The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to hydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion, laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likely via mannose-6 phosphate receptors.
Purified laronidase is a glycoprotein with a molecular weight of approximately 83 kDa. Laronidase is comprised of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modifications sites.
Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs). MPS I is a heterogeneous and multisystemic disorder characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolase which catalyses the hydrolysis of terminal α-L-iduronic residues of dermatan sulfate and heparan sulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAGs, dermatan sulfate and heparan sulfate in many cell types and tissues.
After intravenous administration of laronidase with an infusion time of 240 minutes and at a dose of 100 U/kg body weight pharmacokinetic properties were measured at Weeks 1, 12 and 26.
| Parameter | Infusion 1 | Infusion 12 | Infusion 26 |
|---|---|---|---|
| Mean ± SD | Mean ± SD | Mean ± SD | |
| Cmax (U/ml) | 0.197 ± 0.052 | 0.210 ± 0.079 | 0.302 ± 0.089 |
| AUC∞ (h•U/ml) | 0.930 ± 0.214 | 0.913 ± 0.445 | 1.191 ± 0.451 |
| CL (ml/min/kg) | 1.96 ± 0.495 | 2.31 ± 1.13 | 1.68 ± 0.763 |
| Vz (l/kg) | 0.604 ± 0.172 | 0.307 ± 0.143 | 0.239 ± 0.128 |
| Vss (l/kg) | 0.440 ± 0.125 | 0.252 ± 0.079 | 0.217 ± 0.081 |
| t1/2 (h) | 3.61 ± 0.894 | 2.02 ± 1.26 | 1.94 ± 1.09 |
Cmax showed an increase over time. The volume of distribution decreased with continued treatment, possibly related to antibody formation and/or decreased liver volume. The pharmacokinetic profile in patients less than 5 years old was similar to that of older and less severely affected patients.
Laronidase is a protein and is expected to be metabolically degraded through peptide hydrolysis. Consequently, impaired liver function is not expected to affect the pharmacokinetics of laronidase in a clinically significant way. Renal elimination of laronidase is considered to be a minor pathway for clearance.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, repeated dose toxicity and toxicity to reproduction. Genotoxic and carcinogenic potential are not expected.
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