PMID- 25940675
OWN - NLM
STAT- MEDLINE
DCOM- 20160912
LR  - 20181113
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 80
IP  - 5
DP  - 2015 Nov
TI  - Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 
      mimetic, in a first-in-human study.
PG  - 1051-63
LID - 10.1111/bcp.12676 [doi]
AB  - AIMS: The aim of the present study was to evaluate the 
      pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single 
      intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 
      (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus 
      (T2DM). METHODS: T2DM subjects (glycosylated haemoglobin: 7.0-10.5%; on stable 
      metformin therapy and/or diet and exercise) were randomized to receive a single 
      dose of placebo or PF-05231023 (0.5-200 mg). Safety evaluations were performed up 
      to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was 
      developed for triglyceride - an early marker of drug activity. RESULTS: No 
      antidrug antibody or serious adverse events (AEs) were observed. The most 
      frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 
      levels peaked immediately post-IV dosing, with mean terminal half-lives of 
      6.5-7.7 h and 66.5- 96.6 h for intact C- and N-termini, respectively. Intact 
      C-terminus exposures increased proportionally with increasing dose, whereas 
      N-terminus exposures appeared to trend higher than dose-proportionally. Although 
      no apparent effect on plasma glucose was seen, dose-dependent decreases in 
      triglyceride were observed, with a maximum reduction of 48.5 +/- 10.0% 
      (mean +/- standard deviation) for the 200 mg dose compared with a reduction of 
      19.1 +/- 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a 
      reduction in total cholesterol and low-density lipoprotein cholesterol and an 
      increase in high-density lipoprotein cholesterol were observed in the high-dose 
      groups. CONCLUSIONS: Single IV doses of PF-05231023 up to 200 mg were generally 
      safe and well tolerated by subjects with T2DM. The observed early sign of 
      pharmacology supports further clinical testing of PF-05231023 upon repeated 
      administration.
CI  - (c) 2015 The British Pharmacological Society.
FAU - Dong, Jennifer Q
AU  - Dong JQ
AD  - Pfizer, Inc., Cambridge, MA, USA.
FAU - Rossulek, Michelle
AU  - Rossulek M
AD  - Pfizer, Inc., Cambridge, MA, USA.
FAU - Somayaji, Veena R
AU  - Somayaji VR
AD  - Pfizer, Inc., Cambridge, MA, USA.
FAU - Baltrukonis, Daniel
AU  - Baltrukonis D
AD  - Pfizer, Inc., Groton, CT, USA.
FAU - Liang, Yali
AU  - Liang Y
AD  - Pfizer, Inc., Groton, CT, USA.
FAU - Hudson, Krischan
AU  - Hudson K
AD  - Pfizer, Inc., Cambridge, MA, USA.
FAU - Hernandez-Illas, Martha
AU  - Hernandez-Illas M
AD  - MRA Clinical Research, South Miami, FL, USA.
FAU - Calle, Roberto A
AU  - Calle RA
AD  - Pfizer, Inc., Cambridge, MA, USA.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20150729
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PF-05231023)
RN  - 0 (Triglycerides)
RN  - 0 (fibroblast growth factor 21)
RN  - 62031-54-3 (Fibroblast Growth Factors)
SB  - IM
MH  - Administration, Intravenous
MH  - Antibodies, Monoclonal, Humanized/administration & dosage/adverse 
      effects/*pharmacokinetics/pharmacology
MH  - Diabetes Mellitus, Type 2/*blood
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Fibroblast Growth Factors/administration & dosage/adverse 
      effects/*agonists/*pharmacokinetics/pharmacology
MH  - Humans
MH  - Hypoglycemic Agents/administration & dosage/adverse 
      effects/pharmacokinetics/pharmacology
MH  - Male
MH  - Middle Aged
MH  - Triglycerides/blood
PMC - PMC4631178
OTO - NOTNLM
OT  - FGF21
OT  - T2DM
OT  - pharmacodynamics
OT  - pharmacokinetics
EDAT- 2015/05/06 06:00
MHDA- 2016/09/13 06:00
PMCR- 2016/11/01
CRDT- 2015/05/06 06:00
PHST- 2014/11/18 00:00 [received]
PHST- 2015/04/23 00:00 [revised]
PHST- 2015/04/29 00:00 [accepted]
PHST- 2015/05/06 06:00 [entrez]
PHST- 2015/05/06 06:00 [pubmed]
PHST- 2016/09/13 06:00 [medline]
PHST- 2016/11/01 00:00 [pmc-release]
AID - 10.1111/bcp.12676 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2015 Nov;80(5):1051-63. doi: 10.1111/bcp.12676. Epub 2015 
      Jul 29.