Pharmacokinetic and pharmacodynamic properties of canakinumab in patients with gouty arthritis

Abstract

Pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1β monoclonal antibody, canakinumab, in gouty arthritis patients from three studies are reported. Canakinumab has low serum clearance (0.214 L/day), low steady-state volume of distribution (7.44 L), a 25.8-day half-life, and approximately 60% subcutaneous absolute bioavailability in a typical 93-kg patient. Creatinine clearance had a small positive impact on serum canakinumab clearance that is not likely to be clinically relevant. Binding to circulating IL-1β was demonstrated by increases in total serum IL-1β following canakinumab dosing. Total IL-1β kinetics and canakinumab pharmacokinetics were characterized by a population-based pharmacokinetic-binding model, where the estimated apparent in vivo dissociation constant (signifying binding affinity of canakinumab to circulating IL-1β) was 0.99 nmol/L in gouty arthritis patients. Canakinumab treatment provided rapid, sustained decreases in C-reactive protein and serum amyloid A, provided superior pain relief to triamcinolone acetonide, and increased time to first recurrent attack (P ≤ 0.01 favoring all canakinumab doses vs. triamcinolone acetonide).

Feasibility randomised multicentre, double-blind, double-dummy controlled trial of anakinra, an interleukin-1 receptor antagonist versus intramuscular methylprednisolone for acute gout attacks in patients with chronic kidney disease (ASGARD): protocol study

“…[20][21][22] It was associated with increased adverse events after a single injection 23 which was felt in part due to its prolonged action which can be for many weeks. 24 This study will use anakinra (Kineret), an IL-1 receptor antagonist that competes with IL-1beta for its receptor. A pilot study of its use in gout showed prompt resolution of symptoms in patients treated with anakinra, 25 including in three patients with renal impairment.…”

De novoisolation of antibodies with pH-dependent binding properties

“…For instance, mAbs directed against soluble targets such as cytokines, can induce significant target accumulation due to the formation of stable antibody-antigen complexes that are recycled via the interaction with the neonatal Fc receptor (FcRn). [18][19][20][21][22] FcRn is responsible for the long serum half-life of IgGs that bind this receptor in the slightly acidic environment of the early endosome and are then returned to the extra-cellular compartment. 23 Interestingly, if the antibody-antigen interaction is stable under these conditions, the bound antigen is recycled with the antibody and persists in circulation.…”

Pharmacokinetics considerations for gout treatments

“…The halflife is 25.6 days. Canakinumab has low serum clearance (0.214 l/day), low steady-state volume of distribution (7.44 lL) and approximately 60% subcutaneous absolute bioavailability in a typical 93-kg patient [33]. Because canakinumab is a human IgG with a large molecular size, little renal excretion is expected because little intact immunoglobulin can be filtered by the kidney [34].…”

“…Indeed, most of the IgG elimination occurs via intracellular catabolism, following receptor mediator endocytosis [35]. In patients in the Childhood Arthritis Prospective Study (CAPS), creatinine clearance did not have any noticeable effect on the clearance of canakinumab, and therefore, no dose adjustment is required for patients with renal impairment [33,34]. Age and sex do not seem to modify the clearance or volume of distribution of the drug.…”

“…Age and sex do not seem to modify the clearance or volume of distribution of the drug. No study of canakinumab has been performed in patients with impaired hepatic function because most of the IgG elimination occurs via intracellular catabolism [33]. For the same reason, no in vitro metabolism or drug interaction studies have investigated canakinumab, and drugs such as allopurinol, febuxostat or colchicine are not expected to influence its pharmacokinetics.…”