Pharmacokinetics and Pharmacodynamics of Hyaluronan Infused into Healthy Human Volunteers

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.