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: Jon Tinsley, Neil Robinson, Kay E Davies
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 55 Issue 6 Pg. 698-707 (Jun 2015) ISSN: 1552-4604 [Electronic] England
• PMID: 25651188 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Chemical References

• 2-argininylbenzothiazole
• Benzothiazoles
• Benzoxazoles
• Utrophin
• Arginine

Topics

• Administration, Oral
• Adolescent
• Adult
• Area Under Curve
• Arginine (analogs & derivatives, chemistry)
• Benzothiazoles (chemistry)
• Benzoxazoles (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Half-Life
• Healthy Volunteers
• Humans
• Male
• Middle Aged
• Muscular Dystrophy, Duchenne (drug therapy)
• No-Observed-Adverse-Effect Level
• Utrophin (biosynthesis, chemistry)
• Young Adult