Development of a Pharmacokinetic Model Describing Neonatal Fc Receptor‐Mediated Recycling of HL2351, a Novel Hybrid Fc‐Fused Interleukin‐1 Receptor Antagonist, to Optimize Dosage Regimen

HL2351 (hIL‐1Ra‐hyFc) is a novel recombinant protein formed by the fusion of two human interleukin‐1 receptor antagonist components into one antibody‐derived fragment crystallizable portion. Although HL2351 has a pharmacological mechanism of action similar to that of anakinra as a commercialized biopharmaceutical drug, HL2351 has been desired to reduce the dose frequency and improve therapeutic efficacy due to its long circulation half‐life. In this study, we aimed to develop a population pharmacokinetic (PK) model for HL2351 using a neonatal Fc receptor (FcRn)–mediated recycling model based on a quasi‐steady‐state approximation of target‐mediated drug disposition (TMDD) for the description of interactions between the drug and FcRn. FcRn recycling was expected in the case of HL2351 because of PK related to the antibody portion. A TMDD model was also applied to describe interactions of IL1R with HL2351 or anakinra. PK data were collected from a phase I study conducted in six groups (1, 2, 4, 8, 12 mg/kg HL2351 and 100 mg anakinra single subcutaneous administration; n = 8 per group). In consequence, the PK of anakinra and HL2351 following administration of multiple doses at different dosages were simulated. Optimized doses were considered based on average concentrations of IL1R bound to anakinra and HL2351. HL2351 at doses of 326 mg or 4.267, 4.982, 5.288, 5.458, or 5.748 mg/kg once weekly or HL2351 at 1726 mg or 21.92, 26.86, 29.10, 30.36, or 32.53 mg/kg once biweekly would have similar therapeutic effects with anakinra at a dose of 100 mg or 1, 2, 3, 4, or 8 mg/kg administered once daily, respectively.