TY - JOUR
T1 - Pharmacokinetics, safety and tolerability of miglustat in the treatment of pediatric patients with GM2 gangliosidosis
AU - Maegawa, Gustavo H.B.
AU - van Giersbergen, Paul L.M.
AU - Yang, Sandra
AU - Banwell, Brenda
AU - Morgan, Christopher P.
AU - Dingemanse, Jasper
AU - Tifft, Cynthia J.
AU - Clarke, Joe T.R.
N1 - Funding Information:
We thank Vivian Cruz, R.N., Lynn MacMillian, R.N., Margaret Mackrell, R.N., and Barbara Chapman, R.N. who assisted in the clinical assessments. We are grateful for Dr. John Callahan and members of Clinical Biochemical Genetics Laboratory at the Hospital for Sick Children who provided equipments for sample processing and storage. Life for Luke Foundation supported the fellowship of GHBM. We also acknowledge the nursing staff of the General Clinical Research Center at CNMC for sample collection and processing, and the dedicated families of our patients. This study was supported in part by a grant from Actelion Pharmaceuticals, US and by Grant 5-M01-RR-020359-04 from the National Center for Research Resources, NIH.
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
KW - GM2 gangliosidosis
KW - Miglustat
KW - Pharmacokinetics
KW - Safety
KW - Sandhoff disease
KW - Substrate reduction therapy
KW - Tay-Sachs disease
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U2 - 10.1016/j.ymgme.2009.04.013
DO - 10.1016/j.ymgme.2009.04.013
M3 - Article
C2 - 19447653
AN - SCOPUS:67649656119
SN - 1096-7192
VL - 97
SP - 284
EP - 291
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 4
ER -