title: Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations.
abstract: BACKGROUND
  Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease characterized by an absence or marked reduction of lysosomal N-acetylgalactosamine-4-sulfatase activity. Affected individuals have widespread accumulation of unmetabolized glycosaminoglycan substrates leading to detrimental effects. Recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) is an approved enzyme replacement therapy for patients with MPS VI. Despite the known efficacy of weekly 4-h rhASB infusions, some clinicians wish to treat patients using reduced infusion times. This study compared the pharmacodynamics, pharmacokinetics, and tissue biodistribution of rhASB when administered as 2- and 4-h intravenous infusions using a feline model of MPS VI.
  
  
  METHODS
  Study animals were MPS VI-affected cats that demonstrate clinical signs and biochemical derangements similar to human MPS VI patients. Beginning at age 4weeks, animals received weekly 2-h (N=6) or 4-h (N=6) IV infusions of rhASB for 26weeks (Naglazyme® [galsulfase] Solution for Intravenous Infusion; BioMarin Pharmaceutical, Inc.). The control group consisted of untreated MPS VI-affected cats (N=6). The pharmacokinetic parameters of plasma rhASB and urinary glycosaminoglycan were determined at weeks 13 and 26. Animals were euthanized 48h after the last infusion and tissue concentration of ASB, GAG and β-glucuronidase were measured in the liver, spleen, aorta, and kidney. Skeletal and ophthalmological evaluations were performed within 2weeks of euthanasia.
  
  
  RESULTS
  At week 13, the mean AUC0-t in animals treated with 4-h infusions was similar to 2-h infusions while the Cmax of the 4-h infusion was 50% of the 2-h infusion. By week 26, the mean AUC0-t of the 4-h infusion was 1.3-fold higher than the 2-h infusion (p<0.05) while Cmax of the 4-h infusion was 70% of the 2-h infusion (p<0.05). Among animals treated with 2- and 4-h infusions, there was no difference in urinary GAG excretion, tissue GAG storage, tissue galsulfase activity, and β-glucuronidase but all were significantly different than control animals (for each, p<0.001). Radiographic skeletal abnormality scores for animals were also similar for both treatment groups and significantly higher than control animals (p<0.001). There was no significant difference in corneal clouding scores among treated and untreated animals.
  
  
  CONCLUSIONS
  There was no significant difference in clinical outcomes when rhASB was administered to MPS VI affected cats as 2- and 4-h infusions over 26weeks. Additional studies may determine if shorter infusion times are appropriate for MPS VI patients without significant infusion-associated reactions.
authors.affiliation: Department of Pathology and Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Therese
authors.initials: T
authors.lastname: Ruane
authors.affiliation: Department of Pathology and Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Haskins
authors.affiliation: BioMarin Pharmaceutical, Inc., Novato, CA, United States.
authors.forename: Alphonsus
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Ryan Veterinary Hospital, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Aguirre
authors.affiliation: Pet Emergency Treatment Services, Inc., Lancaster, PA 17603, United States.
authors.forename: Van W Rafe
authors.initials: VW
authors.lastname: Knox
authors.affiliation: BioMarin Pharmaceutical, Inc., Novato, CA, United States.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: BioMarin Pharmaceutical, Inc., Novato, CA, United States.
authors.forename: Troy
authors.initials: T
authors.lastname: Tompkins
authors.affiliation: BioMarin Pharmaceutical, Inc., Novato, CA, United States. Electronic address: CO'Neill@bmrn.com.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D002415:Cats; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D056947:Enzyme Replacement Therapy; D005260:Female; D006025:Glycosaminoglycans / Q000652:urine; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009087:Mucopolysaccharidosis VI / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000652:urine; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase
keywords: Enzyme replacement therapy; Galsulfase; Infusion duration; Maroteaux–Lamy syndrome; Mucopolysaccharidosis VI; Recombinant human N-acetylgalactosamine 4-sulfatase