First‐in‐Human Study for a Selective Rearranged During Transfection Tyrosine Kinase Inhibitor, GSK3352589, to Investigate the Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers

Abstract

Rearranged during transfection (RET), a neuronal growth factor receptor tyrosine kinase, regulates the development of sympathetic, parasympathetic, motor, and sensory neurons in the enteric nervous system. The intended site of action for GSK3352589 is intestinal tissues. GSK3352589 is an RET kinase inhibitor that was administered in double‐blind, randomized, placebo‐controlled single‐dose (SD) and repeat‐dose (RD) studies in healthy subjects to investigate its safety/tolerability and pharmacokinetics. In the SD study (n = 28), GSK3352589 was dosed from 2 to 400 mg, including a food effect arm (25 mg). In the RD study (n = 40), GSK3352589 was dosed for 14 days with food twice daily from 5 to 200 mg. With single (fed and fasted) and repeat (fed) doses, bioavailability was low and less than dose‐proportional. There was a food effect with 25 mg once daily but may not be clinically relevant. Elimination half‐life was ≥17 hours at SD ≥ 15 mg. Accumulation ratios for Cmax, AUCt, AUCtau, and AUC24 after twice‐daily dosing to steady state ranged from 1.2 to 1.8 for all doses except the 200‐mg dose, which had ratios between 1.9 and 2.7. Administration of GSK3352589 after SD and RD was well tolerated with no safety concerns in healthy subjects.

Pharmacokinetics and Safety Study of HN0037, a Novel Anti‐Human Herpes Simplex Virus Inhibitor, in Healthy Volunteers

“…Food content is considered to change gastrointestinal (GI) physiology, including delayed gastric emptying, increased bile flow, change in GI pH, increased splanchnic blood flow, possible luminal metabolism, and other physical or chemical interactions. [18][19][20] The food-effect results were consistent with the expectations for a BCS II compound. Accordingly, exposure to HN0037 increased when a single oral dose was administered after a meal.…”