Fabry Disease is a glycosphingolipid storage disorder that is caused by deficient activity of the lysosomal enzyme α-galactosidase A, resulting in accumulation of globotriaosylceramide (Gb3 or GL-3, also known as ceramidetrihexoside (CTH)), the glycosphingolipid substrate for this enzyme. Agalsidase alfa catalyses the hydrolysis of Gb3, cleaving a terminal galactose residue from the molecule. Treatment with the enzyme has been shown to reduce accumulation of Gb3 in many cell types including endothelial and parenchymal cells. Agalsidase alfa has been produced in a human cell line to provide for a human glycosylation profile that can influence uptake by mannose-6-phosphate receptors on the surface of target cells. The selection of 0.2 mg/kg dose (infused over 40 minutes) for the registration clinical studies was intended to temporarily saturate the ability of the mannose-6-phosphate receptors to internalize the agalsidase alfa in the liver and allow distribution of enzyme to other relevant organ tissues. Data with patients indicates that at least 0.1mg/kg is required to achieve a pharmacodynamics response.
Single doses ranging from 0.007-0.2 mg enzyme per kg body weight were administered to adult male patients as 20-40 minute intravenous infusions while female patients received 0.2 mg enzyme per kg body weight as 40 minute infusions. The pharmacokinetic properties were essentially unaffected by the dose of the enzyme. Following a single intravenous dose of 0.2 mg/kg, agalsidase alfa had a biphasic distribution and elimination profile from the circulation. Pharmacokinetic parameters were not significantly different between male and female patients. Elimination half-lives were 108 ± 17 minutes in males compared to 89 ± 28 minutes in females and volume of distribution was approximately 17% body weight in both sexes. Clearance normalised for body weight was 2.66 and 2.10 ml/min/kg for males and females, respectively. Based on the similarity of pharmacokinetic properties of agalsidase alfa in both males and females, tissue distribution in major tissues and organs is also expected to be comparable in male and female patients.
Following six months of agalsidase alfa treatment 12 of 28 male patients showed altered pharmacokinetics including an apparent increase in clearance. These changes were associated with the development of low titre antibodies to agalsidase alfa but no clinically significant effects on safety or efficacy were observed in the patients studied.
Based on the analysis of pre- and post-dose liver biopsies in males with Fabry Disease, the tissue half-life has been estimated to be in excess of 24 hours and hepatic uptake of the enzyme estimated to be 10% of administered dose.
Agalsidase alfa is a protein. It is not expected to bind to proteins. It is expected that its metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis. Agalsidase alfa is unlikely to be a candidate for drug-drug interactions.
Renal elimination of agalsidase alfa is considered to be a minor clearance pathway since pharmacokinetic parameters are not altered by impaired renal function.
As metabolism is expected to occur by peptide hydrolysis, impaired liver function is not expected to affect the pharmacokinetics of agalsidase alfa in a clinically significant manner.
In children (aged 7-18 years), agalsidase alfa administered at 0.2 mg/kg was cleared faster from the circulation than in adults. Mean clearance of agalsidase alfa in children aged (7-11 years), in adolescents (aged 12-18 years), and adults was 4.2 ml/min/kg, 3.1 ml/min/kg, and 2.3 ml/min/kg, respectively. Pharmacodynamic data suggest that at a dose of 0.2 mg/kg agalsidase alfa, the reductions in plasma Gb3 are more or less comparable between adolescents and young children.
Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity. Genotoxic and carcinogenic potential are not expected. Reproduction toxicity studies in female rats and rabbits have shown no effect on pregnancy or the developing foetus. No studies have been conducted with respect to parturition or peri/post-natal development. It is not known whether agalsidase alfa crosses the placenta.
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