Test Article: Levocetirizine Location in CTD: 4.2.2.2.3
Report No: RRLE92G0902 Species (Strain): Rat (SD)
Gender/Number of Animals: Male, Female/2 per time point Feeding condition: Fed
Method of Administration: Oral
Vehicle/Formulation: Distilled water/Solution Dose (mg/kg/day): 4, 8, 25, 75
Dosing duration: 13 weeks
Sample: Plasma
Analyte: ucb 28556
Assay: Gas liquid chromatography-achiral
Gender Dose (mg/kg/day) Cmax (µg/mL) tmax (hr) AUC0-24 (µg･hr/mL)
4 1.71 1.5 3.08 8 5.48 3.0 32.5 25 21.2 1.5 107 Male
75 72.5 1.5 441 4 1.23 1.5 1.98 8 3.55 1.5 10.6 25 16.6 1.5 46.8 Female
75 89.0 1.5 386 Each value was calculated by mean (n=2 per time point)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 11
2.6.5.4. 薬物動態試験：反復投与後の吸収（続き）
Test Article: Levocetirizine Location in CTD: 4.2.2.2.4
Report No: RRLE99G1201 Species (Strain): Rat (SD)
Gender/Number of Animals: Male, Female/2 per time point Feeding condition: Fed
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
Sample: Plasma Analyte:
Assay: HPLC-chiral
ucb 28556 Compound Dose
(mg/kg/day) Gender Cmax
(µg/mL)
tmax
(hr)
AUC0-12
(µg･hr/mL)
Cmax
(µg/mL)
tmax
(hr)
AUC0-12
(µg･hr/mL)
Male 14.1 3.0 68.4 ND NC NC
18.7
Female 17.1 1.5 41.8 ND NC NC
Male 39.3 1.5 160 ND NC NC
37.5
Female 30.8 1.5 108 ND NC NC
Male 63.0 1.5 405 ND NC NC
Levocetirizine
75 Female 56.9 3.0 481 ND NC NC
Male 12.1 3.0 57.5 3.19 1.5 13.1
37.5
Female 19.3 1.5 57.1 5.99 1.5 15.7
Male 30.6 1.5 200 10.5 1.5 54.5
Cetirizine
75 Female 55.3 1.5 251 13.1 1.5 56.0
Each value was calculated by mean (n=2 per time point), ND: Not determined, NC: Not calculated
2.6.5. 薬物動態試験概要表
2.6.5 - p. 12
ucb 28556, gsk002*
gsk002*
* 新薬承認情報提供時に置き換え
2.6.5.4. 薬物動態試験：反復投与後の吸収（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.2.5
Report No: RRLE99J1301 Species (Strain): Dog (Beagle) Gender/Number of Animals: Male, Female/2-4 Feeding Condition: Fasted
Method of Administration: Oral
Vehicle/Formulation: Water /Solution Dose (mg/kg/day): 1
Dosing duration: 8 days
Radionuclide: 14C
Specific activity (MBq/mg): 3.65
Sample: Plasma Analyte: Radioactivity, ucb 28556
Assay: LSC, HPLC-achiral
Single Repeat (Day 8)
Radioactivity ucb 28556 Radioactivity ucb 28556 PK Parameters
Male Female Male Female Male Female Male Female
Cmax (µg/mL) 2.88 ± 0.71 #1, 2 2.25 ± 0.60 #1, 2 2.83 ± 0.66 #1 2.25 ± 0.60 #1 3.40 #2 2.57 #2 3.40 2.53 tmax (hr) 1.5 ± 0.58 #1 2.8 ± 1.5 #1 2.0 ± 1.4 #1 2.8 ± 1.5 #1 4.0 2.0 4.0 2.0
AUC0-∞ (µg･hr/mL) NC NC 42.60 27.85 NC NC 50.50 39.90
t1/2 (hr) NC NC 6.84 8.84 NC NC 9.46 8.29
Mean (n=2), #1: Mean ± SD (n=4)
#2: µg eq./mL for Cmax, NC: Not calculated
2.6.5. 薬物動態試験概要表
2.6.5 - p. 13
2.6.5.4. 薬物動態試験：反復投与後の吸収（続き）
Test Article: Levocetirizine Location in CTD: 4.2.2.2.6
Report No: RRLE92G1003 Species (Strain): Dog (Beagle) Gender/Number of Animals: Male, Female/4 Feeding condition: Fed
Method of Administration: Oral
Vehicle/Formulation: -/Gelatin capsule Dose (mg/kg/day): 8, 25, 75
Dosing duration: 13 weeks
Sample: Plasma
Analyte: ucb 28556
Assay: Gas liquid chromatography-achiral
Sampling time Gender Dose (mg/kg/day)
Cmax
(µg/mL)
tmax
(hr)
AUC0-24
(µg･hr/mL)
8 15.4 ± 1.5 1.5 ± 0.0 124 ± 18
25 37.3 ± 7.2 1.5 ± 0.0 295 ± 53
Male
75 85.5 ± 27.5 1.9 ± 0.8 818 ± 340
8 18.3 ± 5.9 1.5 ± 0.0 105 ± 22
25 40.4 ± 14.0 1.5 ± 0.0 320 ± 35 Day 1
Female
75 117.1 ± 15.5 1.5 ± 0.0 1027 ± 154
8 18.8 ± 7.5 1.9 ± 0.8 194 ± 70
25 83.3 ± 33.8 1.9 ± 0.8 822 ± 241 Male
75 188.6 ± 19.4 1.5 ± 0.0 2379 ± 330
8 25.1 ± 6.3 1.5 ± 0.0 188 ± 46
25 74.0 ± 17.1 1.9 ± 0.8 795 ± 149 Week 13
Female
75 145.7 ± 17.2 1.9 ± 0.8 1934 ± 333 #1 Mean ± SD (n=4)
#1: Emesis before sampling after dosing (n=1)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 14
2.6.5.4. 薬物動態試験：反復投与後の吸収（続き）
Test Article: Levocetirizine Location in CTD: 4.2.2.2.7
Report No: RRLE97F0201 Species (Strain): Dog (Beagle) Gender/Number of Animals: Male, Female/4 Feeding condition: Fed
Method of Administration: Oral
Vehicle/Formulation: -/Gelatin capsule Dose (mg/kg/day): Levocetirizine: 37.5, 75, Cetirizine: 75 Dosing duration: 13 weeks
Sample: Plasma Analyte:
Assay: HPLC-chiral ucb 28556
Sampling
time Compound Dose
(mg/kg/day) Gender Cmax
(µg/mL) tmax
(hr)
AUC0-24
(µg･hr/mL) Cmax
(µg/mL) tmax
(hr)
AUC0-24
(µg･hr/mL)
Male 45.9 ± 18.4 1.9 ± 0.8 352 ± 81 ND NC NC 37.5
Female 47.0 ± 5.8 1.5 ± 0.0 386 ± 39 ND NC NC Male 66.5 ± 22.6 1.9 ± 0.8 643 ± 203 ND NC NC Levocetirizine
75 #1
Female 65.7 ± 30.4 1.5 ± 0.0 631 ± 425 ND NC NC Male 34.9 ± 11.5 1.9 ± 0.8 378 ± 173 27.9 ± 9.6 1.9 ± 0.8 385 ± 166
Day 1
Cetirizine 75 #1
Female 36.4 ± 8.9 2.3 ± 0.9 406 ± 170 30.6 ± 9.6 2.3 ± 0.9 400 ± 163
Male 70.6 ± 23.0 1.9 ± 0.8 846 ± 236 ND NC NC 37.5
Female 65.6 ± 18.0 1.5 ± 0.0 810 ± 133 ND NC NC Male 122 ± 14 2.6 ± 0.8 1680 ± 202 ND NC NC Levocetirizine
75 Female 141 ± 40 1.9 ± 0.8 1655 ± 342 ND NC NC Male 56.3 ± 11.2 4.1 ± 3.3 937 ± 170 53.6 ± 9.4 4.1 ± 3.3 887 ± 159
Week 13
Cetirizine 75
Female 54.1 ± 18.6 3.4 ± 1.9 822 ± 269 47.6 ± 16.2 3.4 ± 1.9 724 ± 242 Mean ± SD (n=4), ND: Not determined, NC: Not calculated
#1: Emesis before sampling after dosing (n=1/sex)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 15
ucb 28556, gsk002*
gsk002*
* 新薬承認情報提供時に置き換え
2.6.5.5. 薬物動態試験：分布
2.6.5.5.1. 組織内分布
2.6.5.5.1.1. ラット
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.1
Report No.: RRLE95H0901 Species (Strain): Rat (SD)
Gender/Number of Animals: Male/1 per time point
Vehicle/Formulation: Saline/Solution Method of Administration: Oral
Dose (mg/kg): 2 Radionuclide: 14C Specific Activity (MBq/mg): 4.33
Sampling time (hr): 0.5, 1, 2, 4, 8, 12, 24, 48, 96, 168 Assay: LSC
Concentration (µg eq./g or mL) Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Blood plasma 0.999 0.177 0.176 0.164 0.074 0.088 0.069 0.052 < 2BG < BG Whole blood 0.674 0.129 0.186 0.113 0.087 0.075 0.089 0.084 < 2BG 0.037
Liver 14.786 6.350 3.701 1.885 0.609 0.505 0.303 0.158 0.347 0.021
Kidneys 5.990 1.210 1.481 0.755 0.251 0.254 0.193 0.142 0.166 0.014 Lungs 1.410 0.262 0.338 0.145 0.096 0.069 0.053 0.043 0.049 < 2BG Spleen 0.553 0.239 0.156 0.066 0.047 0.037 0.036 < 2BG 0.042 < BG Heart 1.004 0.144 0.128 0.072 0.038 0.034 < 2BG < 2BG 0.039 < BG Thymus 0.354 0.099 0.105 0.044 0.033 < 2BG < 2BG 0.087 < 2BG < BG Cerebrum 0.053 < 2BG 0.044 < 2BG < 2BG < 2BG < BG < BG 0.035 < BG Cerebellum 0.056 < 2BG 0.042 0.020 0.020 0.013 < 2BG < BG 0.037 < 2BG Salivary glands 0.632 0.142 0.146 0.073 0.042 0.052 0.034 < 2BG 0.020 < BG n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 16
2.6.5.5.1.1. ラット（続き）
Test Article: 14C-Levocetirizine Concentration (µg eq./g or mL)
Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Trachea 3.437 0.339 0.234 0.063 0.053 0.042 0.023 < 2BG 0.044 < BG Gonads 0.084 0.061 0.069 0.036 < 2BG < BG < 2BG < BG 0.040 < BG Adrenals 1.214 0.323 0.337 0.133 0.150 0.096 < 2BG < 2BG 0.103 < 2BG Thyroid 1.818 < 2BG < 2BG < BG < BG < BG < BG < BG < BG < BG Pituitary 1.014 < BG < BG < BG < BG < BG < BG < BG < BG < BG Eyes 0.406 0.100 < 2BG 0.093 < 2BG < 2BG < 2BG < 2BG < BG < BG Vitreous + aqueous humour 0.637 < BG < BG < BG < 2BG < BG < BG < 2BG < BG < 2BG Lens < 2BG < BG < BG < BG < BG < BG < BG < BG < BG < BG Spinal cord 0.227 0.032 0.053 0.026 0.030 < 2BG < 2BG < 2BG 0.059 < BG Bone marrow 0.760 0.189 < 2BG < 2BG < 2BG < BG 0.674 < BG < 2BG < BG Muscle 0.344 0.077 0.077 0.032 < 2BG 0.030 < 2BG < BG 0.015 < BG Adipose tissue 0.145 0.126 0.098 < 2BG 0.067 0.131 < 2BG < 2BG 0.061 < BG Skin 0.220 0.086 0.094 0.060 0.053 < 2BG < 2BG < 2BG 0.024 < BG Fur 0.206 0.038 0.032 0.043 < 2BG < 2BG 0.047 0.030 0.049 < 2BG Carcass 0.138 0.051 0.051 0.021 0.017 0.112 0.062 0.010 < BG < BG n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 17
2.6.5.5.1.1. ラット（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.1
Report No.: RRLE95H0901 Species (Strain): Rat (SD)
Gender/Number of Animals: Female/1 per time point Vehicle/Formulation: Saline/Solution Method of Administration: Oral
Dose (mg/kg): 2 Radionuclide: 14C Specific Activity (MBq/mg): 4.33
Sampling time (hr): 0.5, 1, 2, 4, 8, 12, 24, 48, 96, 168 Assay LSC
Concentration (µg eq./g or mL) Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Blood plasma 0.457 0.202 0.411 0.084 < 2BG 0.065 < BG < BG < BG < BG Whole blood 0.334 0.163 0.327 0.112 0.083 0.082 < 2BG 0.114 0.092 < BG
Liver 4.838 2.317 3.089 0.896 0.345 0.276 0.161 0.056 0.029 0.013
Kidneys 2.631 1.027 1.867 0.564 0.255 0.256 0.146 0.037 0.073 0.024 Lungs 0.861 0.233 0.632 0.332 0.161 0.283 0.140 < 2BG < 2BG < 2BG Spleen 0.292 0.111 0.308 0.172 0.106 0.129 0.139 < 2BG 0.016 < 2BG Heart 0.429 0.153 0.348 0.077 0.052 0.048 0.047 < BG < 2BG < BG Thymus 0.186 0.085 0.274 0.095 0.056 0.064 0.078 < BG < BG < BG Cerebrum < 2BG < 2BG 0.057 0.066 0.035 0.034 0.042 < BG < BG < BG Cerebellum 0.038 < 2BG 0.051 0.042 0.033 0.027 0.036 < BG < BG < BG Salivary glands 0.306 0.137 0.292 0.102 0.059 0.051 0.075 < 2BG < BG < 2BG n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 18
2.6.5.5.1.1. ラット（続き）
Test Article: 14C-Levocetirizine Concentration (µg eq./g or mL)
Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Trachea 0.266 0.139 0.466 0.091 < 2BG 0.053 0.070 < BG < BG < BG Gonads 0.245 0.115 0.338 0.159 0.095 0.083 0.092 < 2BG < BG < 2BG Adrenals 0.580 0.219 0.611 0.200 0.164 0.153 0.184 < 2BG < BG < BG Thyroid 0.480 < BG 0.955 < BG < BG < BG < BG < BG < BG < BG Pituitary 0.417 < BG < 2BG 0.509 < BG < BG < BG < BG < BG < BG Eyes 0.124 0.087 0.459 < 2BG < 2BG < BG < 2BG < BG < BG < BG Vitreous + aqueous humour < 2BG < BG 0.341 0.069 < BG < BG < 2BG < BG < BG < 2BG Lens < BG < BG < 2BG < BG < BG < BG < BG < BG < BG < BG Spinal cord 0.060 < 2BG 0.059 0.112 0.043 0.038 0.044 < BG < 2BG < BG Bone marrow 0.301 < 2BG 1.081 2.166 < BG < 2BG < BG < BG < BG < BG Muscle 0.150 0.137 0.228 0.094 0.033 0.043 < 2BG < BG < BG < BG Adipose tissue 0.064 0.063 0.117 0.112 0.106 0.409 < 2BG < BG < BG < BG Skin 0.146 0.083 0.193 0.057 0.072 0.037 < 2BG < BG < 2BG < 2BG Fur 0.043 0.111 0.055 0.115 0.057 0.056 0.045 < 2BG 0.014 0.036 Carcass 0.055 0.033 0.062 0.027 0.025 0.020 0.015 0.006 0.002 0.004 n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 19
2.6.5.5.1.1. ラット（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.1
Report No.: RRLE95H0901 Species (Strain): Rat (SD)
Gender/Number of Animals: Male/1 per time point
Vehicle/Formulation: Saline/Solution Method of Administration: Oral
Dose (mg/kg): 25 Radionuclide: 14C Specific Activity (MBq/mg): 4.33
Sampling time (hr): 0.5, 1, 2, 4, 8, 12, 24, 48, 96, 168 Assay: LSC
Concentration (µg eq./g or mL) Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Blood plasma 6.036 10.402 14.602 3.581 1.017 1.206 0.700 0.595 < BG < BG Whole blood 4.318 7.435 9.337 2.769 0.968 1.089 0.794 0.755 < 2BG < 2BG Liver 87.561 111.924 148.607 50.346 9.884 9.674 4.221 2.637 0.796 0.288 Kidneys 38.291 62.805 65.012 23.942 6.401 3.710 2.225 1.506 0.310 0.238 Lungs 7.417 12.441 17.612 6.244 3.513 1.886 0.780 0.407 0.119 < 2BG Spleen 3.800 6.276 10.380 3.715 1.731 1.074 0.474 0.410 < BG < BG Heart 6.523 11.690 14.668 3.790 0.904 0.682 < 2BG < 2BG < BG < BG Thymus 2.235 4.884 7.749 2.929 1.052 0.767 < 2BG < 2BG < BG < BG Cerebrum < 2BG 0.754 1.336 0.982 0.753 0.512 < 2BG < BG < 2BG < 2BG Cerebellum 0.485 0.800 1.141 0.936 0.556 0.455 < 2BG < 2BG < 2BG < BG Salivary glands 4.563 3.193 9.718 3.771 1.013 0.933 0.465 < 2BG < BG 0.503 n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 20
2.6.5.5.1.1. ラット（続き）
Test Article: 14C-Levocetirizine Concentration (µg eq./g or mL)
Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Trachea 6.079 6.180 9.022 4.009 0.962 0.762 0.486 < 2BG < BG < BG Gonads 0.636 1.635 2.988 2.093 1.104 0.810 0.508 < 2BG < BG < 2BG Adrenals 9.762 12.541 18.181 8.902 3.520 2.170 1.205 < 2BG < BG < 2BG Thyroid 12.436 11.423 15.434 6.175 < 2BG < 2BG < BG < BG < BG < BG Pituitary 14.014 13.188 0.554 < 2BG < 2BG < BG < BG < BG < BG < BG Eyes 2.559 3.866 8.563 2.351 1.261 1.065 < 2BG < BG < BG < BG Vitreous + aqueous humour < BG < 2BG 3.960 < 2BG < 2BG < 2BG < BG < BG < BG < BG Lens < BG < BG NV < BG < BG < BG < BG < BG < BG < BG Spinal cord 0.524 0.874 1.764 1.198 0.722 0.645 0.629 < 2BG < BG < 2BG Bone marrow 6.896 9.517 16.037 4.761 2.447 < BG < BG < BG < BG < BG Muscle 1.958 4.366 3.919 2.169 0.491 < 2BG < 2BG < BG < BG < BG Adipose tissue 3.936 1.890 2.790 1.561 1.119 0.896 < 2BG < 2BG < BG < BG Skin 1.725 3.894 5.413 1.966 0.633 0.496 < 2BG < 2BG < 2BG < BG Fur 0.706 2.054 0.558 16.312 0.403 0.399 < BG 0.599 0.251 0.290 Carcass 0.820 1.777 2.486 0.845 0.235 0.212 0.416 0.092 0.027 0.011 n=1 per time point
< BG: counting values were under the BG value (25dpm), NV: No value
2.6.5. 薬物動態試験概要表
2.6.5 - p. 21
2.6.5.5.1.1. ラット（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.1
Report No.: RRLE95H0901 Species (Strain): Rat (SD)
Gender/Number of Animals: Female/1 per time point Vehicle/Formulation: Saline/Solution Method of Administration: Oral
Dose (mg/kg): 25 Radionuclide: 14C Specific Activity (MBq/mg): 4.33
Sampling time (hr): 0.5, 1, 2, 4, 8, 12, 24, 48, 96, 168 Assay LSC
Concentration (µg eq./g or mL) Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Blood plasma 22.931 18.023 10.732 5.184 2.749 < 2BG 0.604 < BG < BG < BG Whole blood 18.525 12.249 9.303 4.125 1.986 < 2BG 0.475 < 2BG < 2BG < 2BG Liver 144.107 90.421 91.237 45.571 17.270 6.666 1.603 0.511 0.262 < 2BG Kidneys 116.190 88.528 90.376 30.429 11.772 4.237 1.507 0.573 0.287 < 2BG Lungs 24.786 21.535 12.151 7.695 6.255 3.052 0.666 < 2BG < 2BG < BG Spleen 16.359 11.073 8.033 5.447 3.289 1.744 0.539 < BG < BG < BG Heart 24.979 20.134 12.709 5.704 2.779 0.822 < 2BG < BG < BG < BG Thymus 9.002 8.087 6.471 3.722 2.410 0.927 < 2BG < BG < BG < BG Cerebrum 1.045 1.011 0.921 0.793 0.965 0.385 < BG < BG < BG < BG Cerebellum 1.095 1.247 0.893 0.752 0.716 0.439 < 2BG < BG < BG < BG Salivary glands 18.294 15.630 11.187 5.576 2.192 1.008 < 2BG < BG < BG < BG n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 22
2.6.5.5.1.1. ラット（続き）
Test Article: 14C-Levocetirizine Concentration (µg eq./g or mL)
Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr 96hr 168hr
Trachea 14.331 11.955 8.405 3.860 2.408 < 2BG < 2BG < BG < BG < BG Gonads 13.673 11.628 5.229 4.050 2.528 1.535 0.552 < 2BG < BG < BG Adrenals 37.496 28.306 22.286 9.051 5.486 2.499 < 2BG < 2BG < BG < 2BG Thyroid 29.494 24.594 18.244 7.352 < 2BG < 2BG < BG < BG < BG < BG Pituitary 43.746 26.343 21.599 < 2BG < 2BG < BG < BG < BG < BG < BG Eyes 8.854 7.580 5.674 3.211 1.780 0.801 < BG < 2BG < BG < BG Vitreous + aqueous humour < 2BG 1.459 1.968 < 2BG < BG < BG < BG < BG < BG < BG Lens NV < BG < BG < BG < BG < BG < BG < BG < BG < BG Spinal cord 1.174 1.301 0.997 0.558 0.952 0.590 < BG < BG < BG < BG Bone marrow 31.813 15.870 16.378 7.711 < 2BG < BG < BG < BG < BG < BG Muscle 8.864 8.267 5.360 3.801 1.459 0.635 < BG < BG < BG < BG Adipose tissue 5.617 2.656 13.825 2.044 1.278 < 2BG < 2BG < BG < BG < BG Skin 7.444 6.016 4.233 2.520 1.258 0.851 < 2BG < BG < BG < 2BG
Fur 0.884 1.104 0.982 1.403 0.880 17.883 0.466 1.145 0.235 0.205
Carcass 3.066 2.674 2.172 1.166 0.546 0.236 0.874 0.044 0.040 0.057 n=1 per time point
< BG: counting values were under the BG value (25dpm), NV: No value
2.6.5. 薬物動態試験概要表
2.6.5 - p. 23
2.6.5.5.1.2. イヌ
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.2
Report No.: RRLE99J1301 Species (Strain): Dog (Beagle)
Gender/Number of Animals: Male, Female/1 per time point Vehicle/Formulation: Water/Solution Method of Administration: Oral
Dose (mg/kg): 1 Radionuclide: 14C Specific Activity (MBq/mg): 3.65 Sampling time (hr): 2, 6, 24, 48
Assay LSC
Concentration (µg eq./g or mL) Tissues
2hr (Male) 6hr (Female) 24hr (Male) 48hr (Female)
Blood plasma 1.778 2.595 0.598 0.100
Whole blood 1.452 1.687 0.388 0.059
Adrenals 0.985 0.901 0.423 0.083
Aqueous humor + vitreous body 0.139 0.080 0.042 < 2BG
Bile 97.546 146.337 31.397 9.847
Bladder 1.235 1.255 0.302 0.057
Bone marrow 0.418 0.538 0.120 < 2BG
Brain stem 0.222 0.266 0.193 0.047
Cerebellum 0.203 0.229 0.129 0.030
Cerebrum 0.177 0.243 0.126 0.039
Eye balls 0.860 1.057 0.405 0.136
Fat 0.290 0.134 0.071 < 2BG
Fur 0.037 0.023 < 2BG < 2BG
Heart 1.453 1.219 0.379 0.053
Kidneys 1.994 1.707 0.574 0.127
Lens 0.027 0.058 0.051 0.017
Liver 3.641 3.185 1.130 0.276
Lungs 1.733 1.304 0.490 0.108
n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 24
2.6.5.5.1.2. イヌ（続き）
Test Article: 14C-Levocetirizine Concentration (µg eq./g or mL)
Tissues
2hr (Male) 6hr (Female) 24hr (Male) 48hr (Female)
Lymph nodes (mesenteric) 0.678 0.876 0.187 0.051
Lymph nodes (popliteal) 0.912 0.784 0.304 0.051
Muscle 1.109 0.836 0.233 0.034
Oesophagus 1.013 0.775 0.219 0.042
Ovaries - 0.613 - 0.055
Pancreas 1.960 1.433 0.648 0.132
Parotids 1.154 1.168 0.314 0.058
Parathyroids 1.084 1.540 0.274 < 2BG
Pituitary 1.451 1.581 0.422 0.086
Prostate 1.324 - 0.359 -
Salivary glands
(mandibular and sublinguals)
1.378 1.066 0.339 0.076
Skin 0.466 0.441 0.094 0.023
Spinal cord 0.164 0.162 0.184 0.067
Spleen 1.152 0.841 0.302 0.056
Testes 0.797 - 0.302 -
Thymus 0.656 0.561 0.193 < 2BG
Thyroids 1.232 0.809 0.288 0.046
Trachea 0.609 0.547 0.162 0.033
Uterus - 0.814 - 0.056
Stomach 1.31 0.87 0.61 0.07
Stomach content NS 0.67 1.49 NS
Duodenum 1.53 1.04 0.47 0.10
Duodenum content 4.86 1.82 2.82 1.17
Jejunum 2.19 1.16 0.49 0.09
Jejunum content 25.08 13.05 3.18 0.69
Ileum 1.31 0.99 0.50 0.05
Ileum content NS NS 4.69 NS
Large intestine 2.74 1.31 1.53 0.32
Large intestine content 17.8 8.73 21.58 4.49
n=1 per time point
< BG: counting values were under the BG value (25dpm), -: Not applicable, NS: No sample
2.6.5. 薬物動態試験概要表
2.6.5 - p. 25
2.6.5.5.1.2. イヌ（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.2
Report No.: RRLE99J1301 Species (Strain): Dog (Beagle)
Gender/Number of Animals: Male, Female/1 per time point Vehicle/Formulation: Water/Solution Method of Administration: Oral
Dose (mg/kg): 1 Dosing period 9 days Radionuclide: 14C Specific Activity (MBq/mg): 3.65 Sampling time (hr): 2, 6, 24, 48
Assay: LSC
Concentration (µg eq./g or mL) Tissues
2hr (Male) 6hr (Female) 24hr (Male) 48hr (Female)
Blood plasma 3.650 1.811 0.525 0.290
Whole blood 2.870 1.311 0.446 0.233
Adrenals 1.518 1.110 0.397 0.277
Aqueous humor + vitreous body 0.110 0.133 0.033 < 2BG
Bile 124.101 230.023 38.043 17.138
Bladder 1.417 1.193 0.461 0.182
Bone marrow 0.716 0.814 0.152 0.161
Brain stem 0.384 0.450 0.190 0.110
Cerebellum 0.363 0.997 0.156 0.096
Cerebrum 0.372 0.464 0.172 0.107
Eye balls 1.934 1.730 0.945 0.523
Fat 0.403 0.189 < 2BG < 2BG
Fur 0.102 0.062 < 2BG 0.429
Heart 2.276 1.146 0.296 0.153
Kidneys 3.526 2.323 0.614 0.294
Lens 0.107 0.280 0.100 0.116
Liver 6.685 4.828 1.433 0.963
n=1 per time point
< BG: counting values were under the BG value (25dpm)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 26
2.6.5.5.1.2. イヌ（続き）
Test Article: 14C-Levocetirizine Concentration (µg eq./g or mL)
Tissues
2hr (Male) 6hr (Female) 24hr (Male) 48hr (Female)
Lungs 1.932 1.449 0.526 0.306
Lymph nodes (mesenteric) 1.857 1.074 0.358 0.240
Lymph nodes (popliteal) 1.603 0.877 0.285 0.194
Muscle 1.277 0.970 0.141 0.082
Oesophagus 1.207 0.805 0.155 0.106
Ovaries - 0.944 - 0.170
Pancreas 3.180 1.993 0.555 0.511
Parotids 1.644 1.126 0.286 0.150
Parathyroids 2.251 1.320 < 2BG < BG
Pituitary 2.810 1.505 0.442 < 2BG
Prostate 1.526 - 0.288 -
Salivary glands (mandibular and sublinguals) 2.023 1.108 0.269 0.178
Skin 0.846 0.412 0.118 0.148
Spinal cord 0.439 0.492 0.229 0.128
Spleen 1.704 0.964 0.327 0.187
Testes 1.205 - 0.360 -
Thymus 0.871 0.355 0.164 0.120
Thyroids 1.342 1.223 0.278 0.163
Trachea 0.902 0.491 0.150 0.099
Uterus - 0.996 - 0.175
Stomach 1.90 1.03 0.39 0.52
Stomach content NS NS 1.14 3.78
Duodenum 1.90 1.28 0.40 0.16
Duodenum content 3.40 7.00 2.31 0.63
Jejunum 2.77 1.31 0.39 0.22
Jejunum content 22.00 15.60 2.37 1.73
Ileum 1.92 9.38 0.45 0.32
Ileum content 5.84 NS 7.03 2.38
Large intestine 3.12 3.92 2.18 0.39
Large intestine content 21.95 37.57 14.86 2.29
n=1 per time point
< BG: counting values were under the BG value (25dpm), -: Not applicable, NS: No sample
2.6.5. 薬物動態試験概要表
2.6.5 - p. 27
2.6.5.5.2. 全身オートラジオグラフィ
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.3
Report No.: RRLE99G1401 Species (Strain): Rat (Wistar)
Gender/Number of Animals: Male, Female/1 per time point Vehicle/Formulation: Water/Solution Method of Administration: Oral
Dose (mg/kg): 2 Radionuclide: 14C Specific Activity (MBq/mg): 1.702
Sampling time (hr): 2, 6, 12, 24, 96
Assay: QWBA
Result: The radioactivity became to be highest in most tissues at 2 or 6 hours after administration. The radioactivity was high in the liver, kidney and pancreas except for gastrointestinal tract. Thereafter, the radioactivity disappeared rapidly from the body and became to be less than the lower limit of quantification (1.6µg eq./g) in most tissues at 12 hours after administration.
Based on the above, it was considered that the drug related material after single oral administration to rats was distributed widely to tissues and then eliminated rapidly from the body.
2.6.5. 薬物動態試験概要表
2.6.5 - p. 28
2.6.5.6. 薬物動態試験：蛋白結合 2.6.5.6.1. 蛋白結合
2.6.5.6.1.1. In vitro
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.1, 4.2.2.3.2
Report No.: RRLE95H0901, RRLE99J1301 Study system: In vitro
Target entity, test system and method: The plasma protein binding of 14C-ucb 28556 after 2-3hr incubation at 37°C was investigated over a range of concentrations (0.5-250µg/mL) by equilibrium dialysis.
Plasma protein binding of ucb 28556 (%) Concentration
(µg/mL) Rat Dog (Male) Dog (Female)
0.5 86.6 #1 90.78 ± 0.57 87.61 ± 0.71
1 86.8 ± 0.7 90.34 ± 1.29 88.43 ± 0.93
2 85.4 ± 1.6 90.79 ± 0.41 88.20 ± 0.31
5 86.6 ± 0.5 89.35 ± 0.19 86.79 ± 0.34
10 86.7 ± 0.7 89.54 ± 0.96 85.63 ± 2.99
20 86.5 ± 0.4 87.97 ± 0.39 84.41 ± 2.40
50 86.5 ± 0.9 85.74 ± 0.45 83.93 ± 2.20
100 85.4 ± 1.0 84.88 ± 0.22 83.13 ± 2.28
150 83.5 ± 0.3 83.45 ± 0.58 83.86 ± 3.76
200 82.4 ± 0.1 82.76 ± 0.59 84.63 ± 2.84
250 81.0 ± 0.5 81.98 ± 0.44 83.03 ± 1.72
Mean ± SD (n=3, #1: n=2) 2.6.5. 薬物動態試験概要表
2.6.5 - p. 29
2.6.5.6.1.1. In vitro（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.4
Report No.: RRLE04K2002 Study system: In vitro Target entity, test system and method:
14C-Levocetirizine or Cetirizine (0.2-5µg/mL) by equilibrium dialysis.
Plasma protein binding (%)
ucb P071 #1 Concentration
(µg/mL) ucb 28556 ucb P071
ucb 28556 0.2 92.2 ± 0.1 89.3 ± 0.4 86.1 ± 0.9 92.7 ± 1.2 0.5 92.1 ± 0.2 89.1 ± 0.5 86.3 ± 1.7 92.1 ± 1.5
1 91.9 ± 0.3 89.0 ± 0.4 85.3 ± 1.0 92.8 ± 0.7
5 91.6 ± 0.2 #2 89.2 ± 0.2 85.8 ± 1.0 92.7 ± 0.9
General mean 92.0 89.2 85.9 92.6
Mean ± SD (n=6, #2: n=5)
#1: Cetirizine was added.
2.6.5. 薬物動態試験概要表
2.6.5 - p. 30
The human plasma protein binding of ucb 28556, gsk002* or ucb P071was investigated after 2hr incubation at 37°C with
gsk002*
* 新薬承認情報提供時に置き換え
2.6.5.6.1.2. Ex vivo
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.1
Report No.: RRLE95H0901 Species (Strain): Rat (SD)
Gender/Number of Animals: Male, Female, Pregnant/1-4 Vehicle/Formulation: Saline/Solution Method of Administration: Oral
Dose (mg/kg): 2, 25 Radionuclide: 14C Specific Activity (Bq/mg): 4.33
Assay: Equilibrium dialysis
Protein binding (%)
2mg/kg 25mg/kg Sampling time (hr)
Male Female Pregnant Male Female Pregnant
0.5 86.5 NS 88.9 83.1 81.4 84.6
1 NQ NQ 86.8 84.8 82.6 84.7
2 NQ NS 86.4 79.4 84.8 88.8
4 NQ NQ NQ 83.8 87.7 90.5
Mean ± SD 86.5 NQ 87.3 ± 1.3 82.8 ± 2.4 84.1 ± 2.8 87.2 ± 3.0 NQ: Not quantification
NS: No sample
2.6.5. 薬物動態試験概要表
2.6.5 - p. 31
2.6.5.6.1.2. Ex vivo（続き）
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.2
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 (Bq/mg): 3.65
Assay: Equilibrium dialysis
Single Animal No Sampling time (hr)
Protein binding (%) General mean
1 88.9 ± 0.4
B31 (Male)
2 88.8 ± 0.2
2 90.9 ± 0.1
B21 (Male)
24 91.3 ± 0.1
90.0 ± 1.2
1 92.6 ± 0.2
B49 (Female)
6 95.5 ± 0.3
2 92.1 ± 0.1
B44 (Female)
48 88.8 ± 2.8
92.2 ± 2.8
Mean ± SD (n=3)
Protein binding (%) Sampling day (day)
B61 (Male) B77 (Male) B48 (Female) B68 (Female) 1 95.9 ± 0.3 93.7 ± 0.3 89.0 ± 0.8 89.3 ± 0.4 3 95.5 ± 0.0 94.4 ± 0.2 88.8 ± 0.8 89.2 ± 0.2 5 93.7 ± 0.4 91.9 ± 0.4 88.6 ± 1.2 89.4 ± 0.5 7 93.2 ± 1.5 90.6 ± 0.4 89.5 ± 0.7 90.5 ± 0.1 8 95.3 ± 0.2 93.0 ± 0.2 89.1 ± 0.3 90.4 ± 0.1 9 94.4 ± 0.2 93.9 ± 0.5 89.9 ± 0.2 89.8 ± 1.8
General mean 93.8 ± 1.5 89.5 ± 0.8
Mean ± SD (n=3)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 32
2.6.5.6.1.3. 結合蛋白
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.5
Report No.: RRLE00K3002 Study system: In vitro Target entity, test system and
method:
Protein binding: The plasma protein, HSA, HSA-NEFA, α1-AGP, γ-globulin, VLDL, LDL and HDL binding of 14C-ucb 28556 was investigated over a range of concentrations by equilibrium dialysis.
Protein Concentration of Levocetirizine (nM) Protein binding (%)
Plasma 200-4984 91.21 ± 0.66 #1
HSA 227-5272 97.56 ± 0.10
HSA-NEFA #2 211-4722 88.95 ± 0.39
α1-AGP 142-3476 44.71 ± 3.74
γ-globulin 122-2891 12.92 ± 2.32
VLDL 123-2767 8.51 ± 2.48 #3
LDL 136-3175 22.74 ± 1.95
HDL 159-3666 51.58 ± 1.11
Mean ± SD (n=5-6 per each concentration, #1: n=3, #3: n=4) NEFA: Non esterified fatty acid, #2: NEFA/HSA=1.25
2.6.5.6.1.4. 結合部位の検討
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.5
Report No.: RRLE00K3002 Study system: In vitro
Target entity, test system and method: Binding site of ucb 28556 was investigated in presence of warfarin (site I) or diazepam (site II) by equilibrium dialysis.
Protein Concentration of Levocetirizine (µM) Ka (mM-1)
HSA (40µM) 0.755-153 11.02 ± 2.40
HSA + warfarin (300µM) 0.661-141 14.76 ± 0.55
HSA + diazepam (300µM) 0.558-139 1.81 ± 1.00
Mean ± SD (n=5-6 per each concentration)
2.6.5. 薬物動態試験概要表
2.6.5 - p. 33
2.6.5.6.2. 血球中への移行
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.5
Report No.: RRLE00K3002 Study system: In vitro
Target entity, test system and method: Human blood cells were incubated with 14C-Levocetirizine (216-5391nM) for 30min at 37°C Result: Binding to blood cells was 27.4%.
2.6.5. 薬物動態試験概要表
2.6.5 - p. 34
2.6.5.7. 薬物動態試験：妊娠又は授乳動物における試験
2.6.5.7.1. 妊娠ラットでの組織内分布
Test Article: 14C-Levocetirizine Location in CTD: 4.2.2.3.1
Report No.: RRLE95H0901 Species (Strain): Rat (SD)
Gender/Number of Animals: Female (14th day of pregnancy)/1 per time point Vehicle/Formulation: Saline/Solution
Method of Administration: Oral Dose (mg/kg): 2, 25 Radionuclide: 14C Specific Activity (MBq/mg): 4.33
Sampling time (hr): 0.5, 1, 2, 4, 8, 12, 24, 48
Assay: LSC
Concentration (µg eq./g or mL) 2mg/kg
Tissues
0.5hr 1hr 2hr 4hr 8hr 12hr 24hr 48hr Blood plasma 0.869 1.377 0.991 0.201 0.389 0.037 0.032 < 2BG
Whole blood 0.653 1.027 0.741 0.165 0.275 0.084 0.032 0.052
Foetuses 0.105 0.290 0.346 0.081 0.149 0.019 0.034 < BG
Placenta 0.348 0.885 1.028 0.271 0.482 0.053 0.078 < 2BG
Amniotic fluid 0.100 0.139 0.135 0.058 0.191 < BG < BG < BG
25mg/kg Blood plasma 12.574 21.185 19.906 11.133 2.779 < 2BG < 2BG < BG
Whole blood 6.723 15.763 13.985 8.825 NS < 2BG 0.561 < BG
Foetuses 1.052 3.499 4.639 2.916 1.318 0.481 < BG < BG
Placenta 3.425 11.883 14.765 8.240 1.059 1.157 0.295 < BG
Amniotic fluid 0.786 1.201 2.389 1.205 3.880 < BG < BG < BG n=1 data per time point
< BG: counting values were under the BG value (25dpm) NS: No sample
2.6.5. 薬物動態試験概要表
2.6.5 - p. 35