Pharmacokinetics of Tildrakizumab (MK‐3222), an Anti‐IL‐23 Monoclonal Antibody, After Intravenous or Subcutaneous Administration in Healthy Subjects

Abstract

Tildrakizumab, a high-affinity humanized IgG1k antibody that selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function, is under investigation for treatment of moderate-to-severe chronic plaque psoriasis. The objective of this analysis was to assess the pharmacokinetics (PK), bioavailability and safety/tolerability of single ascending doses of tildrakizumab following intravenous (IV) and subcutaneous (SC) dosing in healthy subjects. P05661 was a phase 1, single dose, randomized, placebo-controlled study of tildrakizumab IV doses of 0.1, 0.5, 3 and 10 mg/kg, or placebo. P05776 was a phase 1, single-dose, randomized, placebo-controlled study of tildrakizumab SC doses of 50 or 200 mg, or placebo. Following either single IV or SC dosing, tildrakizumab exhibited slow systemic clearance, limited volume of distribution and a long t_½. Both the C_max and the area under the curve (AUC) increased proportionally with doses from 0.1 mg/kg to 10 mg/kg, or 50 to 200 mg. The bioavailability of SC dosing was ~80% (90% CI: 62%–103%) for 50 mg and ~73% (90% CI: 46%–115%) for 200 mg, respectively, versus 0.5 mg/kg and 3 mg/kg IV. Across both studies, 6 of 43 evaluable subjects were positive for post-treatment antidrug antibodies; 2 of these were positive for neutralizing antibodies. Most adverse events (AEs) were mild; the most frequent AEs included upper respiratory tract infection and headache. Single doses of tildrakizumab 0.1, 0.5, 3 and 10 mg/kg administered IV or single doses of 50 mg and 200 mg administered SC were safe and well tolerated in healthy adult subjects.