Subcutaneous Injection Performance in Yucatan Miniature Pigs with and without Human Hyaluronidase and Auto-injector Tolerability in Humans

Abstract

Recombinant human hyaluronidase PH20 (rHuPH20) facilitates subcutaneous (SC) delivery of co-administered therapeutic agents by locally and transiently degrading hyaluronan in the SC space, and can be administered with therapeutics using a variety of devices. Two SC delivery studies were carried out to assess auto-injector (AI) performance, each in 18 Yucatan miniature pigs. Abdominal injections were administered using three auto-injectors of 1 mL (AI1) and 2 mL (AI2 and sAI2) with different injection speeds and depths (5.5–7.5 mm) and two pre-filled syringe (PFS) devices of 1 and 2 mL. The injection included a placebo buffer with and without rHuPH20 to evaluate the effect of rHuPH20 on SC injection performance. The feasibility of using similar devices to deliver a placebo buffer in humans was investigated. rHuPH20 was not studied in humans. In miniature pigs, postinjection swelling was evident for most PFS/AI injections, particularly 2 mL. Swelling heights and back leakage were typically lower with rHuPH20 co-administration versus placebo for most device configurations (1 or 2 mL PFS or AI). Auto-injections with versus without rHuPH20 also resulted in reduced swelling firmness and faster swelling resolution over time. Slow injections with rHuPH20 had shorter and more consistent injection time versus placebo. In humans, minimal injection site swelling and negligible back leakage were observed for 2-mL injections of placebo, while more erythema was observed in humans versus miniature pigs. Even at high delivery rates with PFS or AI, the addition of rHuPH20 resulted in improved SC injection performance versus placebo in miniature pigs.

Identifying a predictive relationship between maximal flow rate and viscosity for subcutaneous administration of macromolecules with recombinant human hyaluronidase PH20 in a miniature pig model

“…These results suggest that rHuPH20 can improve the performance of delivery devices by degrading HA in the extracellular matrix of the SC space, reducing the SC tissue constraints to bulk fluid flow that otherwise impede the device hardware, thereby allowing for higher delivery rates required for large-volume SC administration (Bookbinder et al., 2006 ; Kang et al., 2012 ). Similar results were observed in a recent study of miniature pigs, in which the addition of rHuPH20 to test solutions administered subcutaneously resulted in shorter injection times and reduced swelling at the injection site with some auto-injector devices (Shi et al., 2021 ).…”

“…In addition, previous pre-clinical studies have demonstrated that infusion of human Ig facilitated by rHuPH20 was effective in reducing HA in the SC space in a Yucatan miniature pig model (Kang et al., 2012 ). A previous study reported similarities between Yucatan miniature pigs and humans in terms of injection-site swelling and back leakage when test solutions were administered in the SC space (Shi et al., 2021 ). It has also been demonstrated that rHuPH20 can facilitate SC infusion of a polyclonal human gamma Ig solution in a Yucatan miniature pig model by significantly reducing in-line pressure, resulting in increased fluid dispersion while minimizing infusion-related local swelling and induration (Kang et al., 2012 ).…”

Safety of recombinant human hyaluronidase PH20 for subcutaneous drug delivery

“…These devices improve the ease of administration for patients and caregivers over needle and syringe delivery systems. Preclinical studies have shown that the addition of rHuPH20 to a SC injection via an autoinjector resulted in improved SC injection performance compared with placebo for volumes up to 2 mL even at high delivery rates [94]. It is a reasonable hypothesis to suggest that similar results are likely to be seen when rHuPH20 is used in a device in a human study.…”

A review of Formulations of Commercially Available Antibodies

“…The coadministration of hyaluronidase has been shown to not only increase bioavailability and reduce t max , but also to improve overall injection by lower swelling and reduced injection time due to the onset of action for hyaluronidase. 19,20 However, the onset is not rapid enough to enable the use of an autoinjector which typically injects the solution in under 15 seconds. 15…”

“…The DAR in Polivy TM is 3.5, and in Padcev TM is 3.8. Polivy TM is a lyophilized powder and after reconstitution with 1.8 mL or 7.2 mL WFI contains 20 mg/mL polatuzumab vedotin-piiq, sucrose 40 mg/mL, polysorbate 20 (1 mg/mL), and a pH 5.3 succinate 0.008M buffer. Padcev TM is a lyophilized powder and after reconstitution with 2.3 mL or 3.3 mL WFI contains 10 mg/mL enfortumab vedotin-ejfv, trehalose dihydrate 55 mg/mL, polysorbate 20 (0.2 mg/mL), and a pH 6.0 histidine 0.02M buffer.…”