title: Pharmacokinetic and pharmacodynamic characteristics of single-dose Canakinumab in patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  Interleukin (IL)-1β, an inflammatory molecule, contributes to the development of atherothrombosis and worsening of islet β-cell function. Canakinumab, a human monoclonal antibody, targets IL-1β-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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  The findings from this study suggest that IL-1β 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.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: adele.noe@novartis.com.
authors.forename: Adele
authors.initials: A
authors.lastname: Noe
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Campbell
authors.initials: C
authors.lastname: Howard
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Tom
authors.initials: T
authors.lastname: Thuren
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
authors.forename: Ann
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D008297:Male; D008687:Metformin / Q000008:administration & dosage; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D002097:C-Reactive Protein; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D008687:Metformin; C541220:canakinumab
keywords: canakinumab; high-sensitivity C-reactive protein; interleukin-1β; pharmacodynamics; pharmacokinetics; type 2 diabetes mellitus