1) Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res 1993;
10: 1093-1095.
2) Marino A M, Yarde M, Patel H, et al. Validation of the 96 well Caco-2 cell culture model for high throughput permeability assessment of discovery compounds. Intl J Pharmaceut 2005; 297:
235-241.
3) FDA Guidance for industry: Drug interaction studies- Study design, data analysis, implications for dosing, and labeling recommendations. Draft Guidance, February 2012.
4) Giacomini et al. Membrane transporters in drug development. Nature Reviews. 2010; 9: 215-236.
5) Zane PA, Brindle SD, Gause DO et al., Physicochemical factors associated with binding and retention of compounds in ocular melanin of rats: correlation using data from whole-body autoradiography and molecular modeling for multiple linear regression analyses. Pharmaceutical Research, 1990; 7:935-941.
6) Leblanc B, Jezequel S, et al., Binding of drugs to eye melanin is not predictive of ocular toxicity.
Regulatory Toxicology and Pharmacology, 1998; 28: 124-132.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 1
CTD 第 2 部
2.6 非臨床試験の概要文及び概要表
2.6.5 薬物動態試験概要表
ブリストル・マイヤーズ株式会社
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 2
目次
1 薬物動態試験：一覧表 ... 3 2 分析方法及びバリデーション試験 ... 6 3 薬物動態試験：単回投与後の吸収 ... 10 4 薬物動態試験：反復投与後の吸収 ... 15 5 薬物動態試験：分布 ... 16 6 薬物動態試験：蛋白結合 ... 39 7 薬物動態試験：妊娠又は授乳動物における試験 ... 41 8 薬物動態試験：その他の分布試験 ... 50 9 薬物動態試験：In vivoでの代謝 ... 55 10 薬物動態試験：In vitroでの代謝 ... 62 11 薬物動態試験：推定代謝経路 ... 70 12 薬物動態試験：薬物代謝酵素の誘導／阻害 ... 73 13 薬物動態試験：累積排泄 ... 80 14 薬物動態試験：胆汁中排泄 ... 85 15 薬物動態試験：薬物相互作用 ... 87 16 薬物動態試験：その他 ... 88
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 3 1 薬物動態試験：一覧表
Table 2.6.5.1: Pharmacokinetics: Overview
Test Article: Daclatasvir
Type of Study Test System Method of
Administration Testing
Facility Study Number / DCN Location Absorption
Single-dose PK Mouse IV, oral BMS NA / 930022297 CTD 4.2.2.2.1
Single-dose PK Rat IV, oral, intraportal BMS NA / 930022297 CTD 4.2.2.2.1
Single-dose PK Dog IV, oral BMS NA / 930022297 CTD 4.2.2.2.1
Single-dose PK Monkey IV, oral BMS NA / 930022297 CTD 4.2.2.2.1
Membrane permeability PAMPA, Caco-2 cells NA BMS NA / 930022297 CTD 4.2.2.2.1
Human BCRP substrate MDCK cells NA BMS NA/ 930051246 CTD 4.2.2.2.2
Human MRP2 substrate Membrane vesicles from
SF-9 cells NA BMS NCPK 22 / 930066616 CTD 4.2.2.5.7
Distribution
In vitro serum protein binding Mouse, rat, rabbit, dog,
monkey, and human NA BMS NA / 930022297 CTD 4.2.2.2.1
In vitro plasma protein binding Human NA NCPK 52 / 930069481 CTD 4.2.2.3.1
Blood cell partitioning Mouse, rat, dog, monkey,
and human NA BMS NA / 930022297 CTD 4.2.2.2.1
Tissue distribution (Single dose),
QWBA Rat (male) Oral 20N-0711 / 930029499 CTD 4.2.2.3.4
Tissue distribution(Single and
multiple doses), QWBA Rat (male and female) Oral NCPK 26/ 930066888 CTD 4.2.2.3.5
Tissue distribution, QWBA Pregnant rat Oral NCPK 26/ 930066888 CTD 4.2.2.3.5
Organ distribution, Mouse IV, oral BMS NA / 930022297 CTD 4.2.2.2.1
Organ distribution Rat IV, oral BMS NA / 930022297 CTD 4.2.2.2.1
Organ distribution Dog Oral BMS NA / 930022297 CTD 4.2.2.2.1
Organ distribution Monkey Oral BMS DM07005 / 930023427 CTD 4.2.2.3.6
Distribution into milk Rat Oral NCPK 26/ 930066888 CTD 4.2.2.3.5
Placental transfer Rat Oral NCPK 26/ 930066888 CTD 4.2.2.3.5
Hepatocyte uptake Rat hepatocytes NA BMS NA / 930022297 CTD 4.2.2.2.1
Hepatocyte uptake Cryopreserved human
hepatocytes NA BMS NCPK 24/ 930066612 CTD 4.2.2.3.2
OATP1B1, 1B3, and 2B1 substrate HEK-293 cells NA BMS NCPK 23 / 930066617 CTD 4.2.2.3.3
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 4 Table 2.6.5.1: Pharmacokinetics: Overview
Test Article: Daclatasvir
Type of Study Test System Method of
Administration Testing
Facility Study Number / DCN Location rOatp1, rOatp2, rOatp4, and human
OATP1B3 substrate Xenopus laevis oocytes NA BMS NA/ 930022297 CTD 4.2.2.2.1
Metabolism
In vitro metabolism rate Mouse, rat, dog, monkey, human liver microsomes,
and hepatocytes NA BMS NA / 930022297 CTD 4.2.2.2.1
In vitro metabolite formation
Mouse, rat, rabbit, dog, monkey, human liver microsomes and hepatocytes;
Aroclor 1254-induced rat S9
NA BMS NA / 930057616 CTD 4.2.2.4.1
In vivo metabolite formation Intact mouse, rat, monkey, and human; BDC rat, dog,
and monkey Oral BMS NA / 930041493 CTD 4.2.2.4.2
In vivo metabolite formation Rabbit Oral BMS NCPK6 / 930066897 CTD 4.2.2.4.3
[3H]Daclatasvir in vitro covalent
binding Rat, monkey, and human
liver microsomes NA BMS NA/ 930022297 CTD 4.2.2.2.1
[14C]Daclatasvir in vitro covalent
binding Rat, dog, monkey, and
human liver microsomes NA BMS NA/ 930063706 CTD 4.2.2.4.8
PXR Transactivation HepG2/C3A cells NA BMS NA / 930022297 CTD 4.2.2.2.1
CYP induction Human hepatocytes NA 3210-1057-1800/
930037531 CTD 4.2.2.4.5
CYP induction Human hepatocytes NA XT123054 (NCPK 33)/
930066871 CTD 4.2.2.4.6
CYP induction Human hepatocytes NA BMS NCPK 47/ 930068344 CTD 4.2.2.7.1
CYP inhibition Recombinant CYP enzymes NA BMS NA / 930022297 CTD 4.2.2.2.1
CYP inhibition Human liver microsomes NA BMS NA/ 930047552 CTD 4.2.2.4.7
Reaction phenotyping, CYP Human liver microsomes and recombinant CYP
enzymes NA BMS NA / 930022297 CTD 4.2.2.2.1
Reaction phenotyping, CYP Human liver microsomes and recombinant CYP
enzymes NA BMS NCPK 18/ 930066867 CTD 4.2.2.4.4
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 5 Table 2.6.5.1: Pharmacokinetics: Overview
Test Article: Daclatasvir
Type of Study Test System Method of
Administration Testing
Facility Study Number / DCN Location Excretion
Mass balance Mouse Oral MBA00393/ 930039863 CTD 4.2.2.5.1
Mass balance Rat Oral MBA00391/ 930039861 CTD 4.2.2.5.2
Mass balance Rabbit Oral 421005/ 930065128 CTD 4.2.2.5.4
Mass balance Monkey Oral MBA00394/ 930039859 CTD 4.2.2.5.5
Mass balance Human Oral MBA00411/ 930037202 CTD 4.2.2.5.6
Excretion into bile BDC rat Oral MBA00392/ 930039858 CTD 4.2.2.5.3
Excretion into bile BDC dog Oral BMS PK_3852/ 930041493 CTD 4.2.2.4.2
Excretion into bile BDC monkey Oral BMS PK_3855/ 930041493 CTD 4.2.2.4.2
Excretion into bile Rat, dog, and monkey IV BMS NA / 930022297 CTD 4.2.2.2.1
Other Pharmacokinetic Studies
P-gp inhibition Caco-2 cells NA BMS NA / 930022297 CTD 4.2.2.2.1
Human P-gp inhibition MDCK-MDR1 cells NA BMS NCPK 25/ 930066927 CTD 4.2.2.7.3
Human BCRP inhibition MDCK cells NA BMS NA/ 930051248 CTD 4.2.2.7.4
Human MRP2 inhibition membrane vesicles from
SF-9 cells NA BMS NA/ 930053239 CTD 4.2.2.7.5
Human BSEP and NTCP Inhibition SF-9 and CHO cells NA NCPK 29/ 930066894 CTD 4.2.2.7.8
Human OAT1, OAT3, OCT1,
and OCT2 Inhibition HEK-293 cells NA BMS NCPK 19/ 930066932 CTD 4.2.2.7.9
OATP2B1 Inhibition HEK-293 cells NA BMS NCPK 21/ 930066614 CTD 4.2.2.7.7
Human OATP 1B3 Inhibition HEK-293 cells NA BMS NA/ 930053227 CTD 4.2.2.7.6
Human OATP1B1 inhibition HEK-293 cells NA BMS NA / 930022297 CTD 4.2.2.2.1
Human UGT1A1 inhibition Human liver microsomes NA BMS NCPK 8/ 930066872 CTD 4.2.2.7.2
Abbreviations: BMS: Bristol-Myers Squibb. BCRP: breast cancer resistance protein. BDC: bile duct-cannulated. BSEP: bile salt export pump. :
, ( . ( ). ( . CYP: cytochrome
P450. IV: intravenous. NA: not applicable. MRP: membrane resistance protein. NTCP: N+-taurocholate-cotransporting peptide. OAT: organic anion transporter. OATP: organic anion transporting polypeptide. OCT: organic cation transporter. PAMPA: parallel artificial membrane permeability assay. P-gp:
P-glycoprotein. PK: pharmacokinetics. QPS: QPS Pharmaceutical Servcies (Newark, DE). QWBA: Quantitative whole-body autoradiography. rOatp: rat organic anion transporting polypeptide. ( ). UGT: uridine-diphosphoglucuronosyl transferase.
( ).
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 6 2 分析方法及びバリデーション試験
Table 2.6.5.2: Pharmacokinetics: Analytical Methods and Validation Reports Document
Control
Number Analyte Sample
Matrix Method Regression Model
Standard Curve Range
(ng/mL)
Inter- Precision
(%CV)
Intra- Precision
(%CV)
Accuracy Deviation) (%
Stability
(RT, F/T, LTS) Study Number 930023498 Daclatasvir mouse
plasma (K2EDTA)
LC-MS/
MS 1/x2 weighted
linear 5-2000 NA ≤ 4.4 ± 2.9 RT = 24 h, LTS
= 3 months at
−20°C
DM10043 DS10043
930036285 Daclatasvir mouse plasma (EDTA)
LC-MS/
MS 1/x2 weighted
linear 2-2000 NA ≤ 9.9 ± 3.5
RT = 24 h, F/T
= 5 cycles, LTS
= 90 days at
−20°C, 7 days at −70°C
DN11083 DS08152
930022756 Daclatasvir rat plasma
(K2EDTA) LC-MS/
MS 1/x2 weighted
linear 5-2000 ≤ 3.7 ≤ 3.3 ± 2.1
RT = 24 h, F/T
= 5 cycles, LTS=287 days at −20°C
DN07054 DN08011 DN11038 DS07055 DS07207 DS08002 DS08011 DS10042
930031499
Daclatasvir rat plasma
(EDTA) LC-MS/
MS 1/x2 weighted
linear 2-2000 ≤ 2.1 ≤ 4.0 ± 4.9
RT = 24 h, F/T
= 5 cycles, LTS=93 days at
−20°C
DS08101
Asunaprevir rat plasma (EDTA) LC-MS/
MS 1/x2 weighted
linear 2-2000 ≤ 5.3 ≤ 9.2 ± 7.6
RT = 24 h, F/T
= 5 cycles, LTS
= 93 days at
−20°C
DS08101
BMS-791325 rat plasma (EDTA) LC-MS/
MS 1/x2 weighted
linear 2-2000 ≤ 4.0 ≤ 9.4 ± 6.2
RT = 24 h, F/T
= 5 cycles, LTS
= 93 days at
−20°C
DS08101
BMS-794712 rat plasma (EDTA) LC-MS/
MS 1/x2 weighted
linear 0.40-400 ≤ 3.2 ≤ 9.0 ± 2.9 RT = 24 h, F/T
= 5 cycles, LTS
= 93 days at DS08101
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 7 Table 2.6.5.2: Pharmacokinetics: Analytical Methods and Validation Reports
Document Control
Number Analyte Sample
Matrix Method Regression Model
Standard Curve Range
(ng/mL)
Inter- Precision
(%CV)
Intra- Precision
(%CV)
Accuracy Deviation) (%
Stability
(RT, F/T, LTS) Study Number
−20°C
930034167
Daclatasvir rat plasma
(EDTA) LC-MS/
MS 1/x2 weighted
linear 2-2000 ≤ 9.2 ≤ 4.5 ± 5.5
RT = 31 h 45 min, F/T = 5 cycles, LTS = 155 days at
−20°C
DN08034 DS08126 DM11028 DN11082 DN12003 DN12004
Asunaprevir rat plasma (EDTA) LC-MS/
MS 1/x2 weighted
linear 2-2000 ≤ 10.0 ≤ 8.7 ± 5.6
RT = 31 h 45 min, F/T = 5 cycles, LTS = 155 days at
−20°C
DM09003 DS08126
BMS-791325 rat plasma (EDTA) LC-MS/
MS 1/x2 weighted
linear 2-2000 ≤ 4.3 ≤ 5.8 ± 4.0
RT = 31 h 45 min, F/T = 5 cycles,
LTS=155 days at −20°C
DM09003
BMS-794712 rat plasma (EDTA) LC-MS/
MS 1/x2 weighted
linear 0.2-200 ≤ 19.4 ≤ 10.1 ± 7.0
RT = 31 h 45 min, F/T = 5 cycles, LTS = 155 days at
−20°C
DM09003
930023499 Daclatasvir rabbit plasma (K2EDTA)
LC-MS/
MS 1/x2 weighted
linear 5-2000 NA ≤ 2.0 ± 7.7 RT = 24 h, LTS
= 3 months at
−20°C
DN07051 DN08012 930022772 Daclatasvir dog
plasma (K2EDTA)
LC-MS/
MS 1/x2 weighted
linear 5-2000 NA ≤ 4.1 ± 6.6 RT = 24 h, LTS
= 74 days at
−20°C
DS07058 DS07186
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 8 Table 2.6.5.2: Pharmacokinetics: Analytical Methods and Validation Reports
Document Control
Number Analyte Sample
Matrix Method Regression Model
Standard Curve Range
(ng/mL)
Inter- Precision
(%CV)
Intra- Precision
(%CV)
Accuracy Deviation) (%
Stability
(RT, F/T, LTS) Study Number
930037671
Daclatasvir dog plasma (EDTA)
LC-MS/
MS 1/x2 weighted
linear 2-2000 NA ≤ 4.5 ± 4.5
RT = 24 h 15 min, F/T = 5, LTS = 80 days at −20°C
DM09002 DM09009
Asunaprevir dog plasma (EDTA)
LC-MS/
MS 1/x2 weighted
linear 2-2000 NA ≤ 8.9 ± 17.0
RT = 24 h 15 min, F/T = 5, LTS = 80 days at −20°C
DM09009
BMS-791325 dog plasma (EDTA)
LC-MS/
MS 1/x2 weighted
linear 2-2000 NA ≤ 6.9 ± 8.0
RT = 24 h 15 min, F/T = 5, LTS = 80 days at −20°C
DM09002 DM09009
BMS-794712 dog plasma (EDTA)
LC-MS/
MS 1/x2 weighted
linear 0.2-200 NA ≤ 7.3 ± 6.9
RT = 24 h 15 min, F/T = 5, LTS = 80 days at −20°C
DM09002 DM09009
930033791 Daclatasvir monkey plasma (EDTA)
LC-MS/
MS 1/x2 weighted
linear 5-2000 NA ≤ 1.2 ± 1.6 RT = 24 h, F/T
= 5, LTS = 137 days at −20°C
DS08003 DS08039
930034172
Daclatasvir monkey plasma (K2EDTA)
LC-MS/
MS 1/x2 weighted
linear 2-2000 NA ≤ 9.0 ± 14.5
RT = 23 h 15 min, F/T = 5, LTS = 104 days at −20°C
DM09008 DS08077 DS08143
Asunaprevir monkey plasma (K2EDTA)
LC-MS/
MS 1/x2 weighted
linear 2-2000 NA ≤ 18.6 ± 16.0
RT = 23 h 15 min, F/T = 5, LTS = 104 days at −20°C
DM09008 DS09019 DS08143 930034995 ribavirin monkey
plasma (EDTA)
LC-MS/
MS 1/x2 weighted
linear 5-1000 ≤ 3.3 ≤ 4.0 ± 4.8 RT = 24 h, F/T
= 5, LTS = 184 days at −20°C
DS08077 DS08147 DS09019
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 9 Table 2.6.5.2: Pharmacokinetics: Analytical Methods and Validation Reports
Document Control
Number Analyte Sample
Matrix Method Regression Model
Standard Curve Range
(ng/mL)
Inter- Precision
(%CV)
Intra- Precision
(%CV)
Accuracy Deviation) (%
Stability
(RT, F/T, LTS) Study Number
930034929 Peginterferon alfa-2b (PegIntron)
monkey plasma (Li
Heparin) ECLA
4-parameter logistic w/
1/y2 weighting
500-32000 pg
/mL ≤ 12.5 ≤ 8.3 ± 8.1
RT = 24 h 10 min, F/T = 3, LTS = 196 days at −70°C
DS08077 DS08147 DS09019 Abbreviations: NA: not applicable. F/T = freeze-thaw stability. LC-MS/MS = liquid chromatography tandem mass spectrometry, LTS = long-term stability, RT = room temperature, and ECLA = electrochemiluminescent assay. Additional non-GLP analyses were performed for multiple analytes in various biological matrices, more details are available in the toxicokinetic reports.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 10 3 薬物動態試験：単回投与後の吸収
Table 2.6.5.3A: Pharmacokinetics: Absorption After a Single Dose (Mouse)
Test Article: Daclatasvir Location in Dossier: CTD 4.2.2.2.1 Study No./Document Control Number: NA/ 930022297 Species/ Strain: Mouse/ P-gp double (mdr1a/1b) knockout and Wild type Gender/ Number of Animals: Male/ 3 per timepoint
Vehicle/ Formulation: PEG-400/ propylene glycol/ ethanol/ water (30:25:10:35)/ Solution
Dose (mg/kg): 3
Sample: Plasma
Analyte: Daclatasvir
Assay: LC-MS/MS
P-gp Knockout Mice Wild-type Mice
Feeding condition: Non-fasted Fasted Non-fasted Fasted
Method of Administration: Injection Gavage Injection Gavage
Route: IV Oral IV Oral
Cmax (μg/mL) NA 1.8 NA 2.3
AUC(0-8 h) (μg•h/mL) 12.4 11.2 5.4 6.6
Tmax (h) NA 2.0 NA 0.5
CL (mL/min/kg) 4.0 NA 9.3 NA
Vss (L/kg) 0.61 NA NC NA
T-HALF (h) 1.6 NA 1.1 NA
Bioavailability (%) NA 91 a NA 123 a
BMS-795853 AUC(0-8 h) (μg•h/mL) 0.80 0.92 0.18 0.26
BMS-795853 AUC(0-8 h) / Daclatasvir AUC(0-8 h) 0.0645 0.0821 0.0333 0.0394
BMS-805215 AUC(0-8 h) (μg•h/mL) 1.53 2.09 0.74 0.67
BMS-805215 AUC(0-8 h) / Daclatasvir AUC(0-8 h) 0.123 0.187 0.137 0.102
Additional Information: NA: not applicable. NC: not calculated as the terminal profile was not well characterized. P-gp: P-glycoprotein. PEG: polyethylene glycol. Pharmacokinetic parameters were generated from composite serum concentration-time curves. BMS-795853 (descarboxymethyl daclatasvir) and BMS-805215 (pyrrolidine-hydroxylated rearranged daclatasvir) are metabolites of daclatasvir; see Table 2.6.5.11 for structures. Metabolite-to-parent ratios are based on molar concentrations.
a Bioavailability was calculated using the AUC(0-8 h) of daclatasvir after oral and IV administration of daclatasvir.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 11 Table 2.6.5.3B: Pharmacokinetics: Absorption After a Single Dose (Rat)
Test Article: Daclatasvir Location in Dossier: CTD 4.2.2.2.1 Study No./Document Control Number: NA/ 930022297
Species/ Strain: Rat/ Sprague-Dawley
Gender/ Number of Animals: Male/ 3
Vehicle/ Formulation: PEG-400/ Solution
Sample: Plasma
Analyte: Daclatasvir
Assay: LC-MS/MS
Feeding condition: Non-fasted Non-fasted Fasted Fasted
Method of Administration: Infusion (10 minutes) Infusion (10 minutes) Gavage Infusion (30 minutes)
Route: IV IV Oral IPT
Dose (mg/kg): 2 5 5 2
Cmax (μg/mL) NA NA 0.59 ± 0.10 1.6 ± 0.25
AUC(INF) (μg•h/mL) 3.7 ± 0.15 5.66 ± 0.63 3.6 ± 0.97 2.8 ± 0.49
Tmax (h) NA NA 2.7 ± 1.2 0.5 ± 0.0
CLTp (mL/min/kg) 9.1 ± 0.36 14.8 ± 1.6 NA NA
Vss (L/kg) 1.2 ± 0.10 3.6 ± 1.1 NA NA
T-HALF (h) 3.3 ± 0.58 4.7 ± 1.0 NA 1.2 ± 0.05
MRT (h) 2.2 ± 0.3 4.0 ± 1.0 NA NA
Bioavailability (%) NA NA 50.4 a NA
Additional Information: NA: not applicable. PEG: polyethylene glycol. IPT: intraportal vein. Values are mean ± standard deviation.
a Bioavailability was calculated using the dose-normalized AUC(INF) of daclatasvir after oral and 2 mg/kg IV administration of daclatasvir.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 12 Table 2.6.5.3C: Pharmacokinetics: Absorption After a Single Dose (Dog)
Test Article: Daclatasvir Location in Dossier: CTD 4.2.2.2.1 Study No./Document Control Number: NA/ 930022297
Species/ Strain: Dog/ Beagle
Gender/ Number of Animals: Male/ 5
Sample: Plasma
Analyte: Daclatasvir
Assay: LC-MS/MS
Vehicle/Formulation: PEG-400/ water (85:15)/ Solution PEG-400/ povidone K-30/ Vitamin E TPGS/ Tween 80 (95:2:2:1)/ Solution
Feeding condition: Non-fasted Fasted
Method of Administration: Infusion (5 minutes) Gavage
Route: IV Oral
Dose (mg/kg): 1 3
Cmax (μg/mL) NA 0.85 ± 0.51
AUC(INF) (μg•h/mL) 1.31 ± 0.75 5.66 ± 3.64
Tmax (h) NA 2.9 ± 1.6
CLTp (mL/min/kg) 20.3 ± 21.3 NA
Vss (L/kg) 5.4 ± 4.6 NA
T-HALF (h) 3.9 ± 1.4 NA
MRT (h) 4.8 ± 1.0 NA
Bioavailability (%) NA 144
Additional Information: NA: not applicable. PEG: polyethylene glycol. TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate. Values are mean ± standard deviation. This was not a crossover-design study. Bioavailability value was calculated based on mean AUC values after oral and IV dosing.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 13 Table 2.6.5.3C (continued): Pharmacokinetics: Absorption After a Single Dose (Dog)
Test Article: Daclatasvir Location in Dossier: CTD 4.2.2.2.1 Study No./Document Control Number: NA/930022297
Species/ Strain: Dog/ Beagle
Gender/ Number of animals: Male/ 3
Sample: Plasma
Analyte: Daclatasvir
Assay: LC-MS/MS
Vehicle/Formulation: PEG-400/ ethanol/ 10 mM phosphate buffer pH 6.8
(60:10:30)/ Solution
PEG-400/ ethanol/
water (60:10:30)/
Solution Powder in capsule Powder in capsule
Feeding condition: Not Fasted Fasted Fasted Fasted
Method of administration: Infusion (10 minutes) Gavage Gavage Gavage
Pretreatment: None Pentagastrin Pentagastrin Famotidine
Route: IV Oral Oral Oral
Dose (mg/kg): 1 3 3 3
Cmax (μg/mL) NA 1.8 ± 0.30 1.5 ± 0.58 1.3 ± 1.0
AUC(INF) (μg•h/mL) 3.3 ± 1.4 13 ± 3.8 9.1 ± 4.3 5.4 ± 4.4
Tmax (h) NA 1.8 ± 2.0 2.3 ± 1.6 2.3 ± 1.5
CLTp (mL/min/kg) 5.5 ± 2.1 NA NA NA
Vss (L/kg) 1.4 ± 0.29 NA NA NA
T-HALF (h) 3.5 ± 0.68 NA NA NA
MRT (h) 4.5 ± 1.0 NA NA NA
Bioavailability (%) NA 130 ± 25 89 ± 14 48 ± 24
BMS-795853 AUC(0-24 h) (μg•h/mL) 0.313 ± 0.123 1.29 ± 0.538 ND ND
BMS-795853AUC/ Daclatasvir AUC 0.09 ± 0.029 0.10 ± 0.011 NA NA
BMS-805215 AUC(0-24 h) (μg•h/mL) 0.0445 ± 0.0166 0.226 ± 0.0453 ND ND
BMS-805215 AUC/ Daclatasvir AUC 0.0135 ± 0.0119 0.0174 ± 0.0119 NA NA
Additional Information: NA: not applicable. ND: not determined. PEG: polyethylene glycol. Values are mean ± standard deviation. This was a crossover-design study. BMS-795853 (descarboxymethyl daclatasvir) and BMS-805215 (pyrrolidine-hydroxylated rearranged daclatasvir) are metabolites of daclatasvir; see Table 2.6.5.11 for structures. Metabolite-to-parent ratios based on molar concentrations.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 14 Table 2.6.5.3D: Pharmacokinetics: Absorption After a Single Dose (Monkey)
Test Article: Daclatasvir Location in Dossier: CTD 4.2.2.2.1 Study No./Document Control Number: NA/ 930022297
Species/ Strain: Monkey/ Cynomolgus
Gender/ Number of Animals: Male/ 3
Sample: Plasma
Analyte: Daclatasvir
Assay: LC-MS/MS
Vehicle/ Formulation: PEG-400/water (85:15)/ Solution PEG-400/ Povidone K-30/ TPGS/ Tween 80 (95:2:2:1)/ Solution
Feeding condition: Non-fasted Fasted
Method of Administration: Infusion (5 minutes) Gavage
Route: IV Oral
Dose (mg/kg): 1.13 2.83
Cmax (μg/mL) NA 0.20 ± 0.030
AUC(INF) (μg•h/mL) 1.63 ± 0.47 1.45 ± 0.32
Tmax (h) NA 2.0 ± 0.0
CLTp (mL/min/kg) 12.4 ± 4.2 NA
Vss (L/kg) 2.2 ± 0.88 NA
T-HALF (h) 3.7 ± 0.31 NA
MRT (h) 3.0 ± 0.48 NA
Bioavailability (%) NA 38 ± 17
BMS-805215 AUC(0-24 h) (μg•h/mL) 0.204 ± 0.113 0.23 ± 0.08
BMS-805215 AUC/ Daclatasvir AUC 0.125 ± 0.043 0.15 ± 0.035
Additional Information: NA: not applicable. PEG: polyethylene glycol. TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate. Values are mean ± standard deviation. Metabolite-to-parent ratios based on molar concentrations. BMS-795853 (descarboxymethyl daclatasvir) and BMS-805215 (pyrrolidine-hydroxylated rearranged daclatasvir) are metabolites of daclatasvir; see Table 2.6.5.11 for structures. BMS-795853 concentrations after oral dosing were below the limit of quantification (14.6 ng/mL). Bioavailability was calculated using the dose-normalized AUC(INF) of daclatasvir after oral and IV administration of daclatasvir.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 15 4 薬物動態試験：反復投与後の吸収
Table 2.6.5.4: Pharmacokinetics: Absorption after Repeated Doses
Absorption after repeated pharmacological doses was not studied. Repeat-dose toxicokinetic data appear in the Toxicology Summary.
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 16 5 薬物動態試験：分布
Table 2.6.5.5A: Pharmacokinetics: Organ Distribution (Male Rats, Single Dose, Quantitative Whole-body Autoradiography) Test Article: [14C]Daclatasvir Location in Dossier: CTD 4.2.2.3.4
Study No. / Document Control No.: QPS 20N-0711/ 930029499 Species/ Strain: Rat/ Long-Evans and Sprague-Dawley
Sex/ Number of Animals: Male/ 1 per timepoint Feeding condition: Fasted
Vehicle/ Formulation: PEG 400 / Povidone K-30 / Vitamin E TPGS / 0.1 M H3PO4 buffer pH 3 (15:5:5:75, w/w/w/w) Method of Administration: Oral gavage
Dose: 10.5 mg/kg (115 μCi/kg)
Radionuclide: 14C
Specific activity: 10.96 μCi/mg
Sampling Times: 0.5, 1, 2, 4, 8, 12, 24, 48, 96, 168, and 840 hours (Long-Evans rats); 1, 8, and 24 hours (Sprague-Dawley rats) Assay: Quantitative whole-body autoradiography
Time after Dosing:
Radioactivity Concentration (μg-equivalents/g)
Long-Evans Rats Sprague-Dawley Rats
0.5 h 1 h 2 h 4 h 8 h 12 h 24 h 48 h 96 h 168 h 840 h 1 h 8 h 24 h Adipose (brown) 2.29 2.79 3.25 0.69 0.26 0.098 BLQ BLQ BLQ BLQ NS 1.42 0.18 BLQ
Adipose (white) 0.52 0.98 0.82 0.21 BLQ BLQ BLQ BLQ NS NS NS 0.21 BLQ BLQ
Adrenal gland 6.85 9.13 6.26 2.60 0.598 0.32 0.13 0.13 0.09 0.10 0.15 3.54 0.35 0.14
Bile 29.8 59.5 67.5 5.04 3.61 2.87 0.27 BLQ NS NS NS 25.3 1.13 0.69
Blood 1.06 0.89 0.51 0.198 BLQ BLQ BLQ BLQ BLQ BLQ NS 0.43 BLQ BLQ
Bone 0.23 0.24 0.11 BLQ BLQ BLQ BLQ BLQ NS NS NS BLQ BLQ BLQ
Bone marrow 1.50 2.04 1.38 0.64 0.29 0.20 BLQ 0.10 0.09 0.13 NS 0.91 0.16 0.07
Brain (entire) BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ NS NS NS BLQ BLQ BLQ
Brain cerebellum BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ NS NS NS BLQ BLQ BLQ
Brain cerebrum BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ NS NS NS BLQ BLQ BLQ
Brain medulla BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ NS NS NS BLQ BLQ BLQ
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 17
Table 2.6.5.5A: Pharmacokinetics: Organ Distribution (Male Rats, Single Dose, Quantitative Whole-body Autoradiography) Test Article: [14C]Daclatasvir Location in Dossier: CTD 4.2.2.3.4
Study No. / Document Control No.: QPS 20N-0711/ 930029499
Time after Dosing:
Radioactivity Concentration (μg-equivalents/g)
Long-Evans Rats Sprague-Dawley Rats
0.5 h 1 h 2 h 4 h 8 h 12 h 24 h 48 h 96 h 168 h 840 h 1 h 8 h 24 h
Cecum 2.13 5.12 4.97 26.6 21.4 6.17 0.16 0.07 NS NS NS 1.47 22.3 0.28
Cecum contents BLQ 1.57 154 1494 a 775 a 83.4 11.6 0.93 NS NS NS BLQ 337 4.75
Epididymis 0.30 0.36 0.62 0.38 0.21 0.097 BLQ 0.09 NS NS NS BLQ 0.14 0.07
Eye 0.46 0.27 0.42 0.86 0.43 0.66 0.41 0.43 0.74 0.35 0.82 0.11 BLQ BLQ
Eye lens BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ
Eye uveal tract 1.65 2.78 2.67 3.37 3.62 2.85 2.74 3.94 1.91 b 2.19 b 1.97 b 0.39 0.11 BLQ Harderian gland 1.56 2.95 4.16 3.83 1.80 1.13 0.40 0.24 0.18 BLQ NS 1.13 1.85 0.69 Kidney 3.38 3.03 1.93 1.31 0.43 0.45 0.11 0.20 0.12 0.16 BLQ 1.66 0.44 0.20 Kidney cortex 3.89 3.73 2.62 1.81 0.89 0.65 0.31 0.35 0.21 0.22 0.09 2.10 0.58 0.51 Kidney medulla 2.12 2.19 1.09 0.597 0.37 0.28 BLQ 0.09 0.098 0.08 BLQ 0.94 0.22 0.09 Large intestine 2.03 1.71 1.42 0.68 0.46 4.91 0.14 0.17 NS NS NS 0.99 0.22 0.32 Large intestinal contents BLQ BLQ 101 725 a 1047 a 137 10.7 0.995 BLQ NS NS BLQ 3.89 12.7
Liver 8.77 8.52 4.81 3.03 1.42 0.45 0.21 0.22 0.12 0.11 BLQ 3.70 0.96 0.18
Lung 1.54 1.62 0.76 0.42 BLQ BLQ BLQ BLQ BLQ BLQ NS 0.64 0.09 BLQ
Lymph nodes 1.16 1.33 1.20 0.63 0.19 0.24 0.13 0.23 0.10 0.15 NS 0.85 0.39 0.18
Muscle 1.05 1.24 0.67 0.27 BLQ BLQ BLQ BLQ NS NS NS 0.44 BLQ BLQ
Myocardium 1.54 2.16 1.27 0.54 0.16 BLQ BLQ BLQ NS NS NS 0.89 0.11 BLQ
Pancreas 1.89 2.58 1.45 0.63 0.19 0.12 BLQ BLQ NS NS NS 1.06 0.16 BLQ
Pituitary gland 4.04 3.14 2.61 1.28 0.47 0.42 0.15 0.23 0.09 NS NS 1.33 0.32 0.198 Prostate gland 0.24 0.87 0.57 0.27 0.12 0.11 BLQ BLQ NS NS NS 0.46 0.14 0.08
ダクラタスビル塩酸塩 2.6.5 薬物動態試験概要表 Page 18
Table 2.6.5.5A: Pharmacokinetics: Organ Distribution (Male Rats, Single Dose, Quantitative Whole-body Autoradiography) Test Article: [14C]Daclatasvir Location in Dossier: CTD 4.2.2.3.4
Study No. / Document Control No.: QPS 20N-0711/ 930029499
Time after Dosing:
Radioactivity Concentration (μg-equivalents/g)
Long-Evans Rats Sprague-Dawley Rats
0.5 h 1 h 2 h 4 h 8 h 12 h 24 h 48 h 96 h 168 h 840 h 1 h 8 h 24 h Salivary gland 2.43 2.59 4.81 1.35 0.42 0.21 BLQ 0.09 NS 0.08 NS 1.66 0.27 0.15 Skin (pigmented) 0.74 0.85 0.83 0.57 0.18 0.22 0.13 0.21 0.11 0.11 0.210 NA NA NA Skin (non-pigmented) 0.49 0.97 0.70 0.19 0.18 BLQ BLQ BLQ NS NS NS 0.33 0.20 0.07 Small intestine 19.1 17.3 8.50 9.62 1.16 0.397 0.11 0.07 NS NS NS 12.3 0.88 0.395 Small intestinal contents 177 71.3 32.7 193 12.0 1.92 0.81 0.44 NS NS NS 97.1 18.9 4.47
Spinal cord BLQ BLQ BLQ BLQ BLQ BLQ BLQ BLQ NS NS NS BLQ BLQ BLQ
Spleen 2.42 2.39 1.73 0.695 0.44 0.37 0.31 0.30 0.13 0.19 0.08 1.05 0.44 0.26
Stomach 7.33 16.1 5.30 1.63 0.44 0.15 BLQ BLQ NS NS NS 1.18 0.56 0.18
Stomach contents 486 82.4 24.9 12.5 0.76 0.10 BLQ BLQ NS NS NS 456 BLQ 1.78
Testis BLQ 0.12 0.19 0.18 0.14 0.08 BLQ BLQ NS NS NS BLQ 0.099 BLQ
Thymus 0.56 0.85 1.28 0.68 0.24 0.25 0.12 0.20 0.10 0.14 0.08 0.45 0.28 0.21 Thyroid 2.51 2.25 2.68 1.25 0.41 0.34 0.12 0.11 0.21 0.23 0.098 0.93 0.31 0.26 Urinary bladder 1.60 1.04 0.91 0.44 0.38 0.097 BLQ BLQ NS NS NS 2.52 0.31 0.096
Urine 0.20 1.25 0.58 0.21 0.23 0.07 BLQ BLQ NS NS NS 0.16 BLQ BLQ
Additional Information: BLQ: below limit of quantification (0.069 μg-equivalents/g). NS: Not sampled. TGPS: d-α-tocopheryl polyethylene glycol 1000 succinate.
a Value is higher than upper limit of quantification (595 μg equivalent/g).
b Mean of multiple readings of eye uveal tract sample