title: Pharmacokinetic and pharmacodynamic evaluation of elosulfase alfa, an enzyme replacement therapy in patients with Morquio A syndrome.
abstract: OBJECTIVE
  Morquio A syndrome (mucopolysaccharidosis IVA; MPS IVA) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, an enzyme required for degradation of the glycosaminoglycan keratan sulfate. Enzyme replacement therapy with elosulfase alfa provides a potential therapy for Morquio A syndrome. We analyzed the pharmacokinetics and pharmacodynamics of elosulfase alfa in Morquio A patients from a phase III clinical trial.
  
  
  METHODS
  In a randomized double-blind study, elosulfase alfa at 2.0 mg/kg was administrated weekly or every other week for 24 weeks. Pharmacokinetic parameters of elosulfase alfa were determined at weeks 0 and 22 by non-compartmental analysis. Safety was assessed throughout the study. The relationship of pharmacokinetic parameters to patient demographics, pharmacodynamic assessments, immunogenicity, and efficacy and safety outcomes were assessed graphically by treatment group.
  
  
  RESULTS
  Elosulfase alfa exposure and half-life (t(½)) increased for both dose regimens during the study. There appeared to be no consistent trend between drug clearance (CL) and patient's sex, race, body weight, or age. All patients developed anti-drug antibodies, but no association was noted between total antibody titer and CL. In contrast, positive neutralizing antibody (NAb) status appeared to associate with decreased CL and prolonged t(½) for patients in the cohort dosed weekly. NAb may interfere with receptor-mediated cellular uptake and lead to increased circulation time of elosulfase alfa.
  
  
  CONCLUSIONS
  Despite the association between NAb and decreased drug clearance, neither dosing cohort showed associations between drug exposure and change in urinary keratan sulfate, 6-min walk test distances, or the occurrence of adverse events.
authors.affiliation: BioMarin Pharmaceutical Inc., 105 Digital Dr, Novato, CA, 94949, USA, yqi@bmrn.com.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Qi
authors.forename: Donald G
authors.initials: DG
authors.lastname: Musson
authors.forename: Becky
authors.initials: B
authors.lastname: Schweighardt
authors.forename: Troy
authors.initials: T
authors.lastname: Tompkins
authors.forename: Lynne
authors.initials: L
authors.lastname: Jesaitis
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Shaywitz
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Neill
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood; D002648:Child; D002811:Chondroitinsulfatases / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004311:Double-Blind Method; D056947:Enzyme Replacement Therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D011994:Recombinant Proteins; D002811:Chondroitinsulfatases; C102295:GALNS protein, human