Comparable Pharmacokinetics, Safety, and Tolerability of Etrolizumab Administered by Prefilled Syringe or Autoinjector in a Randomized Trial in Healthy Volunteers

Abstract

Introduction: Etrolizumab is a novel, dual-action anti-β7 integrin antibody studied in phase 3 trials in patients with inflammatory bowel disease. An autoinjector (AI) is being developed in parallel to complement the prefilled syringe with needle safety device (PFS-NSD) for subcutaneous (SC) administration in these trials. Here we demonstrate the comparable pharmacokinetics, tolerability, and safety of both devices.

Methods: This randomized, open-label, two-part study in healthy participants evaluated the comparability of etrolizumab exposure between the AI and the PFS-NSD. Part 1 (pilot) involved a small number of participants, and initial results were used to finalize the design of the larger part 2 (pivotal) study. In both parts, participants were randomly assigned to receive a single SC dose of etrolizumab 105 mg by AI or PFS-NSD. Randomization was stratified by body weight. Primary pharmacokinetic outcomes were Cmax, AUClast, and AUC0-inf.

Results: One hundred and eighty healthy participants (part 1, n = 30; part 2, n = 150) received a single SC dose of etrolizumab by AI or PFS-NSD. Primary pharmacokinetic results from part 1 supported modification of the part 2 study design. Results from part 2 demonstrated that etrolizumab exposure was equivalent between devices, with geometric mean ratios (GMRs) between AI and PFS-NSD of 102% (90% confidence interval [CI] 94.2-111) for Cmax, 98.0% (90% CI 89.3-107) for AUClast, and 97.6% (90% CI 88.6-107) for AUC0-inf. Median tmax and mean terminal t1/2 were also similar between devices. GMRs and 90% CIs of all primary pharmacokinetic parameters were fully contained within the predefined equivalence limits (80-125%).

Conclusion: This pharmacokinetic study demonstrated that single SC injections of etrolizumab 105 mg using an AI or a PFS-NSD resulted in equivalent etrolizumab exposure and similar safety and tolerability in healthy participants. Taken together, these results support the use of an AI for etrolizumab administration.

Trial registration: NCT02996019.

Keywords: Auto-injector; Crohn’s disease; Etrolizumab; Inflammatory bowel disease; Pharmacokinetic comparability; Prefilled syringe; Ulcerative colitis.

Figures

Fig. 1

Prefilled etrolizumab autoinjector

Fig. 2

Participant disposition. AI autoinjector, AUC area under the curve, PFS-NSD prefilled syringe with needle safety device, PK pharmacokinetic, SC subcutaneous. aExcluded because of eligibility criteria (weight restriction). Participants were excluded from specific PK analyses because of insufficient PK data for calculations

Fig. 3

Impact of body weight on etrolizumab aCmax and b AUC0–inf. AI autoinjector, AUC area under the curve, AUC0–infAUC extrapolated to infinity, Cmax maximum concentration, PFS-NSD prefilled syringe with needle safety device, SC subcutaneous

Fig. 4

Etrolizumab serum concentrations (arithmetic mean ± standard deviation) over time with AI and PFS-NSD on a linear scale (a) and a semilogarithmic scale (b) in the pivotal study. AI autoinjector, PFS-NSD prefilled syringe with needle safety device

Fig. 5

Etrolizumab serum concentrations over time by ADA status with (a) AI and (b) PFS-NSD. ADA antidrug antibody, AI autoinjector, PFS-NSD prefilled syringe with needle safety device