Pharmacokinetics and Pharmacodynamics of Hyaluronan Infused into Healthy Human Volunteers
Sara Rae Hamilton#1, Mandana Veiseh#2, Cornelia Tölg#3, Rommel Tirona4, Jakob Richardson3, Richard Brown5, Mario Gonzalez6, Michael Vanzieleghem7, Patricia Anderson8, Samuel Asculai9, Françoise Winnik10, Rashmin Savani11, David Freeman12, Leonard Luyt13, James Koropatnick*, 14, Eva Ann Turley*, 15
1 London Regional Cancer Program, Cancer Research Laboratories, London, Ontario, Canada, and Department of Biochemistry, University of Western Ontario, London, Ontario, Canada
2 Life Sciences Division, Lawrence Berkeley National Laboratories, Berkeley CA
3 London Regional Cancer Program, Cancer Research Laboratories, London, Ontario, Canada
4 Department of Physiology & Pharmacology and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
5 BioMS Medical Corporation, Edmonton, Alberta, Canada
10 Département de Chimie et Faculté de Pharmacie, Université de Montréal, Pavillon J.A. Bombardier, CP 6128 Succursale Centre Ville, Montréal, QC, Canada
11 William Buchanan Chair in Pediatrics, Director, Division of Neonatal-Perinatal Medicine, Associate Director, Division of Pulmonary & Vascular Biology University of Texas Southwestern Medical Center, Dallas, TX
12 Faculty of Medicine, University of Western Ontario, London, Ontario, Canada
13 London Regional Cancer Program, Cancer Research Laboratories and Department of Chemistry
14 London Regional Cancer Program, Cancer Research Laboratories and Departments of Oncology, Microbiology and Immunology, Pathology, and Physiology and Pharmacology, University of Western Ontario and Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada
15 London Regional Cancer Program, Cancer Research Laboratories (London, Ontario, Canada) and Departments of Biochemistry and Oncology, University of Western Ontario, London, Ontario, Canada
The pharmacodynamics and elimination kinetics of escalating doses (1.5-12 mg/kg) of hyaluronan (HA) infusions were studied in healthy human volunteers. Metabolic breakdown of serum HA and associated adverse events were monitored throughout the study. The HA-binding capacities of circulating CD4+ and CD8+ T lymphocytes, CD19+ Blymphocytes and CD14+ peripheral blood monocytes (PBMC) were also quantified. Breakdown of infused HA into small fragments (<37 kDa) were not detected and adverse events related to HA infusions were infrequent and non-serious in nature. Binding of FITC-HA was greatest to CD14+ monocytes and the binding capacity of these cells for FITC-HA was significantly increased by the final HA infusion. At that time, binding to CD14+ monocytes was related to serum HA levels suggesting a close relationship between PK and PD of serum HA. Drug level analysis demonstrated a disproportional increase in the area under the serum concentration vs. time curve with increasing HA dose. The observed non-linear HA kinetics appears to result from a saturable elimination process as revealed by pharmacokinetic modeling. These results have implications for the use of injected HA for drug delivery or in imaging applications.
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/-nc/3.0/) which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.
* Address correspondence to these authors at the London Regional Cancer Program, 790 Commissioners Rd E, London, Ontario, N6A4L6. Business, Canada; Tel: 519-685-8600 ext 53677; Fax: 519-685-6816; E-mail: email@example.com@uwo.ca#These authors contributed equally.