Chemical formula: C₁₀H₂₁NO₄ Molecular mass: 219.278 g/mol PubChem compound: 51634
Miglustat is an inhibitor of glucosylceramide synthase, the enzyme responsible for the first step in the synthesis of most glycolipids.
Miglustat is a pharmacokinetic enzyme stabiliser of cipaglucosidase alfa.
Gaucher disease is an inherited metabolic disorder caused by a failure to degrade glucosylceramide resulting in lysosomal storage of this material and widespread pathology. In vitro, glucosylceramide synthase is inhibited by miglustat with an IC50 of 20-37 µM. In addition, inhibitory action on a non-lysosomal glycosylceramidase has been demonstrated experimentally in vitro. The inhibitory action on glucosylceramide synthase forms the rationale for substrate reduction therapy in Gaucher disease.
Niemann-Pick type C disease is a very rare, invariably progressive and eventually fatal neurodegenerative disorder characterised by impaired intracellular lipid trafficking. The neurological manifestations are considered secondary to the abnormal accumulation of glycosphingolipids in neuronal and glial cells.
Miglustat binds selectively with cipaglucosidase alfa in the blood during infusion; thereby stabilising the conformation of cipaglucosidase alfa and minimising the loss of enzyme activity while in circulation. This selective binding between cipaglucosidase alfa and miglustat is transient with disassociation occurring in the lysosome. Miglustat alone has no effect on glycogen reduction.
Pharmacokinetic parameters of miglustat were assessed in healthy subjects, in a small number of patients with type 1 Gaucher disease, Fabry disease, HIV-infected patients, and in adults, adolescents and children with Niemann-Pick type C disease or type 3 Gaucher disease.
The kinetics of miglustat appear to be dose linear and time independent. In healthy subjects miglustat is rapidly absorbed. Maximum plasma concentrations are reached about 2 hours after dose. Absolute bioavailability has not been determined. Concomitant administration of food decreases the rate of absorption (Cmax was decreased by 36% and tmax delayed 2 hours), but has no statistically significant effect on the extent of absorption of miglustat (AUC decreased by 14%).
The apparent volume of distribution of miglustat is 83 l. Miglustat does not bind to plasma proteins. Miglustat is mainly eliminated by renal excretion, with urinary recovery of unchanged drug accounting for 70-80% of the dose. Apparent oral clearance (CL/F) is 230 ± 39 ml/min. The average half-life is 6–7 hours.
Following administration of a single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the radioactivity was recovered in urine and 12% in faeces. Several metabolites were identified in urine and faeces. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150 h suggesting the presence of one or more metabolites with very long half-life. The metabolite accounting for this has not been identified, but may accumulate and reach concentrations exceeding those of miglustat at steady state.
The pharmacokinetics of miglustat is similar in adult type 1 Gaucher disease patients and Niemann-Pick type C disease patients when compared to healthy subjects.
Pharmacokinetic data were obtained in paediatric patients with type 3 Gaucher disease aged 3 to 15 years, and patients with Niemann-Pick type C disease aged 5–16 years. Dosing in children at 200 mg t.i.d. adjusted for body surface area resulted in Cmax and AUCτ values which were approximately two-fold those attained after 100 mg t.i.d. in type 1 Gaucher disease patients, consistent with the dose-linear pharmacokinetics of miglustat. At steady state, the concentration of miglustat in cerebrospinal fluid of six type 3 Gaucher disease patients was 31.4–67.2% of that in plasma.
Limited data in patients with Fabry disease and impaired renal function showed that CL/F decreases with decreasing renal function. While the numbers of subjects with mild and moderate renal impairment were very small, the data suggest an approximate decrease in CL/F of 40% and 60% respectively, in mild and moderate renal impairment. Data in severe renal impairment are limited to two patients with creatinine clearance in the range 18–29 ml/min and cannot be extrapolated below this range. These data suggest a decrease in CL/F by at least 70% in patients with severe renal impairment.
Over the range of data available, no significant relationships or trends were noted between miglustat pharmacokinetic parameters and demographic variables (age, BMI, gender or race).
There are no pharmacokinetic data available in patients with liver impairment or in the elderly (>70 years).
The rate of absorption (tmax) of miglustat was approximately 2 to 3 hours. At the clinical dose, 260 mg, plasma miglustat attained a Cmax of approximately 3000 ng/mL and an AUC0-∞ of approximately 25,000 ng h/mL.
A significant food effect was observed and resulted in a decreased Cmax by 36% and delayed absorption by approximately 2 hours.
Miglustat is largely unmetabolised with <5% of a radiolabeled dose recovered as glucuronides.
The terminal elimination half-life was approximately 6 hours for miglustat. Oral clearance was approximately 10.5 L/h and terminal phase volume of distribution was approximately 90 L.
Miglustat demonstrated dose proportional kinetics.
Based on pooled population pharmacokinetic analysis, gender, age (18 to 74 years), and race/ethnicity did not have clinically meaningful effect on the exposure to miglustat in combination with cipaglucosidase alfa.
The pharmacokinetics of miglustat in combination with cipaglucosidase alfa therapy have not been evaluated in patients with hepatic impairment.
The AUC0-24hr of miglustat increased by 21%, 32%, and 41% in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/minute, estimated by Cockcroft-Gault), moderate (CLcr 30 to 59 mL/minute), and severe (CLcr 15 to 29 mL/minute) renal impairment, respectively, compared to patients with normal renal function. The effect of end stage renal disease on the pharmacokinetics of miglustat is unknown.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, and mutagenicity.
Carcinomas in the large intestine of mice occurred occasionally following oral treatment with miglustat at 210, 420 and 840/500 mg/kg/day for a period of 2 years. These doses correspond to 8, 16, and 33/19 times a human dose of 200 mg three times per day. The relevance of these findings to humans taking miglustat is unknown at the substantially lower studied doses at 195 to 260 mg every other week for Pompe disease.
There was no effect of miglustat in combination with cipaglucosidase alfa therapy on spermatogenesis in animal studies; however, a decrease in sperm motility was observed in rats treated with miglustat in combination with cipaglucosidase alfa, which appeared to be associated with miglustat.
In rats, miglustat administered orally at doses of 60 mg/kg/day and above resulted in seminiferous tubule and testicular atrophy/degeneration. Decreased spermatogenesis with altered sperm morphology and motility and decreased fertility were observed in rats orally dosed with miglustat 20 mg/kg/day oral gavage 14 days prior to mating with doses at exposures less than the human therapeutic systemic exposure based on body surface area comparisons (mg/m²). Decreased spermatogenesis was reversible in rats following 6 weeks of active substance withdrawal.
In a segment I fertility and early embryonic development study in rats, pre-implantation loss was observed in the female fertility component of the study in both miglustat alone (60 mg/kg) and the combination treatment group (cipaglucosidase alfa 400 mg/kg with oral miglustat 60 mg/kg) and was considered miglustat-related.
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