Noe, A, Howard, C, Thuren, T, Taylor, A and Skerjanec, A (2014) Pharmacokinetic and Pharmacodynamic Characteristics of Single-Dose Canakinumab in Patients With Type 2 Diabetes Mellitus. Clinical Therapeutics.

Abstract

PURPOSE: Interleukin (IL)-1beta, an inflammatory molecule, contributes to the development of atherothrombosis and worsening of islet beta-cell function. Canakinumab, a human monoclonal antibody, targets IL-1beta-dependent inflammation and reduces the vascular inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), and other inflammatory cardiovascular biomarkers. Here, we aimed to assess the pharmacokinetic (PK) and pharmacodynamic characteristics, including the effect on hsCRP, of canakinumab in patients with type 2 diabetes mellitus (T2DM) after a 2-hour single-dose intravenous infusion. METHODS: This multicenter, randomized, double-blind, placebo-controlled, dose-escalation study was conducted in patients with T2DM (diagnosed >/=6 months before screening) on a stable daily dose of metformin. Patients were randomly assigned to receive a single intravenous dose of canakinumab 0.03, 0.1, 0.3, 1.5, or 10 mg/kg or placebo. The study was initially designed with 1 small cohort (15 patients, 0.3 mg/kg) on a stable dose of metformin >/=500 mg/d for an initial tolerability evaluation; all other patients were on a stable dose of >/=850 mg/d of metformin. The PK profile was assessed at 0 and 2 hours and at days 2, 14, 28, 56, 84, and 168. Changes in hsCRP and hemoglobin (Hb) A1c levels were assessed at weeks 4, 8, 12, and 24. FINDINGS: Of the 231 enrolled patients, 222 completed the study. Median hsCRP values at screening ranged from 1.8 to 3.2 mg/L, and the median daily dose of metformin ranged from 1000 to 2000 mg. Exposure to canakinumab was dose proportional. The mean half-life ranged from 17 to 26 days, and mean systemic clearance ranged from 0.094 to 0.128 mL/h/kg. Dose-related reductions in hsCRP were significantly greater with canakinumab compared with those with placebo at week 4 (-0.2 mg/L, -0.5 mg/L, -1.5 mg/L, and -1.7 mg/L with the 0.1-, 0.3-, 1.5-, and 10-mg/kg doses, respectively; all, P < 0.05). Significant reductions in hsCRP were maintained up to week 12 with the 2 highest doses of canakinumab (-0.8 mg/L with 1.5 mg/kg and -1.3 mg/L with 10 mg/kg; both, P < 0.05). A placebo-adjusted decrease in HbA1c of 0.31% at week 12 was reported with canakinumab 10 mg/kg (P = 0.038), and a reduction of 0.23% at week 4 was found with canakinumab 1.5 mg/kg (P = 0.011). IMPLICATIONS: The findings from this study suggest that IL-1beta blockade after single-dose administration of canakinumab at 1.5 and 10 mg/kg provided sustained suppression of hsCRP levels for 12 weeks in patients with T2DM. ClinicalTrials.gov identifier: NCT00900146

Item Type:	Article
Additional Information:	NIBR author: Taylor, A institute: NIBR contributor address: Novartis Pharma AG, Basel, Switzerland. Electronic address: adele.noe@novartis.comNovartis Pharmaceuticals Corporation, East Hanover, New JerseyNovartis Pharmaceuticals Corporation, East Hanover, New JerseyNovartis Institutes for BioMedical Research, Cambridge, MassachusettsNovartis Pharma AG, Basel, Switzerland
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/24238