Abstract
TRPV4 channels expressed on pulmonary endothelial cells are activated by elevated pulmonary vascular pressure, resulting in endothelial shape change, pulmonary barrier disruption and edema. As such, TRPV4 blocker GSK2798745 was recently investigated in Phase I/IIa trials to reduce pulmonary edema caused by heart failure (HF). In the absence of a suitable TRPV4 target engagement biomarker, we hypothesized that an ex vivo assay could be utilized to predict pharmacological activity at the intended site of action (endothelial cells) of subjects. In this assay, the ability of GSK2798745 to block TRPV4 agonist GSK1016790-induced impendence reduction in human umbilical vein endothelial cells (HUVECs) in the presence of human whole blood was assessed. Blood from healthy volunteers drawn 1-12 h after single or repeated dose of GSK2798745 (5 mg) inhibited GSK1016790-induced impedance reduction by {greater than or equal to}85%. Similarly, blood samples from 16 HF subjects dosed with GSK2798745 (2.4 mg) inhibited GSK1016790-induced HUVEC impedance reduction by {greater than or equal to}58% 1-24 h after single dosing and {greater than or equal to}78% 1-24 h after 7 days of repeated dosing. No inhibition was detected using blood from placebo subjects. Using matched GSK2798745 plasma levels, a pharmacokinetic/pharmacodynamic (PK/PD) relationship was calculated as 2.9 nM IC50, consistent with the 6.5 nM IC50 of GSK2798745 obtained from a rat in vivo PK/PD model of pulmonary edema after correcting for rat-to-human differences. These results indicate circulating levels of GSK2798745 in the recently completed Phase I/IIa trials were sufficient to block TRPV4 in lung vascular endothelial cells to a large extent, supporting this dosing regimen for assessing efficacy in HF.
Significance Statement In the absence of a suitable target engagement biomarker, we developed an ex vivo assay to predict the pharmacological activity of the TRPV4 blocker GSK2798745 in healthy volunteers and HF subjects from Phase I/IIa trials. The potency values from the ex vivo assay were consistent with those predicted from a rat in vivo PK/PD model of pulmonary edema, strongly suggest circulating levels of GSK2798745 were sufficient to robustly block TRPV4, supporting use of GSK2798745 for assessing efficacy in HF.
- clinical pharmacology
- endothelial cells
- pharmacokinetic / pharmacodynamic modeling
- pulmonary pharmacology
- transient receptor potential (TRP) receptors
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