The INFUSE-Morphine IIB Study: Use of Recombinant Human Hyaluronidase (rHuPH20) to Enhance the Absorption of Subcutaneous Morphine in Healthy Volunteers

Abstract

Morphine is usually given intravenously (IV) for the treatment of moderate-to-severe pain, but subcutaneous (SC) administration is a viable alternative for parenteral delivery. The pharmacokinetics of SC morphine may be enhanced by coadministration with a hyaluronidase product. In this Phase IV, double-blind, randomized, crossover study, 18 healthy adults received a single dose of 2mg morphine SC with 150U of recombinant human hyaluronidase (rHuPH20), SC with 0.9% normal saline, or IV on three consecutive days. The primary endpoint was time to maximum plasma morphine concentration (T(max)) for SC injection with rHuPH20 vs. SC injection without rHuPH20. Safety and tolerability were assessed each study day, the day after the last injection, and 28 days after the last injection. After SC dosing, morphine mean T(max) was significantly shorter with rHuPH20 than without it. Mean maximum plasma morphine concentration (C(max)) after SC dosing was 29% greater with rHuPH20 than without rHuPH20 (P=0.023), although the extent of exposure of morphine was similar. T(max) was shortest and C(max) was highest with IV administration. For the major active metabolite of morphine, morphine-6-glucuronide, mean T(max) after SC morphine was significantly shorter with rHuPH20 than without rHuPH20 (a difference of approximately 17.5 minutes; P=0.0169). Coadministration of morphine with rHuPH20 appeared safe and well tolerated. Compared with SC morphine alone, rHuPH20 shortens morphine T(max) and raises C(max) in healthy adults, without changing the extent of exposure.