A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers

Abstract

Background Recombinant human hyaluronidase PH20 (rHuPH20) is used in subcutaneous formulations (eg, RITUXAN HYCELA [rituximab and hyaluronidase human], HERCEPTIN HYLECTA [trastuzumab and hyaluronidase-oysk], PHESGO [pertuzumab/trastuzumab/hyaluronidase-zzxf], and Darzalex FASPRO [daratumumab and hyaluronidase-fihj]) to increase the dispersion and absorption of coadministered therapeutics. Although unlikely, subcutaneous products that include rHuPH20 could be mistaken for the intravenous formulation of the corresponding drugs (eg, RITUXAN [rituximab], HERCEPTIN [trastuzumab], and DARZALEX [daratumumab]). To understand the potential effects of inadvertent intravenous injection of rHuPH20, we investigated the safety profile, pharmacokinetics (PK), and pharmacodynamics (PD) of rHuPH20 administered intravenously. Objectives This Phase I, open-label, single-center study in healthy volunteers was designed to assess the safety profile, tolerability, PK, and PD of rHuPH20 administered intravenously. Methods Healthy volunteers received 5 mL intravenous infusion of either 10,000 U (n = 12) or 30,000 U (n = 12) rHuPH20 over 5 minutes. Blood samples for PK and PD analysis were obtained at baseline and at various times after initiation of infusion. Adverse events and laboratory parameters were measured to assess the safety profile and tolerability of the intravenous infusion. The PK of rHuPH20 was assessed using both an enzymatic assay and a mass-based immunoassay, and plasma hyaluronan concentrations were measured as a PD marker using an HPLC–MS/MS disaccharide assay. Results All 24 volunteers (mean age = 36.5 years) completed the study, and no serious adverse events were reported in either treatment group. Overall, 2 adverse events (both Grade 1) were reported; catheter site pain in the 10,000 U group and hypotension in the 30,000 U group. Plasma concentrations of rHuPH20 increased during the 5-minute intravenous infusion (median t max = 6 minutes from intravenous initiation) followed by a rapid plasma clearance (t 1/2 ∼10 minutes from intravenous initiation). Plasma hyaluronan concentrations increased with dose and time (t max range = 45‒120 minutes from intravenous initiation) and returned to baseline within 1 week of administration. Changes in both PK and PD measurements appeared proportional to dose. Conclusions The study demonstrated that intravenous administration of up to 30,000 U rHuPH20 was well tolerated, rapidly cleared from the plasma, and did not appear to be associated with any serious adverse effects at doses used in subcutaneous therapeutic products. ( Curr Ther Res Clin Exp . 2020; 81)

Safety of recombinant human hyaluronidase PH20 for subcutaneous drug delivery

“…The clinical observation of no measurable systemic exposure at the doses tested is supported by the observed low SC bioavailability (<10%) in non-human primates as well as modeling studies that predict low systemic exposure after SC administration in humans [34]. In addition, a study in healthy volunteers demonstrated that intravenously administered rHuPH20 is rapidly cleared from the plasma [14]. Plasma concentrations of rHuPH20, quantified as both rHuPH20 hyaluronidase activity (enzymatic rHuPH20) and as immunoreactive rHuPH20 plasma concentration, increased during a single 5-min IV infusion of 10,000 U (n = 11) or 30,000 U (n = 12) rHuPH20 (median t max = 6 min from IV initiation for both doses of rHuPH20 and both enzymatic and immunoreactive assays, Figure 2) [14].…”

“…In addition, a study in healthy volunteers demonstrated that intravenously administered rHuPH20 is rapidly cleared from the plasma [14]. Plasma concentrations of rHuPH20, quantified as both rHuPH20 hyaluronidase activity (enzymatic rHuPH20) and as immunoreactive rHuPH20 plasma concentration, increased during a single 5-min IV infusion of 10,000 U (n = 11) or 30,000 U (n = 12) rHuPH20 (median t max = 6 min from IV initiation for both doses of rHuPH20 and both enzymatic and immunoreactive assays, Figure 2) [14]. This was followed by an early rapid decline in plasma concentrations of rHuPH20 that were below the limit of quantification within 2 hours [14].…”

“…Plasma concentrations of rHuPH20, quantified as both rHuPH20 hyaluronidase activity (enzymatic rHuPH20) and as immunoreactive rHuPH20 plasma concentration, increased during a single 5-min IV infusion of 10,000 U (n = 11) or 30,000 U (n = 12) rHuPH20 (median t max = 6 min from IV initiation for both doses of rHuPH20 and both enzymatic and immunoreactive assays, Figure 2) [14]. This was followed by an early rapid decline in plasma concentrations of rHuPH20 that were below the limit of quantification within 2 hours [14]. The apparent mean half-life for plasma rHuPH20 concentration was 3.7 and 5.6 min for the enzymatic assay with 10,000 U and 30,000 U rHuPH20 respectively, and 6.6 and 10.4 min for the immunoreactive assay with 10,000 U and 30,000 U, respectively (Figure 2) [14].…”

“…In addition, rHuPH20 is available as ENHANZE ® drug delivery technology, which is used to facilitate and optimize the SC administration of co-administered biotherapeutics. In this setting, rHuPH20 is approved for use as a component in a range of products in different therapeutic areas [8,14]. Table 1 shows products currently approved for use with rHuPH20.…”

Dispersive effects and focused biodistribution of recombinant human hyaluronidase PH20: A locally acting and transiently active permeation enhancer

“…Animal-derived hyaluronidase administrated intravenously was rapidly eliminated from the central compartment when administered to dogs (500 U/kg), humans (500 U/kg), and rats (5000 U/kg), with an elimination half-life of less than 10 minutes [53]. In addition, 10 000 or 30 000 U of rHuPH20 has been administered intravenously to healthy subjects, and the half-life was found to be approximately 10 minutes [54]. Bookbinder et al [18] administered an ID injection of either 5 U of rHuPH20 or buffer (vehicle) control to NCr nu/nu mice, followed by Trypan Blue dye to the same ID site at different time points from 30 minutes to 48 hours after injection of rHuPH20 or buffer.…”