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Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial
- Source :
- Neuromuscular disorders : NMD
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ≥9 years, in wheelchairs for ≥1 to ≤4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population.
- Subjects :
- Male
Duchenne muscular dystrophy
medicine.medical_specialty
Adolescent
Population
Clinical Neurology
Oligonucleotides
Urology
Non-ambulant
Article
law.invention
Dystrophin
Double-Blind Method
Randomized controlled trial
Pharmacokinetics
law
Oligonucleotide
Exon 51
DMD
Post-hoc analysis
Humans
Medicine
Genetics(clinical)
Pediatrics, Perinatology, and Child Health
Child
education
Genetics (clinical)
Drisapersen
education.field_of_study
biology
business.industry
medicine.disease
Muscular Dystrophy, Duchenne
Neurology
Tolerability
Pediatrics, Perinatology and Child Health
biology.protein
Physical therapy
Neurology (clinical)
Inflammation Mediators
Safety
business
Biomarkers
Oligonucleotide, Pharmacokinetics
Subjects
Details
- ISSN :
- 09608966
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Neuromuscular Disorders
- Accession number :
- edsair.doi.dedup.....597c74f3eef604f80957f3b08fe70f18