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Pharmacokinetics and pharmacodynamics of PF‐05231023, a novel long‐acting FGF21 mimetic, in a first‐in‐human study
Author(s) -
Dong Jennifer Q.,
Rossulek Michelle,
Somayaji Veena R.,
Baltrukonis Daniel,
Liang Yali,
Hudson Krischan,
HernandezIllas Martha,
Calle Roberto A.
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12676
Subject(s) - pharmacokinetics , pharmacodynamics , tolerability , medicine , placebo , pharmacology , metformin , triglyceride , dosing , adverse effect , endocrinology , cholesterol , diabetes mellitus , alternative medicine , pathology
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.