Pharmacokinetics of canakinumab and pharmacodynamics of IL-1β binding in patients with cryopyrin associated periodic fever syndromes
Stacey Tannenbaum[1], Abhijit Chakraborty[1], Christiane Rordorf[2], Aurélie Gautier[2] & Philip Lowe[2]
[1] Novartis Pharmaceuticals Inc, East Hanover, New Jersey, USA; [1] Novartis Pharmaceuticals AG, 4002 Basel, Switzerland
Objectives: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a fully human anti-IL1β monoclonal antibody (canakinumab, ACZ885) in pediatric patients <18 years and to compare the PK and PD parameters with those of adults to determine the need for dosing adjustments.
Methods: A clinical efficacy study in patients with cryopyrin associated periodic fever syndrome (CAPS) in which canakinumab was administered intravenously or subcutaneously included 12 pediatric patients. PK and PD data from these studies were pooled with adult PK and PD data from canakinumab trials in other indications for a total of 233 subjects. Extensive characterization of the pharmacokinetics of canakinumab and pharmacodynamics of total IL-1β in serum was performed using PKPD modeling. A dynamic drug-ligand binding and target turnover model based on the relationship:
canakinumab + IL-1β ⇔ canakinumab-IL-1β complex
which integrates both monoclonal and IL-1β inputs and elimination (turnover) and binding affinity, was developed and parameter values estimated for both PK and PD using the NONMEM software.
Results: Estimates of drug clearance and volume of distribution were closely correlated with body weight; pediatric subjects, being smaller, had slower overall clearances and reduced volumes compared with adults, such that the half-lives were similar. The equilibrium dissociation constant for binding of canakinumab to IL-1β (Kd), was similar in adult and pediatric patients.
Conclusions: The linear dependence of canakinumab clearance with body weight justified weight normalized dosing in pediatric patients weighing less than or equal to 40 kg. The pharmacodynamics of canakinumab were comparable between adult and pediatric patients indicating no change in sensitivity with age or in factors that might compete for IL-1β binding.