title: Plasma Pharmacokinetics of Veledimex, a Small-Molecule Activator Ligand for a Proprietary Gene Therapy Promoter System, in Healthy Subjects.
abstract: Major obstacles to developing effective immunotherapy are the ability of tumors to escape the immune system and the toxicity associated with systemic administration. To overcome these challenges, a gene delivery platform technology, RheoSwitch Therapeutic System (RTS), has been developed to enable the regulated expression of a target gene, Ad-RTS-IL-12, administered intratumorally, where IL-12 expression is controlled via the administration of an oral activator ligand, veledimex. Pharmacokinetics in healthy human subjects indicated that veledimex plasma exposure increased with increasing dose after single- and multiple-dose administration in Labrasol slurry and F-22 capsule formulations. No apparent formulation or sex-related difference in veledimex pharmacokinetics (PK) was observed. Minimal or no plasma accumulation of veledimex was observed after once-daily oral administration for 14 days. Veledimex steady state in plasma was reached after 5 daily doses. Food consumption prior to veledimex administration prolonged and enhanced absorption with no impact on the elimination rate and extent of metabolism of veledimex, resulting in significantly increased systemic exposure to veledimex and its 2 major circulating metabolites. Overall, veledimex was well tolerated and exhibited a PK profile supportive of once-daily dosing. For enhanced efficacy, veledimex should be taken under fed conditions to ensure optimal absorption and sufficient systemic exposure.
authors.affiliation: ZIOPHARM Oncology Inc., Boston, MA, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Cai
authors.affiliation: ZIOPHARM Oncology Inc., Boston, MA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: ZIOPHARM Oncology Inc., Boston, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Miao
authors.affiliation: INTREXON Corporation, Germantown, MD, USA.
authors.forename: Suma
authors.initials: S
authors.lastname: Krishman
authors.affiliation: ZIOPHARM Oncology Inc., Boston, MA, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Lebel
authors.affiliation: ZIOPHARM Oncology Inc., Boston, MA, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Barrett
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D058615:Synthetic Biology; D055815:Young Adult
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D054852:Small Molecule Libraries; C000626304:veledimex
keywords: RheoSwitch Therapeutic System; food effect; pharmacokinetics; veledimex