Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis

Gustavo H B Maegawa, Paul L M van Giersbergen, Sandra Yang, Brenda Banwell, Christopher P. Morgan, Jasper Dingemanse, Cynthia J. Tifft, Joe T R Clarke

Research output: Contribution to journalArticle

Abstract

GM2 gangliosidosis (GM2g) is an inherited neurodegenerative disorder caused by deficiency of lysosomal β-hexosaminidase A, resulting in accumulation of GM2 ganglioside, principally in the brain. Substrate reduction therapy is currently under investigation as a treatment. The study investigated the pharmacokinetics and safety of miglustat given as single and multiple doses in infantile and juvenile GM2g patients for 6- and 24-months, respectively. Eleven patients with infantile (n = 6) and juvenile (n = 5) GM2g received oral miglustat at 30-200 mg t.i.d. adjusted to the body surface area. Patients underwent pharmacokinetic assessments on day 1 and at month 3. The pharmacokinetics of miglustat were described by a 2-compartmental model with a lag time, median time to maximum concentration of 2.5 h, and terminal half-life of about 10 h. The pharmacokinetics were time-independent, and did not differ between infantile and juvenile cohorts. The accumulation index was 1.7. Among infantile GM2g patients, the major drug-related adverse events (DRAEs) were abdominal discomfort and flatulence. In the juvenile group, however, the major DRAEs observed were diarrhea and weight loss. One juvenile patient developed peripheral neuropathy, and others showed progression of already established neuropathy, which was judged to be part of the natural progression of the disease. Some mild laboratory abnormalities observed were either transient or attributable to concomitant medications. Miglustat showed similar pharmacokinetic parameters in all patients, with no specific difference between infantile and juvenile forms. Miglustat was shown to be a safe drug, with mild to moderate diarrhea, as an age-dependent DRAE, which was controlled by dietary modification.

Original languageEnglish (US)
Pages (from-to)284-291
Number of pages8
JournalMolecular Genetics and Metabolism
Volume97
Issue number4
DOIs
StatePublished - Aug 2009
Externally publishedYes

Fingerprint

GM2 Gangliosidosis
Pediatrics
Pharmacokinetics
Safety
Drug-Related Side Effects and Adverse Reactions
Pharmaceutical Preparations
G(M2) Ganglioside
Hexosaminidase A
Diarrhea
Therapeutics
Tay-Sachs Disease
Diet Therapy
Flatulence
Body Surface Area
Peripheral Nervous System Diseases
Brain
Neurodegenerative Diseases
Half-Life
Disease Progression
miglustat

Keywords

  • GM2 gangliosidosis
  • Miglustat
  • Pharmacokinetics
  • Safety
  • Sandhoff disease
  • Substrate reduction therapy
  • Tay-Sachs disease

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Maegawa, G. H. B., van Giersbergen, P. L. M., Yang, S., Banwell, B., Morgan, C. P., Dingemanse, J., ... Clarke, J. T. R. (2009). Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis. Molecular Genetics and Metabolism, 97(4), 284-291. https://doi.org/10.1016/j.ymgme.2009.04.013

Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis. / Maegawa, Gustavo H B; van Giersbergen, Paul L M; Yang, Sandra; Banwell, Brenda; Morgan, Christopher P.; Dingemanse, Jasper; Tifft, Cynthia J.; Clarke, Joe T R.

In: Molecular Genetics and Metabolism, Vol. 97, No. 4, 08.2009, p. 284-291.

Research output: Contribution to journalArticle

Maegawa, GHB, van Giersbergen, PLM, Yang, S, Banwell, B, Morgan, CP, Dingemanse, J, Tifft, CJ & Clarke, JTR 2009, 'Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis', Molecular Genetics and Metabolism, vol. 97, no. 4, pp. 284-291. https://doi.org/10.1016/j.ymgme.2009.04.013
Maegawa, Gustavo H B ; van Giersbergen, Paul L M ; Yang, Sandra ; Banwell, Brenda ; Morgan, Christopher P. ; Dingemanse, Jasper ; Tifft, Cynthia J. ; Clarke, Joe T R. / Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis. In: Molecular Genetics and Metabolism. 2009 ; Vol. 97, No. 4. pp. 284-291.
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