An open‐label, single‐dose bioavailability study of the pharmacokinetics of CAT‐354 after subcutaneous and intravenous administration in healthy males

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The safety profile and effective dose of CAT-354 have been determined with intravenous (i.v.) administration, but no information is available on subcutaneous (s.c.) administration. WHAT THIS STUDY ADDS• This study characterized the pharmacokinetics of CAT-354 following s.c. administration of 150 mg and 300 mg doses, and indicated a bioavailability of approximately 60%. AIMTo assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration. METHODSThis was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20-54 years were randomly assigned to one of three dose groups (n = 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed. RESULTSCAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3-9 (median 5) days, with a mean elimination half-life of 19.2 Ϯ 3.1 days (150 mg) and 19.4 Ϯ 3.59 days (300 mg) after s.c. and 21.4 Ϯ 2.46 days after i.v. administration. Volume of distribution at steady state (Vss) was 4960 Ϯ 1440 ml kg -1 after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 Ϯ 82.3 and 307 Ϯ 109 ml day -1 after 150 and 300 mg s.c., respectively; systemic CL of 188 Ϯ 84.0 ml day -1 after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception. CONCLUSIONSCAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.

Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration

“…Following SC administration, the reported bioavailability of mAbs and Fc fusion proteins in humans are: adalimumab, 64%; canakinumab, 63-67%; certolizumab pegol, 76-88%; efalizumab, 50%; etanercept, 76%; golimumab, 53%; omalizumab, 53-71%; rilonacept, 43%; ustekinumab, 57% (2,63), and CAT-354 an anti-IL-13 human monoclonal IgG4 antibody 60-62% (64). Systemic bioavailability data of mAbs in various species are listed in Table II.…”

Targeting Interleukin-13 with Tralokinumab Attenuates Lung Fibrosis and Epithelial Damage in a Humanized SCID Idiopathic Pulmonary Fibrosis Model

“…In this study, we further explored IL-13-directed mechanisms in pulmonary fibrosis via the use of tralokinumab, an investigational human IgG4 monoclonal antibody that selectively neutralizes human IL-13 (27)(28)(29). We observed that the IL-13 pathway was significantly enhanced in biopsy samples from patients who exhibited a rapidly progressing form of IPF compared with patients with IPF with a slower rate of lung function loss (30), and inhibition of human IL-13 with tralokinumab attenuated established pulmonary fibrosis in a humanized SCID mouse model of IPF, notably with a reduction in lung epithelial cell damage.…”

Non‐Clinical Pharmacokinetics, Prediction of Human Pharmacokinetics and First‐in‐Human Dose Selection for CNTO 5825, an Anti‐Interleukin‐13 Monoclonal Antibody

“…The selected maximum dose (10.0 mg/kg, IV) for FIH study of CNTO 5825 provided predicted systemic exposures that were below observed systemic exposures at NO-AEL in rats and cynomolgus monkeys. In addition, the selected doses (0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg) of CNTO 5825 for FIH study were within the range of doses that have been evaluated in clinical studies of related anti-IL-13 mAbs [33][34][35][36].…”