title: Safety, tolerability, and pharmacokinetics of SMT C1100, a 2-arylbenzoxazole utrophin modulator, following single- and multiple-dose administration to healthy male adult volunteers.
abstract: SMT C1100 is a small molecule utrophin modulator in development to treat Duchenne muscular dystrophy. This study evaluated the safety, tolerability, and pharmacokinetics of SMT C1100 in healthy volunteers. This double-blind, placebo-controlled Phase 1 study comprised: Part 1, an escalating, single-dose with/without fasting involving 50 mg/kg, 100 mg/kg, 200 mg/kg, and 400 mg/kg doses; and Part 2, a multiple 10 day dose evaluation involving 100 mg/kg bid and 200 mg/kg bid doses. Adverse events were recorded. SMT C1100 was absorbed rapidly following single and multiple oral doses, with median tmax attained within 2-3.5 hour across all doses. Considerable variability of pharmacokinetic parameters was noted among subjects. Following single doses, systemic exposure increased in a sub-proportional manner, with the 8.0-fold dose increment resulting in 2.7- and 2.4-fold increases in AUC0-∞ and Cmax , respectively. AUC0-∞ and Cmax were estimated as 4.2- and 4.8-fold greater, respectively, following food. Systemic exposure reduced upon repeat dosing with steady-state concentrations achieved within 3-5 days of multiple bid dosing. No serious or severe adverse events were reported. SMT C1100 was safe and well tolerated with plasma concentrations achieved sufficient to cause a 50% increase in concentrations of utrophin in cells in vitro.
authors: Summit Corporation plc, Abingdon, Oxford, UK.
authors: Jon
authors: J
authors: Tinsley
authors: Neil
authors: N
authors: Robinson
authors: Kay E
authors: KE
authors: Davies
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry; D052160:Benzothiazoles / Q000737:chemistry*; D001583:Benzoxazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D019055:No-Observed-Adverse-Effect Level; D049411:Utrophin / Q000096:biosynthesis* / Q000737:chemistry; D055815:Young Adult
chemical_list: C526563:2-argininylbenzothiazole; D052160:Benzothiazoles; D001583:Benzoxazoles; D049411:Utrophin; D001120:Arginine
keywords: Duchene muscular dystrophy; Phase 1; Utrophin; disease modifying therapy; pharmacokinetics
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