PMID- 23529133
OWN - NLM
STAT- MEDLINE
DCOM- 20150416
LR  - 20211021
IS  - 1942-0870 (Electronic)
IS  - 1942-0862 (Print)
IS  - 1942-0862 (Linking)
VI  - 5
IP  - 3
DP  - 2013 May-Jun
TI  - Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B: applying 
      mechanistic modeling to enable preclinical to clinical translation and guide 
      clinical trial design.
PG  - 373-83
LID - 10.4161/mabs.23826 [doi]
AB  - TAM-163, an agonist monoclonal antibody targeting tyrosine receptor kinase-B 
      (TrkB), is currently being investigated as a potential body weight modulatory 
      agent in humans. To support the selection of the dose range for the 
      first-in-human (FIH) trial of TAM-163, we conducted a mechanistic analysis of the 
      pharmacokinetic (PK) and pharmacodynamic (PD) data (e.g., body weight gain) 
      obtained in lean cynomolgus and obese rhesus monkeys following single doses 
      ranging from 0.3 to 60 mg/kg. A target-mediated drug disposition (TMDD) model was 
      used to describe the observed nonlinear PK and Emax approach was used to describe 
      the observed dose-dependent PD effect. The TMDD model development was supported 
      by the experimental determination of the binding affinity constant (9.4 nM) and 
      internalization rate of the drug-target complex (2.08 h(-1)). These mechanistic 
      analyses enabled linking of exposure, target (TrkB) coverage, and pharmacological 
      activity (e.g., PD) in monkeys, and indicated that >/= 38% target coverage 
      (time-average) was required to achieve significant body weight gain in monkeys. 
      Based on the scaling of the TMDD model from monkeys to humans and assuming 
      similar relationship between the target coverage and pharmacological activity 
      between monkey and humans, subcutaneous (SC) doses of 1 and 15 mg/kg in humans 
      were projected to be the minimally and the fully pharmacologically active doses, 
      respectively. Based on the minimal anticipated biological effect level (MABEL) 
      approach for starting dose selection, the dose of 0.05 mg/kg (3 mg for a 60 kg 
      human) SC was recommended as the starting dose for FIH trials, because at this 
      dose level<10% target coverage was projected at Cmax (and all other time points). 
      This study illustrates a rational mechanistic approach for the selection of FIH 
      dose range for a therapeutic protein with a complex model of action.
FAU - Vugmeyster, Yulia
AU  - Vugmeyster Y
AD  - Pharmacokinetics, Dynamics and Metabolism; Pfizer, Inc.; Cambridge, MA USA.
FAU - Rohde, Cynthia
AU  - Rohde C
AD  - Drug Safety R&D; Pfizer, Inc.; Cambridge, MA USA.
FAU - Perreault, Mylene
AU  - Perreault M
AD  - Cardiovascular and Metabolic Diseases Research Unit; Pfizer, Inc.; Cambridge, MA 
      USA.
FAU - Gimeno, Ruth E
AU  - Gimeno RE
AD  - Chief Scientific Officer; Eli Lilly & Co; Indianapolis, IN USA.
FAU - Singh, Pratap
AU  - Singh P
AD  - Pharmacokinetics, Dynamics and Metabolism; Pfizer, Inc.; Cambridge, MA USA.
LA  - eng
PT  - Journal Article
DEP - 20130325
PL  - United States
TA  - MAbs
JT  - mAbs
JID - 101479829
RN  - 0 (Anti-Obesity Agents)
RN  - 0 (Antibodies, Monoclonal)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Animals
MH  - Anti-Obesity Agents/administration & dosage/adverse effects/*pharmacology
MH  - Antibodies, Monoclonal/administration & dosage/adverse effects/*pharmacology
MH  - Body Weight/drug effects
MH  - CHO Cells
MH  - Cachexia/*therapy
MH  - Clinical Trials as Topic
MH  - *Computer Simulation
MH  - Cricetulus
MH  - Dose-Response Relationship, Drug
MH  - Drug Dosage Calculations
MH  - Drug Evaluation, Preclinical
MH  - Female
MH  - Humans
MH  - Immunotherapy/*methods
MH  - Macaca fascicularis
MH  - Macaca mulatta
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Obesity/*therapy
MH  - Receptor Protein-Tyrosine Kinases/*agonists
MH  - Species Specificity
PMC - PMC4169031
OTO - NOTNLM
OT  - Cachexia
OT  - PK/PD modeling
OT  - TAM-163
OT  - TMDD
OT  - TrkB
OT  - antibody
OT  - body weight
OT  - modeling
OT  - pharmacodynamics
OT  - pharmacokinetics
EDAT- 2013/03/27 06:00
MHDA- 2015/04/17 06:00
PMCR- 2014/05/01
CRDT- 2013/03/27 06:00
PHST- 2013/03/27 06:00 [entrez]
PHST- 2013/03/27 06:00 [pubmed]
PHST- 2015/04/17 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - 23826 [pii]
AID - 2012MABS0313R [pii]
AID - 10.4161/mabs.23826 [doi]
PST - ppublish
SO  - MAbs. 2013 May-Jun;5(3):373-83. doi: 10.4161/mabs.23826. Epub 2013 Mar 25.