Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Amicus Therapeutics Europe Limited, Block 1, Blanchardstown Corporate Park, Ballycoolin Road, Blanchardstown, Dublin, D15 AKK1, Ireland e-mail: info@amicusrx.co.uk
Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary track and metabolism products
ATC Code: A16AX06
Miglustat is a pharmacokinetic enzyme stabiliser of cipaglucosidase alfa.
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.
The European Medicines Agency has deferred the obligation to submit the results of studies with Opfolda in one or more subsets of the paediatric population in the treatment of glycogen storage disease Type II (Pompe disease) (see section 4.2 for information on paediatric use).
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, see section 4.2.
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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