Safety, tolerability and pharmacokinetics of a human anti-interleukin-13 monoclonal antibody (CNTO 5825) in an ascending single-dose first-in-human study

Abstract

Aims: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of CNTO 5825 following single-dose intravenous (i.v.) and subcutaneous (s.c.) administration in healthy and healthy atopic subjects.

Methods: Sixty-four subjects received a single dose of placebo or CNTO 5825 (0.1, 0.3, 1.0, 3.0, or 10 mg kg(-1) i.v. in a dose-escalating manner, or 3.0 mg kg(-1) s.c. in healthy subjects; and 10 mg kg(-1) i.v. in healthy atopic subjects). Subjects were observed for 96 h postadministration and followed for 16 weeks. Safety and tolerability were monitored, and serum samples were collected to measure CNTO 5825 concentrations, antibodies to CNTO 5825 and PD biomarkers.

Results: Most adverse events were mild to moderate in severity and considered to be unrelated to CNTO 5825, with no dose-dependent trends seen. The two serious adverse events were considered to be unrelated to CNTO 5825. After i.v. administration, CNTO 5825 exhibited linear PK, with a terminal half-life of ∼22-32 days. After a single 3 mg kg(-1) s.c. dose in healthy subjects, CNTO 5825 was absorbed into the systemic circulation with a median time to maximum serum concentration (tmax) of 5.45 days and absolute bioavailability of ∼75%. The PK profile of CNTO 5825 at 10 mg kg(-1) was similar in both healthy and healthy atopic subjects. No antibodies to CNTO 5825 were detected through week 16. In the CNTO 5825-treated healthy atopic subjects, there was a significant reduction in serum IgE and C-C motif chemokine ligand 17 (P = 0.028 and 0.068 vs. placebo, respectively).

Conclusions: CNTO 5825 was well tolerated, had an acceptable safety profile, exhibited linear PK characteristics, and no detected antibodies to CNTO 5825.

Trial registration: ClinicalTrials.gov NCT01081691.

Figure 1

Mean (±SD) CNTO 5825 serum concentration–time profiles following a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of CNTO 5825 in healthy subjects. , 0.1 mg kg^–1 i.v.; , 0.3 mg kg^–1 i.v.; , 1.0 mg kg^–1 i.v.; , 3.0 mg kg^–1 i.v.; , 10 mg kg^–1 i.v.; , 10 mg kg^–1 i.v., atopic subjects; , 3.0 mg kg^–1 s.c.

Figure 2

Serum levels of IgE (A), CCL17 (B), CCL5 (C), CCL11 (D) and CXCL5 (E) in subjects in the 10 mg kg⁻¹ i.v. atopic cohort following dosing of CNTO 5825 or placebo. , placebo; , CNTO 5825