Comparison of Subcutaneous and Intravenous Administration of Trastuzumab: A Phase I/Ib Trial in Healthy Male Volunteers and Patients With HER2‐Positive Breast Cancer

Abstract

Trastuzumab is a key component of treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in both the early and metastatic settings. It is administered intravenously, with between 17 and 52 infusions in standard regimens over 1 year. Intravenous administration of trastuzumab requires substantial time commitments for patients and health care professionals and can result in patient discomfort. A subcutaneous formulation of trastuzumab, containing recombinant human hyaluronidase to overcome subcutaneous absorption barriers, would reduce the administration duration and remove the need to establish intravenous access, thus improving the overall convenience of trastuzumab administration. This open-label, 2-part, phase I/Ib study (NCT00800436) was undertaken in healthy male volunteers and female patients with HER2-positive early breast cancer to identify the dose of subcutaneous trastuzumab that resulted in exposure comparable with the approved intravenous trastuzumab dose. A subcutaneous trastuzumab dose of 8 mg/kg was found to result in exposure comparable with the intravenous trastuzumab dose of 6 mg/kg. The subcutaneous formulation was well tolerated, with a trend toward fewer adverse events versus intravenous administration; most adverse events were mild in intensity. These results support an ongoing phase III efficacy and safety study comparing a fixed subcutaneous trastuzumab dose with intravenous trastuzumab administration.

Tolerability of High-Volume Subcutaneous Injections of a Viscous Placebo Buffer: A Randomized, Crossover Study in Healthy Subjects

“…Subcutaneous (SC) administration is hampered by the extracellular matrix, which offers a barrier to the delivery of many drugs, limiting both the volume that can be injected at a single site and the amount that can reach the vascular compartment [6]. Therefore, research has focused on methods that permit delivery of larger volumes into the SC space, such as recombinant human hyaluronidase to temporarily degrade interstitial hyaluronan [6,7].…”

A Phase I Dose-Escalation and Bioequivalence Study of a Trastuzumab Biosimilar in Healthy Male Volunteers

“…The other pharmacokinetic parameters (t max , k z , t ) did not differ significantly between FTMB and the Reference product. Trastuzumab was previously tested by Wynne et al [6] in a small cohort of healthy male volunteers (n = 6) as part of an investigation of a subcutaneous formulation, and provided limited data regarding the safety of a single dose of trastuzumab in healthy males. Our study design was intended to mitigate the risks associated with testing trastuzumab in healthy males by adding a dose-escalation part and careful monitoring of cardiac function.…”

The Activity of Hyaluronan and Hyaluronidase PH20 in Inflammation-A Role by Reagent Contaminants?

“…The first clinical study using rHuPH20 with trastuzumab delivered subcutaneously did not have any serious adverse events (SAEs) or severe hypersensitivity reactions [19]. Continuing in the development program, there were no cases of severe hypersensitivity reactions, such as anaphylaxis in the pivotal phase 3 HannaH trial comparing SC versus intravenous (IV) trastuzumab formulations.…”