 Plasma
`concentrations of
`desmethylatomoxetine and 4-hydroxyatomoxetine concentrations.
`4-Hydroxyatomoxetine-O-glucuronide was the predominant metabolite observed in
`the urine. Over a 24 hour period, the measured analytes in the urine across all doses
`accounted for approximately 40% of the total dose in EM subjects.
`0 The *10/*10 homozygous EM subjects had higher mean exposure (Cam and AUC)
`than other EM subjects, however,
`their concenflations
`fall
`in the range of
`concentrations for other EM subjects.
`
`0
`
`0
`
`higher
`
`than N-
`
`Safety
`0 At a quantitative level, the frequency, severity and type of adverse events reported by
`*10/*10 homozygous Japanese subjects are indistinguishable from those reported by
`participants with other EM CYP2D6 genotypes.
`
`130
`
`

`

`All doses of atomoxetine were well tolerated. Two subjects in Part A and one subject
`in Part B were discontinued due to adverse events (nausea and dizziness after a 90 mg
`dose, nausea, orthostatic hypotension, and a mild pale bloodless feeling after a 40 mg
`dose, and urinary incontinence after a 60 mg dose of study drug), although considered
`slight (mild) in intensity.
`Single doses of atomoxetine between 10 and 120 mg resulted in increases in standing
`heart rate in CYP2D6 EM subjects. The magnitude of heart rate increase was not
`proportional to the atomoxetine dose increase.
`Multiple doses of 40-mg of atomoxetine, taken twice daily for 7 days, resulted in
`mean standing heart rate increases in CYP2D6 EM subjects.
`
`CYP2D6 EM subjects reached a plateau to the increases in standing heart rate during
`atomoxetine twice-daily dosing.
`Orthostatic changes in systolic blood pressure and heart rate were not clinically
`significant in CYP2D6 EM subjects.
`According to the sponsor, there was no evidence of a positive relationship between
`QTc interval length and dose, and none of the mean changes in QTc interval during
`atomoxetine treatment resulted in a QTc interval measurement above the normal limit
`for adult men (450 msec).
`
`Ethnic Comparison Report: Japanese Study LYAN and US Study HFBJ
`This report is for comparison of the study results for healthy Japanese subjects in Study
`LYAN with the results for healthy subjects in the US, Study HFBJ. The objectives are
`describe the relationship, if any, between known extensive metabolizer CYP2D6
`alleles and the pharmacokinetics of atomoxetine and the 4-hydroxyatomoxetine
`metabolite following single- and multiple-dose regimens of atomoxetine;
`dose proportionality of atomoxetine Cmax and AUC;
`safety and tolerability following single- and multiple-dose regimens of atomoxetine;
`effect of single and multiple oral doses of atomoxetine on the pharrnacodynamics of
`atomoxetine through repeated vital signs and orthostatic change measurements.
`
`Demographic Comparison
`Table 1. Demographic Comparison of Japanese (Study LYAN) and US (Study HFBJ) Subjects
`Demographic
`HFBJ
`LYAN
`Part A
`Part A
`
`Pan B
`
`Pan B
`
`# Subjects Enrolled
`Completed
`Age (yrs)
`Weight (kg)
`Gender (Male/Female)
`Ethnic Origin
`
`26
`23
`21
`27
`25
`19
`20
`25
`22.0 (20-26)
`23.7 (20-31)
`27.7 (19-40)
`28.5 (19-40)
`76.7 (55.8-107.5)76.4 (55.8-107.5)61.4 (49.9-82.8) 61.7 (49.7-81.8)
`14/13
`1 1/10
`23/0
`26/0
`22 Caucasian
`l7 Caucasian
`23 Japanese
`26 Japanese
`4 Hispanic
`3 Hispanic
`1 Native American 1 Native American
`
`CYP2D6 genotype (EM/PM) 16/11
`‘10 Homozygous
`
`14/7
`
`23/0
`4
`
`23/0
`5
`
`The primary differences (other than ethnic background) were the use of exclusively male
`subjects in Japan who also had relatively smaller body weight and a younger mean age
`
`131
`
`

`

`-
`
`a
`
`..
`
`. . -.
`
`I; ,_.L.'.l._‘|;‘-JfI.F.-..'-.’ .. ..
`
`-,
`
`'
`
`_.
`
`A
`
`.
`
`', ‘,
`
`,
`
`.
`
`4 s
`
`._
`
`.
`
`.
`
`s
`
`than the largely Caucasian subjects in Study HFBJ. However, no gender differences were
`found in the Caucasian population thus all EM subjects for Study HFBJ were included in
`the analysis. No PM subjects were identified in Study LYAN due to the extremely low
`frequency in the Japanese population.
`
`Table 2. CYP2D6 Classification Based on GenOMe and Gene Duplication
`CYP2D6
`CYP2D6 Genotype
`Duplication
`CY'P2D6
`
`Phenotype
`(allele / allele)
`Result
`Phenotype Subpopulations
`
`Poor Metabolizer
`defective ' / defective
`Irrelevant
`PM
`
`Extensive metabolizer
`
`wild type /wild type
`Wild type / wild type
`Defective / wild type
`‘2 e or 10 e / defective
`'2 or ‘10/ '2 or ’10
`
`Yes (’ZXN)
`No
`Irrelevant
`Irrelevant
`Irrelevant
`
`UM
`homozygous EM
`heterozygous EM
`IM
`IM
`
`EM = extensive metabolizer; [M = intermediate metabolizer; PM = poor metabolizer; UM = ultrarapid metabolizer. '
`Indicates any defective allele, which includes the following alleles: ‘3, ‘4, ‘5, ‘6, 7, 8. Gene duplication results in
`CYP2D6 UM. Gene duplication results (2xN) were not available for Study B4Z-LC HFBJ. Determinations of '2 and
`’l 0 alleles were not performed in Study HTBJ.
`
`Pharmacokinetic Results Comparison
`Table 1. Comparison of Pharmacokinetics between EM Subjects from Japan (Study LYAN) and the
`US (Study HFB_J)
`
`Parameter
`Dose
`Group Geometric Mean
`Ratio (90% CI)
`P-Value
`Atomoxetine
`
`
`_
`
`Cm (ng/ml)
`
`0.157 (mg/kg)
`
`95.33
`US
`106.78
`Japanese
`1.88 (mg/kg)
`US
`1211.19
`0.92 (0.79, 1.09)
`0.4224
`
`Japanese
`1120.01
`
`1.12 (0.94, 1.33)
`
`0.2707
`
`AUC (pghr/ml) 0.157 (mg/kg)
`
`0.52
`US
`0.49
`Japanese
`1.88 (mg/kg)
`US
`7.52
`0.91 (0.70, 1.17)
`0.5169
`
`Japanese
`6.82
`
`4-Hydroxyatomoxetine
`
`0.94 (0.73, 1.20)
`
`0.6621
`
`Cmax (rig/ml)
`
`0.631 (mg/kg)
`
`3.93
`US
`4.14
`Japanese
`1.88 (mg/kg)
`US
`9.98
`0.98 (0.80, 1.19)
`0.8343
`
`Japanese
`9.74
`
`1.05 (0.86, 1.29)
`
`0.6713
`
`AUC (pghr/ml) 0.631 (mg/kg)
`
`0.024
`US
`0.021
`Japanese
`0.0258
`0.76 (0.63, 0.93)
`0.11
`US
`1.88 (mg/kg)
`
`Japanese , 0.08
`
`0.87 (0.71, 1.06)
`
`0.2391
`
`None of the differences in geometric means (Cmax 8% to 12% and AUC 6% to 9%) tested
`statistically significant. Furthermore,
`the 90% confidence intervals
`indicate no
`differences that could be considered clinically relevant. The figure below shows the
`proportionality of Cmax and AUC to dose is similar in both groups of subjects. This data is
`also consistent with the proportionality data obtained in the integrated analysis of all US
`clinical pharmacology data.
`
`132
`
`

`

`Table 2. Cumulative Amounts of Atomoxetine and Metabolites Excreted in Urine from 0 to 24 hours
`
`following a Single 90-mg Dose for EM Subjects from Japan (Studv LYAN) and the US (Study HFBJ)
`Compound
`A
`N—Desmethyl-A 4-Hydroxy-A
`4-Hydroxy-A-0-Glucuronide
`Study HFBJ (n=15) (pg)
`151 (74)
`30 (98)
`1150 (34)
`56500 (27)
`(“/6 ofdose)
`0.17
`0.035
`1.20
`59.0
`Study LYAN (n=20) (pg) 153 (143)
`7.4 (195)
`1609 (20)
`40021 (21)
`(% of dose)
`0.17
`0.009
`1.68
`41.8
`
`Table 3. Atomoxetine Clearance Comparison among Different Metabolizers
`Study Homozygous EM
`Heterozygous EM
`lnterrnediate Metabolizer Poor Metabolizer
`HFJB 28.5:7.9(N=7,n=22)
`l9.3ilO.2(N=9,n=32) ND
`2.4:0.5(N=1i,n=37)
`LYAN 26.4:t8.2 (N=20,n=44)
`21.1:23 (N=5,n=20)
`14.7:7.2(N=16,n=37) NA
`12.51.27 (N=8, n=20, ‘lOI‘ 10 only)
`Homozygous EM included ‘lO/wild type, ‘leild type, or wild type/wild type (alleleJallele).
`Heterozygous EM included ‘3/wild type, ‘4/wild type, ’5/wild type, or ‘6/wild type (allele/allele).
`IM included '10/‘10, ‘2/‘10, or ‘5/‘2 (allele/allele).
`PM included ‘4/‘4, or ‘4/‘5 (allele/allele).
`
`Summary
`There is no clinically meaningful difference in the pharmacokinetics of atomoxetine
`and 4-hydroxyatomoxetine in Japanese and US population.
`The distribution of CL/F in EM subjects was similar afier single- and multiple- dose
`regimens of atomoxetine in the Japanese and US populations.
`The dose proportionality of atomoxetine was similar in both populations.
`The similar amount of unchanged atomoxetine and its primary metabolites excreted
`in the urine indicates that the metabolism and excretion of atomoxetine is the same in
`
`both Japanese and US subjects.
`
`CL/F in PM subjects of Study HFBJ was clearly distinct from the CUE in EM
`subjects. The variability of CL/F in EM subjects is higher as shown by the wide width
`of the distribution. The data from LYAN *10/*]0 homozygous EM subjects are
`distinguishable from other EM subjects.
`The safety and tolerance of atomoxetine administered as single oral doses (ranging
`from 10 mg to 120 mg) and multiple doses of 40 mg twice daily, were not different
`between Japanese (n=49 men) and US (n=27 predominantly Caucasian men and
`women) populations.
`The expected pharmacological effects of atomoxetine on the cardiovascular system,
`as measured by positional changes in vital signs, were not different between the
`Japanese and US populations.
`There was no evidence of QTc interval prolongation with the adminisuation of
`atomoxetine in either the Japanese and US populations.
`
`133
`
`

`

`Evaluation 01' Effects of Extrinsic Factors (DDl, Food)
`
`and Pharmacokinen'c
`73-74): Safety
`(Vol.
`B4Z—LC—HFBP
`Coadmim'steredAlomoxetine and Desipramine in Healthy Subjects
`
`Interaction of
`
`The objectives of this study were to evaluate
`(1) the PK of desipramine (CYP2D6 inhibitor) and atomoxetine when coadministration
`of these two drugs to healthy adults,
`(2) the safety of atomoxetine-desipramine coadministration when desipramine is given as
`a single dose,
`(3) the pharmacodynamic interaction of atomoxetine and desipramine by repeated
`measures of postural changes in blood pressure and heart rate, and
`(4) the tolerability of 60-mg twice-daily atomoxetine therapy.
`
`Twenty-two healthy subjects (11 males and 11 females) with CYP2D6 EM genotype
`participated in this open-label, sequential, 2—pen'od, drug interaction study. The study
`medications were atomoxetine capsules 30—, 40- and 60-mg oral dose twice-daily(10-mg,
`CT15503 and 20-mg, CT15502) for 13 consecutive days, desipramine 50-mg single oral
`dose (SO-mg tablet, Lot 3000251) taken alone followed by a washout period of up to 14
`days and given on the 4th atomoxetine dosing day. Morning doses of atomoxetine and
`desipramine were given after an overnight fast of at least 7 hours.
`
`Blood samples for desipramine were obtained prior to dosing, 0.5, 1, 2, 3, 4, 6, 8, 12, 24,
`48, 72, 96, 120, and 144 hours postdose in Period 1, and prior to dosing, then 0.5, 1, 2, 3,
`4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168, 192, and 216 hours postdose in Period 2.
`Blood samples for atomoxetine and its metabolites were taken on Study Day 3 and Day 4
`prior to dosing. then 0.5, 1, 2, 3, 4, 6, 8, and 12 hours postdose.
`
`
`
`Table 1. Values 03‘ Desi ramine Pharmacokinetic Parameters . lean with CV%
`
`AUCo.
`LS Mean
`(n .hr/ml
`AUCQ.
`698 (95)
`569
`740 (106)
`591
`0.96 (0.89, 1.04)
`
`Cm
`
`(11
`/ml)
`N=21
`18.3 (45)
`Alone
`19.2 (50)
`+Atomoxetine
`Ratio of LS Mean (90% CI)
`Tm(hr)
`6.0 (20-1200
`6.0 (2.0—12.0)
`
`Alone
`+Atomoxetine
`
`LS Mean
`Cm
`17.6
`18.1
`0.97 (0.87, 1.08)
`tmfilr)
`23.5 (7.9-52.5)
`24.5 (91.4-58.3)
`
`AUCO4
`(night/ml
`639 (88)
`699 (102)
`
`CUF (UN/kg)
`142 (95)
`144 (117)
`
`Vz/F (L)
`3340 (46)
`3490 (61)
`
`Table 2. Values of Atomoxetine Pharmacokinetic Parameters (Mean with CV%)
`
`AUCOJ
`C55":
`Csmin
`Cum“
`Tm“
`(Eghr/ml)
`(nggml)
`(ng /ml)
`(ng /ml)
`(111')
`N=21
`3.18 (85)
`265 (85)
`105 (138)
`552 (45)
`1.0 (05-40)
`A alone (n=6)
`3.47 (76)
`289 (76)
`110 (124)
`557 (48)
`1.0 (0.54.0)
`A+D (n=6)
`2.69 (57)
`224 (57)
`57 (97)
`591 (46)
`1.0 (05-20)
`A alone (n=15)
`3.01 (52)
`251 (52)
`64 (99)
`647 (35)
`1.0 (05.2.0)
`A+D (n=15)
`
`Ratio of LS Mean (90% CI) 0.87 (0.84, 0.91) 0.95 (0.86, 104)
`
`
`134
`
`

`

`
`
`
`CUF (Uhr) Vz/F (ng) CL/F (Uhr/kg) Vz/F (L)
`A alone (n=6)
`20.4 (6])
`0.327 (73)
`94.8 (41)
`1.48 (55)
`A+D (n=6)
`17.2 (57)
`0.270 (67)
`82.2 (29)
`1.25 (45)
`A alone (n=15)
`29.4 (55)
`0.399 (62)
`132 (42)
`1.76 (45)
`A+D (n=15)
`25.2 (50)
`0.343 (58)
`115 (45)
`1.57 (53)
`
`
`
`Each individual’s atomoxetine and desipramine parameters are highly correlated (Cmu,
`r2=0.537, AUC, r2=0.950). The high correlation can be explained by the fact that both of
`these compounds are primarily biotransformed by the same metabolic pathway, CYP2D6.
`This,
`in turn, suggests that
`the high intersubject variability seen for these CYP2D6
`substrate results from intrinsic differences in CYPZIE activity.
`
`PK Summary
`
`Coadministration of atomoxetine and desipramine, a selective CYP2D6 probe drug, wa