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Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects.
Clin Pharmacokinet. 2020 Apr 25 [Online ahead of print]CP

Abstract

BACKGROUND

Selonsertib is a first-in-class inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with therapeutic potential for fibrotic diseases. This phase I study evaluated the safety, tolerability, pharmacokinetics (PK), and food effect of selonsertib in healthy subjects.

METHODS

This was a double-blinded, randomized, placebo-controlled dose-escalation study. Healthy subjects received 1, 3, 10, 30, or 100 mg of selonsertib or placebo as single or multiple doses once daily for 14 days in the fasted state, or 30 mg or placebo single dose in the fed state. Blood and urine (single-dose cohorts only) samples for selonsertib PK were collected and safety was assessed throughout the study. Ex vivo pharmacodynamic (PD) assessment was performed in blood from a separate cohort of healthy donors using an auranofin-stimulated C-X-C motif chemokine ligand 1 (CXCL1) assay.

RESULTS

Overall, 107 subjects (83 active, 24 placebo) were enrolled and randomized to 11 cohorts. Selonsertib was generally well tolerated; adverse events were generally mild to moderate. Selonsertib was rapidly absorbed with dose-proportional PK of both parent and inactive metabolite GS-607509. There was no food effect on selonsertib PK. Renal excretion was a minor pathway of selonsertib elimination. Selonsertib half maximal effective concentration (EC50) in human whole blood was determined to be 56 ng/mL.

CONCLUSIONS

Selonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food. PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated. Study results support further clinical development of selonsertib.

Authors+Show Affiliations

Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. cara.nelson@gilead.com.Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32333325

Citation

Nelson, Cara H., et al. "Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects." Clinical Pharmacokinetics, 2020.
Nelson CH, Etchevers K, Yi S, et al. Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects. Clin Pharmacokinet. 2020.
Nelson, C. H., Etchevers, K., Yi, S., Breckenridge, D., Hepner, M., Patel, U., Ling, J., & Mathias, A. (2020). Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects. Clinical Pharmacokinetics. https://doi.org/10.1007/s40262-020-00878-y
Nelson CH, et al. Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects. Clin Pharmacokinet. 2020 Apr 25; PubMed PMID: 32333325.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects. AU - Nelson,Cara H, AU - Etchevers,Kim, AU - Yi,Saili, AU - Breckenridge,David, AU - Hepner,Mischa, AU - Patel,Uptal, AU - Ling,John, AU - Mathias,Anita, Y1 - 2020/04/25/ PY - 2020/4/26/entrez JF - Clinical pharmacokinetics JO - Clin Pharmacokinet N2 - BACKGROUND: Selonsertib is a first-in-class inhibitor of apoptosis signal-regulating kinase 1 (ASK1) with therapeutic potential for fibrotic diseases. This phase I study evaluated the safety, tolerability, pharmacokinetics (PK), and food effect of selonsertib in healthy subjects. METHODS: This was a double-blinded, randomized, placebo-controlled dose-escalation study. Healthy subjects received 1, 3, 10, 30, or 100 mg of selonsertib or placebo as single or multiple doses once daily for 14 days in the fasted state, or 30 mg or placebo single dose in the fed state. Blood and urine (single-dose cohorts only) samples for selonsertib PK were collected and safety was assessed throughout the study. Ex vivo pharmacodynamic (PD) assessment was performed in blood from a separate cohort of healthy donors using an auranofin-stimulated C-X-C motif chemokine ligand 1 (CXCL1) assay. RESULTS: Overall, 107 subjects (83 active, 24 placebo) were enrolled and randomized to 11 cohorts. Selonsertib was generally well tolerated; adverse events were generally mild to moderate. Selonsertib was rapidly absorbed with dose-proportional PK of both parent and inactive metabolite GS-607509. There was no food effect on selonsertib PK. Renal excretion was a minor pathway of selonsertib elimination. Selonsertib half maximal effective concentration (EC50) in human whole blood was determined to be 56 ng/mL. CONCLUSIONS: Selonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food. PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated. Study results support further clinical development of selonsertib. SN - 1179-1926 UR - https://www.unboundmedicine.com/medline/citation/32333325/Pharmacokinetics,_Safety,_and_Tolerability_of_Selonsertib,_an_Apoptosis_Signal-Regulating_Kinase_1_(ASK1)_Inhibitor,_Following_First-in-Human_Single_and_Multiple_Ascending_Doses_in_Healthy_Subjects L2 - https://dx.doi.org/10.1007/s40262-020-00878-y DB - PRIME DP - Unbound Medicine ER -
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