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, bioavailability and safety/tolerability of single ascending doses of tildrakizumab after 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. After either single IV or SC dosing, tildrakizumab exhibited slow systemic clearance (CL), limited volume of distribution and a long t . Both the C and the area under the curve (AUC) increased proportionally with doses from 0.1 to 10 mg/kg, or 50-200 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 and 3 mg/kg IV. Across both studies, six of 43 evaluable subjects were positive for post-dose antidrug antibodies; two 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 and 200 mg administered SC were safe and well tolerated in healthy adult subjects.

<p>Tildrakizumab: An Evidence-Based Review of Its Use in the Treatment of Moderate-to-Severe Chronic Plaque Psoriasis</p>

“…Few serious AEs (SAEs) were identified. 15 – 17 , 25 From Kopp et al, 16 only one of the SAEs were considered possibly related to the treatment. Seventeen days after dosing with tildrakizumab 10 mg/kg, one elderly man experienced convulsion.…”

“…In 2008 to 2010, Khalilieh et al performed two randomized, placebo-controlled Phase I trials to assess the pharmacokinetics, bioavailability, and safety of single ascending doses tildrakizumab after intravenous (IV) and SC dosing in healthy subjects. 15 After both IV and SC dosing, tildrakizumab exhibited slow systemic clearance, limited volume of distribution and long half-life (t 1/2 ), ranging from 26.8 to 32.4 days. Furthermore, the maximum concentration (C max ) and the area under the curve (AUC) increased proportionally with dose over a range from 0.1 to 10 mg/kg (IV) and 50-200 mg (SC), respectively.…”

“…Phase I trials did not show any concerning AEs, with a similar incidence of adverse effects across treatment groups. 15,16 In the phase IIb trial, hypertension was reported more often in treatment groups (9 of 308) compared to placebo (0 of 45). 25 Most of these patients had hypertension or borderline hypertension at baseline, and none of the participants discontinued the treatment because of hypertension.…”

Mini Review: New Treatments in Psoriatic Arthritis. Focus on the IL-23/17 Axis

“…Tildrakizumab is a humanized IgG1κ MoAb that binds to the p19 subunit of IL-23 with high affinity and inhibits downstream signaling of IL-23. After SC injection, its half-life is 25 days (Khalilieh et al, 2018). It has been approved for the treatment of moderate-to severe plaque psoriasis.…”

Exposure–response characterisation of tildrakizumab in chronic plaque psoriasis: Pooled analysis of 3 randomised controlled trials

“…Tildrakizumab is a high‐affinity, humanised immunoglobulin G1κ (IgG1κ) monoclonal antibody that specifically binds to IL‐23p19; it does not bind to IL‐12/23p40 11 , 12 . Pharmacokinetics (PK), safety, bioavailability and clinical activity of tildrakizumab were evaluated among healthy subjects 12 and in subjects with moderate‐to‐severe plaque‐type psoriasis 11 in phase 1 studies. In phase 2b 13 and phase 3 14 clinical trials, subcutaneous (SC) tildrakizumab was safe and efficacious in the treatment of chronic plaque psoriasis.…”