title: Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuPH20.
abstract: OBJECTIVE
  To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tocilizumab with and without rHuPH20 (a recombinant human hyaluronidase) in healthy volunteers.
  
  
  METHODS
  This was an open-label, single ascending dose study. Subjects were assigned to tocilizumab 162 mg or tocilizumab 162, 324, or 648 mg plus rHuPH20. PK and PD samples were collected after dosing and were estimated with non-compartmental methods. Geometric mean ratio (GMR) for area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and (maximum serum concentration) Cmax with and without rHuPH20 was estimated using one-way analysis of variance. Safety and tolerability were monitored throughout the study.
  
  
  RESULTS
  48 subjects (12/cohort) received a single dose of tocilizumab with or without rHuPH20. For tocilizumab 162 mg, tocilizumab 162 mg/rHuPH20, tocilizumab 324 mg/rHuPH20, and tocilizumab 648 mg/rHuPH20, mean ± SD tocilizumab PK parameters were 2,510 ± 1,060, 2,860 ± 468, 10,800 ± 3,220, and 29,900 ± 5,280 μg×h/ml for AUC0-∞; 11.5 ± 3.7, 16.2 ± 2.8, 43.8 ± 12.4, and 77.8 ± 14.5 μg/ml for Cmax; and 89.1 ± 41.1, 54.0 ± 19.5, 66.0 ± 26.8, and 86.1 ± 50.6 h for tmax, respectively. Coadministration of tocilizumab 162 mg with rHuPH20 resulted in slightly increased exposure: GMR (90% confidence interval) for AUC0-∞, 1.20 (1.00 - 1.44) and Cmax, 1.45 (1.24 - 1.70). Increasing tocilizumab doses resulted in significant deviation from dose proportionality for tocilizumab Cmax (p = 0.0057) and AUC0-∞ (p < 0.0001). Changes in interleukin-6, soluble interleukin- 6 receptor, and C-reactive protein were also dose dependent and similar with and without rHuPH20.
  
  
  CONCLUSIONS
  Tocilizumab in combination with rHuPH20 resulted in slightly increased tocilizumab exposure compared with tocilizumab alone, whereas PD markers were comparable. Subcutaneous administration of tocilizumab with rHuPH20 was well tolerated.
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Christine
authors.initials: C
authors.lastname: McIntyre
authors.forename: Beate
authors.initials: B
authors.lastname: Bittner
authors.forename: Lucy
authors.initials: L
authors.lastname: Rowell
authors.forename: Zubair
authors.initials: Z
authors.lastname: Hussain
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage* / Q000009:adverse effects; D018836:Inflammation Mediators / Q000097:blood; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D019947:Receptors, Interleukin-6 / Q000097:blood; D011994:Recombinant Proteins / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; C508600:IL6 protein, human; C508603:IL6R protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D002097:C-Reactive Protein; D006821:Hyaluronoglucosaminidase; C502936:tocilizumab