Premium
First‐in‐Human Studies for a Selective RET Tyrosine Kinase Inhibitor, GSK3179106, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers
Author(s) -
Cooper Melisa,
O'ConnorSemmes Robin,
Reedy Beth Ann,
Hacquoil Kimberley,
Gorycki Peter,
Pannullo Kristen,
Verticelli Adeline,
Shakib Sepehr
Publication year - 2018
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.600
Subject(s) - tolerability , medicine , pharmacokinetics , dosing , pharmacology , bioavailability , tyrosine kinase inhibitor , placebo , adverse effect , cancer , pathology , alternative medicine
Rearranged during transfection (RET), a neuronal growth factor receptor tyrosine kinase, regulates the development of the sympathetic, parasympathetic, motor, and sensory neurons in the enteric nervous system. GSK3179106 is a RET kinase inhibitor that was administered in double‐blind, randomized, placebo‐controlled single‐dose and repeat‐dose studies in healthy subjects to investigate its pharmacokinetics and safety/tolerability. In the single‐dose study (n = 16), GSK3179106 was dosed from 10 mg to 800 mg, including a food effect arm. In the repeat‐dose study (n = 46), GSK3179106 was dosed for 14 days with food once daily (QD) from 5 mg to 100 mg and twice daily (BID) at 100 mg and 200 mg. With single fasted doses, bioavailability was low and less than dose proportional. A significant food effect was observed with a 100‐mg QD dose. Drug exposure after QD and BID repeat dosing with food showed dose dependency up to 100 mg but was not dose proportional. There were no significant differences in exposure between 100‐mg and 200‐mg BID doses of GSK3179106. Accumulation was observed with both QD and BID dosing. Single doses up to 800 mg and repeat doses up to 400 mg were well tolerated with no safety concerns in healthy subjects.