Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 55, Issue 6, Pages 698-707Publisher
WILEY-BLACKWELL
DOI: 10.1002/jcph.468
Keywords
Utrophin; Duchene muscular dystrophy; disease modifying therapy; pharmacokinetics; Phase 1
Categories
Funding
- US parent charities
- Parent Project Muscular Dystrophy
- Muscular Dystrophy Association USA
- Cure Duchenne
- Charley's Fund
- Nash Avery Foundation
- Federation to Eradicate Duchenne
- Medical Research Council [MC_UU_12021/2] Funding Source: researchfish
- Rosetrees Trust [M164-F1] Funding Source: researchfish
- MRC [MC_UU_12021/2] Funding Source: UKRI
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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 t(max) 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 AUC(0-infinity) and C-max, respectively. AUC(0-infinity) and C-max 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.
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