GM2 gangliosidosis (GM2g) is an inherited
neurodegenerative disorder caused by deficiency of lysosomal
beta-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.