PMID- 33734452
OWN - NLM
STAT- MEDLINE
DCOM- 20211117
LR  - 20240226
IS  - 1099-081X (Electronic)
IS  - 0142-2782 (Print)
IS  - 0142-2782 (Linking)
VI  - 42
IP  - 5
DP  - 2021 May
TI  - Prediction of a clinically effective dose of THY1773, a novel V(1B) receptor 
      antagonist, based on preclinical data.
PG  - 204-217
LID - 10.1002/bdd.2273 [doi]
AB  - THY1773 is a novel arginine vasopressin 1B (V(1B) ) receptor antagonist that is 
      under development as an oral drug for the treatment of major depressive disorder 
      (MDD). Here we report our strategy to predict a clinically effective dose of 
      THY1773 for MDD in the preclinical stage, and discuss the important insights 
      gained by retrospective analysis of prediction accuracy. To predict human 
      pharmacokinetic (PK) parameters, several extrapolation methods from animal or in 
      vitro data to humans were investigated. The f(u) correction intercept method and 
      two-species-based allometry were used to extrapolate clearance from rats and dogs 
      to humans. The physiologically based pharmacokinetics (PBPK)/receptor occupancy 
      (RO) model was developed by linking free plasma concentration with pituitary 
      V(1B) RO by the E(max) model. As a result, the predicted clinically effective 
      dose of THY1773 associated with 50% V(1B) RO was low enough (10 mg/day, or at 
      maximum 110 mg/day) to warrant entering phase 1 clinical trials. In the phase 1 
      single ascending dose study, TS-121 capsule (active ingredient: THY1773) showed 
      favorable PKs for THY1773 as expected, and in the separately conducted phase 1 RO 
      study using positron emission tomography, the observed pituitary V(1B) RO was 
      comparable to our prediction. Retrospective analysis of the prediction accuracy 
      suggested that the prediction methods considering plasma protein binding, and 
      avoiding having to apply unknown scaling factors obtained in animals to humans, 
      would lead to better prediction. Selecting mechanism-based methods with 
      reasonable assumptions would be critical for the successful prediction of a 
      clinically effective dose in the preclinical stage of drug development.
CI  - (c) 2021 The Authors. Biopharmaceutics & Drug Disposition published by John Wiley & 
      Sons Ltd.
FAU - Inatani, Shoko
AU  - Inatani S
AUID- ORCID: 0000-0001-7957-715X
AD  - Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics 
      Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, 
      Japan.
FAU - Mizuno-Yasuhira, Akiko
AU  - Mizuno-Yasuhira A
AD  - Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics 
      Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, 
      Japan.
FAU - Kamiya, Makoto
AU  - Kamiya M
AD  - Development Headquarters, Taisho Pharmaceutical Co., Ltd., Tokyo, Japan.
AD  - Drug Development, Taisho Pharmaceutical R&D Inc., NJ, USA.
FAU - Nishino, Izumi
AU  - Nishino I
AD  - Development Headquarters, Taisho Pharmaceutical Co., Ltd., Tokyo, Japan.
FAU - Sabia, Helene D
AU  - Sabia HD
AD  - Clinical Operations, Taisho Pharmaceutical R&D Inc., NJ, USA.
FAU - Endo, Hiromi
AU  - Endo H
AD  - Drug Metabolism and Pharmacokinetics, Drug Safety and Pharmacokinetics 
      Laboratories, Research Headquarters, Taisho Pharmaceutical Co., Ltd., Saitama, 
      Japan.
LA  - eng
GR  - Taisho Pharmaceutical Co., Ltd.; Taisho Pharmaceutical R&D Inc./
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20210403
PL  - England
TA  - Biopharm Drug Dispos
JT  - Biopharmaceutics & drug disposition
JID - 7911226
RN  - 0 (Antidiuretic Hormone Receptor Antagonists)
RN  - 0 (Blood Proteins)
RN  - 0 (Receptors, Vasopressin)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Antidiuretic Hormone Receptor Antagonists/*administration & 
      dosage/blood/*pharmacokinetics
MH  - Blood Proteins/metabolism
MH  - Cell Membrane Permeability
MH  - Cytochrome P-450 Enzyme System/metabolism
MH  - Dogs
MH  - Double-Blind Method
MH  - Fasting/metabolism
MH  - Female
MH  - Humans
MH  - Male
MH  - Microsomes, Liver/metabolism
MH  - Middle Aged
MH  - *Models, Biological
MH  - Phenotype
MH  - Protein Binding
MH  - Rats, Sprague-Dawley
MH  - Receptors, Vasopressin/metabolism
MH  - Reproducibility of Results
MH  - Treatment Outcome
MH  - Young Adult
MH  - Rats
PMC - PMC8252455
OTO - NOTNLM
OT  - THY1773
OT  - TS-121
OT  - V1B receptor
OT  - effective dose prediction
OT  - receptor occupancy
COIS- The authors declare no conflict of interest.
EDAT- 2021/03/19 06:00
MHDA- 2021/11/18 06:00
PMCR- 2021/07/02
CRDT- 2021/03/18 12:52
PHST- 2021/02/23 00:00 [revised]
PHST- 2020/09/06 00:00 [received]
PHST- 2021/03/09 00:00 [accepted]
PHST- 2021/03/19 06:00 [pubmed]
PHST- 2021/11/18 06:00 [medline]
PHST- 2021/03/18 12:52 [entrez]
PHST- 2021/07/02 00:00 [pmc-release]
AID - BDD2273 [pii]
AID - 10.1002/bdd.2273 [doi]
PST - ppublish
SO  - Biopharm Drug Dispos. 2021 May;42(5):204-217. doi: 10.1002/bdd.2273. Epub 2021 
      Apr 3.