0.16** 0.16 ± 0.09 Testosterone 7α-hydroxylase
(nmol/min/mg protein) - 0.41 ±
0.03 - 0.35 ±
0.03 - 0.39 ±
0.04 - 0.46 ±
0.08 - 0.39 ±
0.07 - 0.54 ± 0.13*
Lauric acid 11-hydroxylase
(nmol/min/mg protein) 0.73 ±
0.08 0.75 ±
0.11 0.77 ±
0.20 0.65 ±
0.08 0.79 ±
0.14 0.70 ±
0.12 0.83 ±
0.07 0.72 ±
0.09 0.79 ±
0.08 0.73 ±
0.07 0.94 ±
0.13* 0.79 ± 0.11 Lauric acid 12-hydroxylase
(nmol/min/mg protein) 0.60 ±
0.18 0.55 ±
0.06 0.61 ±
0.14 0.37 ±
0.05 0.59 ±
0.18 0.49 ±
0.13 0.65 ±
0.08 0.49 ±
0.07 0.60 ±
0.09 0.57 ±
0.14 0.73 ±
0.16 0.51 ± 0.08 p-Nitrophenol-UDPGT
(µmol/hr/mg protein) 1.92 ±
0.15 1.24 ±
0.24 2.53 ±
0.82 1.44 ±
0.61 2.42 ±
0.70 1.49 ±
0.31 2.23 ±
0.66 1.31 ±
0.20 2.24 ±
0.21 1.17 ±
0.26 2.39 ±
0.38 1.67 ± 0.56 Mean ± SD (n=5), -: Not applicable, *:p < 0.05, **: p < 0.01 (vs control values, Williams' test), BLQ: Below limit of quantification
Testosterone 7α-hydroxylase: CYP2A1 1A1/2, Lauric acid 11-hydroxylase: CYP2E1, Lauric acid 12-hydroxylase: CYP4A1, UDP-glucuronyltransferase: UDPGT
2.6.5. 薬物動態試験概要表
2.6.5 - p. 51
2.6.5.12.1.2.2. イヌ
Test Article: Levocetirizine Location in CTD: 4.2.2.4.8
Report No.: RRLE97F0201 Species (Strain): Dog (Beagle) Gender/Number of Animals: Male, Female/4
Vehicle/Formulation: -/Gelatine capsule Method of Administration: Oral
Dose (mg/kg/day): Levocetirizine: 37.5, 75 Duration of dosing 13 weeks
Control Levocetirizine Dose (mg/kg/day)
0 37.5 75
Gender Male Female Male Female Male Female
Relative liver weights (g/100g bodyweight) 3.34 ± 0.43 2.98 ± 0.29 3.44 ± 0.45 3.04 ± 0.11 3.46 ± 0.11 3.73 ± 0.56**
Microsomal protein (mg/g liver) 25.5 ± 1.7 28.2 ± 1.4 26.5 ± 1.1 26.0 ± 1.1 25.3 ± 0.8 25.6 ± 2.0 CYP concentration (nmol/mg protein) 0.534 ± 0.054 0.560 ± 0.054 0.582 ± 0.058 0.454 ± 0.019 0.557 ± 0.040 0.528 ± 0.102 7-ethoxyresorufin O-deethylase
(nmol/min/mg protein) 0.137 ± 0.035 0.128 ± 0.068 0.155 ± 0.079 0.132 ± 0.051 0.152 ± 0.068 0.160 ± 0.051 Testosterone 2β-hydroxylase
(nmol/min/mg protein) 0.118 ± 0.036 0.090 ± 0.062 0.143 ± 0.021 0.047 ± 0.054 0.144 ± 0.022 0.066 ± 0.080 Testosterone 6β-hydroxylase
(nmol/min/mg protein) 0.513 ± 0.160 0.450 ± 0.119 0.530 ± 0.076 0.306 ± 0.128 0.491 ± 0.078 0.423 ± 0.114 Testosterone 16α-hydroxylase
(nmol/min/mg protein) 0.311 ± 0.049 0.372 ± 0.078 0.364 ± 0.098 0.381 ± 0.060 0.387 ± 0.073 0.409 ± 0.073 Testosterone 16β-hydroxylase
(nmol/min/mg protein) 0.023 ± 0.0 0.025 ± 0.070 0.030 ± 0.083 BLQ 0.029 ± 0.081 0.047 ± 0.005 Testosterone 17β-hydrogenase
(nmol/min/mg protein) 0.337 ± 0.087 0.370 ± 0.049 0.336 ± 0.104 0.349 ± 0.043 0.320 ± 0.059 0.339 ± 0.049 Lauric acid 11-hydroxylase
(nmol/min/mg protein) 0.424 ± 0.019 0.509 ± 0.039 0.466 ± 0.055 0.562 ± 0.047 0.470 ± 0.031 0.509 ± 0.040 Lauric acid 12-hydroxylase
(nmol/min/mg protein) 1.32 ± 0.20 1.26 ± 0.20 1.49 ± 0.19 1.37 ± 0.21 1.43 ± 0.18 1.31 ± 0.20 p-Nitrophenol-UDP-glucuronyltransferase
(µmol/hr/mg protein) 9.74 ± 1.83 7.37 ± 1.05 8.63 ± 0.67 7.91 ± 1.31 8.78 ± 1.50 8.28 ± 1.58 Mean ± SD (n=4), *: p<0.05, **: p<0.01 (vs control values, William’s test), BLQ: Below limit of quantification, 7-ethoxyresorufin O-deethylase: CYP1A, Testosterone 6β-hydroxylase: CYP3A, Testosterone 16α-hydroxylase: CYP2B, Lauric acid 11-hydroxylase: CYP2E, Lauric acid 12-hydroxylase: CYP4A
2.6.5. 薬物動態試験概要表
2.6.5 - p. 52
2.6.5.12.2. 酵素阻害
Test Article: Levocetirizine Location in CTD: 4.2.2.4.9
Report No.: RRLE98A2001
Test System: Human liver microsomes (from 3 individual donors)
Method: Human liver microsomes were incubated with Levocetirizine (100µM) at 37°C for 30min. CYP model substrates were used.
Result: ucb 28556 has no potential for interference with substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. This way also suggests that ucb 28556 is not a high affinity substrate for the CYP isozymes tested above.
CYP isozyme Enzyme activity Inhibition (%)
CYP1A2 7-ethoxyresorufin O-deethylase 0.2 ± 13.9
CYP2C9 Tolbutamide 4-hydroxylase 2.4 ± 4.9
CYP2C19 S-mephenytoin 4-hydroxylase 2.7 ± 4.9
CYP2D6 Bufuralol 1'-hydroxylase 5.3 ± 11.1
CYP2E1 Chlorzoxazone 6-hydroxylase -15.7 ± 11.4
CYP3A4 Testosterone 6β-hydroxylase 5.9 ± 5.4
Mean ± SD (n=3)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 53
2.6.5.13. 薬物動態試験：累積排泄 2.6.5.13.1. ラット
2.6.5.13.1.1. 単回投与
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.5.1
Report No.: RRLE97C0601 Species (Strain): Rat (SD)
Gender/Number of Animals: Male, Female, Pregnant (14th day of pregnancy)/5 Method of Administration: Oral
Vehicle/Formulation: Saline/Solution Dose (mg/kg): 2, 25
Sampling time (hr): Up to 168 Radionuclide: 14C Specific Activity (MBq/mg): -
Assay: LSC
2mg/kg
Recovery of radioactivity (% of administered radioactivity)
Male Female Pregnant #1
Sample collection period (hr post dose)
Urine Feces Total Urine Feces Total Urine Feces Total
0-8 3.0 ± 2.1 - - 20.3 ± 8.2 - - 26.9 ± 6.3 - -
0-24 10.1 ± 3.3 60.1 ± 12.8 - 30.1 ± 9.5 55.1 ± 12.3 - 33.6 ± 7.2 51.3 ± 14.0 - 0-48 11.5 ± 3.4 80.1 ± 12.7 - 31.9 ± 9.9 61.4 ± 13.3 - 35.7 ± 7.9 60.0 ± 13.6 - 0-72 11.9 ± 3.4 81.8 ± 12.8 - 32.5 ± 9.8 63.8 ± 10.3 - 36.1 ± 7.9 60.9 ± 13.9 - 0-96 12.2 ± 3.3 82.5 ± 12.6 - 32.7 ± 9.9 64.0 ± 10.3 - 36.4 ± 8.0 61.0 ± 14.0 -
0-120 12.3 ± 3.3 82.7 ± 12.5 - 32.8 ± 9.9 64.1 ± 10.3 - - - - 0-144 12.4 ± 3.3 82.7 ± 12.5 - 32.9 ± 9.9 64.2 ± 10.3 - - - - 0-168 12.5 ± 3.3 82.8 ± 12.5 - 33.0 ± 9.9 64.2 ± 10.3 - - - - Cage wash or debris 0.28 ± 0.13 21.0 ± 28.9 - 0.96 ± 0.68 1.85 ± 3.57 - 1.15 ± 1.45 11.15 #3 -
Total 12.8 ± 3.3 99.6 ± 14.7 112.4 ± 14.8 33.9 ± 9.5 65.7 ± 9.7 99.7 ± 4.3 37.6 ± 8.2 65.5 ± 7.9 103.1 ± 8.1 25mg/kg
0-168 17.3 ± 5.1 96.8 ± 15.1 - 64.0 ± 3.0 39.9 ± 4.1 - 59.2 ± 6.1 38.8 ± 4.4 - Total #2 - - 114.7 ± 10.6 - - 105.2 ± 2.1 - - 99.5 ± 3.3 Mean ± SD (n=5, #3: n=2), #1: up to 96hr, #2: with cage wash and debris, -: Not applicable
2.6.5. 薬物動態試験概要表
2.6.5 - p. 54
2.6.5.13.1.2. 反復投与
Test Article: Levocetirizine Location in CTD: 4.2.2.5.2
Report No: RRLE99G1201 Species (Strain): Rat (SD) Gender/Number of Animals: Male, Female/3 Method of Administration: Oral
Vehicle/Formulation: Distilled water/Solution
Dose (mg/kg/day): Levocetirizine: 18.7, 37.5, 75, Cetirizine: 37.5, 75 Dosing duration: 13 weeks
Analyte:
Assay: HPLC-chiral
Urinary excretion (% of dose) Compound Analyte Dose
(mg/kg/day) Gender
Week 1 Week 6 Week 13
Male 1.59 ± 1.11 4.45 ± 4.68 9.48 ± 6.21 18.7
Female 22.0 ± 3.1 20.2 ± 3.1 9.96 ± 8.37 Male 6.72 ± 2.10 15.7 ± 7.9 20.9 ± 4.0 37.5
Female 33.7 ± 9.3 28.3 ± 9.3 36.8 ± 15.3 Male 22.0 ± 4.0 24.8 ± 10.8 33.6 ± 3.4 Levocetirizine ucb 28556
75 Female 28.5 ± 9.9 40.5 ± 11.6 31.6 ± 8.7 Male 2.47 ± 2.59 8.65 ± 1.09 7.41 ± 2.90 37.5
Female 28.9 ± 7.8 28.6 ± 1.2 25.8 ± 11.4 Male 13.7 ± 3.17 20.6 ± 6.3 14.4 ± 5.9 ucb 28556
75 Female 26.0 ± 2.4 32.9 ± 6.0 27.2 ± 9.1 Male 0.98 ± 1.16 4.27 ± 0.94 3.56 ± 2.11 37.5
Female 23.0 ± 7.7 24.0 ± 1.7 21.9 ± 11.1 Male 9.40 ± 3.18 14.9 ± 4.2 9.44 ± 5.08 Cetirizine
75 Female 22.2 ± 1.6 31.2 ± 4.7 25.1 ± 7.5 Mean ± SD (n=3)
Excretion of ucb P071 was calculated as each enantiomer was 50% (18.7 and 37.5mg/kg/day).
2.6.5. 薬物動態試験概要表
2.6.5 - p. 55
ucb 28556, gsk002*
gsk002*
* 新薬承認情報提供時に置き換え
2.6.5.13.2. イヌ 2.6.5.13.2.1. 単回投与
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.5.3
Report No: RRLE99J1301 Species (Strain): Dog (Beagle) Gender/Number of Animals: Male, Female/1 or 3 Method of Administration: Oral
Vehicle/Formulation: Water/Solution Dose (mg/kg) 1
Radionuclide 14C
Specific activity (MBq/mg) 3.65
Analyte: Radioactivity Assay: LSC
Excretion (% of dose) Sample Sampling period (hr)
Male Female
Urine 0-24 19.86 ± 3.03 20.58 ± 4.12
Feces 0-24 18.22 ± 20.24 27.22 ± 17.74
Mean ± SD (n=3)
Excretion (% of dose)
B31 (Male) B49 (Female) B21 (Male) B44 (Female) Parameter
0-2hr 0-6hr 0-24hr 0-48hr
Urine 3.0 5.8 23.0 17.1
Feces NS NS 14.1 57.0
Cage wash NS NS 0.8 2.6
Debris NS NS 1.7 3.0
Subtotal 3.0 5.8 39.7 79.7
Gut and intestine #1 15.8 12.1 38.8 5.6
Tissues #2 89.0 78.7 20.5 3.6
Retention 104.8 90.8 59.3 9.2
Total 108 97 99 89
#1: including contents, #2: including whole blood, NS: No sample
2.6.5. 薬物動態試験概要表
2.6.5 - p. 56
2.6.5.13.2.2. 反復投与
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.5.3
Report No: RRLE99J1301 Species (Strain): Dog (Beagle)
Gender/Number of Animals: Male, Female/1 per time point Method of Administration: Oral
Vehicle/Formulation: Water/Solution Dose (mg/kg/day) 1
Dosing duration 9 days
Radionuclide 14C
Specific activity (MBq/mg) 3.65
Analyte: Radioactivity Assay: LSC
Excretion (% of dose)
B61 (Male) B48 (Female) B77 (Male) B68 (Female) Parameter
0-2hr 0-6hr 0-24hr 0-48hr
Urine 22.5 21.3 24.9 35.1
Feces 48.8 62.6 56.4 63.2
Cage wash 0.7 0.6 4.3 5.3
Debris 2.4 2.0 2.2 2.6
Subtotal 74.4 86.5 88.0 106.2
Gut and intestine #1 4.5 3.4 4.2 1.5
Tissues #2 14.3 10.7 2.3 1.4
Retention 18.8 14.1 6.5 2.9
Total 93 101 94 109
#1: including contents, #2: including whole blood
2.6.5. 薬物動態試験概要表
2.6.5 - p. 57
2.6.5.13.2.2 反復投与（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.5.3
Report No: RRLE99J1301 Species (Strain): Dog (Beagle)
Gender/Number of Animals: Male, Female/2 per time point Method of Administration: Oral
Vehicle/Formulation: Water/Solution Dose (mg/kg/day) 1
Dosing duration 9 days
Radionuclide 14C
Specific activity (MBq/mg) 3.65
Analyte: Radioactivity Assay: LSC
Excretion (% of dose)
Male Female Dosing (day)
Urine Feces Urine Feces
1 18.27 20.30 22.91 17.28
2 20.61 31.71 26.15 40.69
3 25.55 77.88 30.37 57.41
4 26.15 48.53 28.47 78.22
5 22.48 76.52 31.70 62.41
6 28.74 67.15 32.04 62.67
7 29.73 45.83 28.72 89.49
8 24.84 66.87 28.77 93.60
1-8 24.54 54.35 28.64 62.72
9 #1 32.66 77.90 45.81 96.02
Mean (n=2, #1: n=1), Sampling period: 0-24hr
2.6.5. 薬物動態試験概要表
2.6.5 - p. 58
2.6.5.13.2.2. 反復投与（続き）
Test Article: Levocetirizine Location in CTD: 4.2.2.5.4
Report No.: RRLE95F0202 Species (Strain): Dog (Beagle) Gender/Number of Animals: Male, Female/2-4
Vehicle/Formulation: -/Gelatine capsule Method of Administration: Oral
Dose (mg/kg/day):
Dosing duration: Male: 29 days, Female: 18 days
Assay: HPLC-chiral
Urinary excretion (% dose) ucb 28556
Day 1 Day 29 Day 18 Day 1 Day 29 Day 18 Compound Dose
(mg/kg/day)
Male Female Male Female Male Female Male Female 33.75 18.9 ± 9.3 15.4 ± 1.7 44.5 ± 20.3 39.4 ± 4.3 ND ND ND ND
67.5 27.8 ± 8.0 23.0 35.5 36.5 ± 8.7 ND ND ND ND Levocetirizine
135/90 #1 8.7 ± 4.7 9.5 ± 1.7 30.6 ± 8.5 47.2 ND ND ND ND Cetirizine 135/90 #1 8.9 ± 3.6 11.4 ± 5.8 32.4 ± 8.7 28.7 ± 6.3 10.6 ± 4.3 12.7 ± 5.8 35.0 ± 9.4 31.5 ± 6.8
33.75 ND ND ND ND 21.5 ± 11.5 28.5 ± 18.7 37.3 ± 1.6 31.1 ± 13.4 67.5 ND ND ND ND 13.9 ± 5.5 15.1 ± 9.4 35.2 ± 12.4 37.9 (dihydrochloride)
135 ND ND ND ND 14.4 ± 6.0 13.7 ± 5.9 23.0 ± 5.2 39.0 ± 11.8 Mean ± SD (n=2-4), ND: Not determined
#1: In animals receiving Levocetirizine and Cetirizine, due to severe clinical signs (emesis, salivation and tremors), the high dose level was reduced to 90mg/kg/day from Day 11 in females and from Day 18 in males.
2.6.5. 薬物動態試験概要表
2.6.5 - p. 59
Levocetirizine: 33.75, 67.5, 135/90, Cetirizine: 135/90, gsk002* (dihydrochloride): 33.75, 67.5, 135
gsk002*
gsk002*
* 新薬承認情報提供時に置き換え
2.6.5.14. 薬物動態試験：胆汁中排泄 2.6.5.14.1. 単回投与
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.5.3
Report No.: RRLE99J1301 Species (Strain): Dog (Beagle) Gender/Number of Animals: Male, Female/1
Vehicle/Formulation: Water/Solution Method of Administration: Oral
Dose (mg/kg): 1 Radionuclide: 14C Specific Activity (MBq/mg): 3.65
Assay: LSC
Animal No. B31 (Male) B49 (Female) B21 (Male) B44 (Female)
Sampling time (hr) 2hr 6hr 24hr 48hr
Concentration in bile (% of dose) 5.58 9.72 1.13 0.32
n=1 per time point
2.6.5. 薬物動態試験概要表
2.6.5 - p. 60