Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study.
OBJECTIVE
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.
Pfizer, Inc., Cambridge, MA, USA.
Jennifer Q
JQ
Dong
Pfizer, Inc., Cambridge, MA, USA.
Michelle
M
Rossulek
Pfizer, Inc., Cambridge, MA, USA.
Veena R
VR
Somayaji
Pfizer, Inc., Groton, CT, USA.
Daniel
D
Baltrukonis
Pfizer, Inc., Groton, CT, USA.
Yali
Y
Liang
Pfizer, Inc., Cambridge, MA, USA.
Krischan
K
Hudson
MRA Clinical Research, South Miami, FL, USA.
Martha
M
Hernandez-Illas
Pfizer, Inc., Cambridge, MA, USA.
Roberto A
RA
Calle
D061605:Administration, Intravenous; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000009:adverse effects / Q000819:agonists* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D014280:Triglycerides / Q000097:blood
D061067:Antibodies, Monoclonal, Humanized; D007004:Hypoglycemic Agents; C000604284:PF-05231023; D014280:Triglycerides; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
FGF21; T2DM; pharmacodynamics; pharmacokinetics