Clinical Pharmacokinetics and Pharmacodynamics of the IL-1 Receptor Antagonist Anakinra: A Systematic Review

Anakinra, an interleukin-1 receptor antagonist (IL-1Ra), has been used clinically for over 20 years, with growing interest in repurposing it across diverse indications. However, clinical dosing strategies for anakinra are variable, with limited pharmacokinetic (PK)/pharmacodynamic (PD) knowledge across patient populations and administration routes available. This systematic review aimed to summarise clinical PK and PD characteristics of anakinra and identify research gaps.

A systematic search of Medline, Embase, and other databases was conducted to identify clinical studies reporting the PK, PD, efficacy, and safety of anakinra. Following the application of predefined inclusion and exclusion criteria, 26 articles were included in the review. Extracted data from these studies were converted into uniform units to enable cross-study comparison, and a descriptive synthesis was performed. All included studies were assessed for risk of bias.

Data were categorised into three groups: noncompartmental analysis (NCA) PK parameters, model-informed PK/PD parameters, and exposure-response (ER) relationships. Across all studies, anakinra demonstrated linear PK following both intravenous (IV) and subcutaneous (SC) administration, with high SC bioavailability and flip-flop kinetics. Covariate analyses from NCA and PK models consistently identified body weight and renal function as key determinants of anakinra PK variability, with clearance increasing with body weight and decreasing with worsening renal function. ER analyses identify a potential target exposure corresponding to an average steady-state concentration (C_avg,ss) of 0.4 mg/L, equivalent to a steady-state area under the concentration-time curve (AUC_{0-24 h,ss}) of 9.6 mg·h/L. However, available anakinra paediatric clinical PK data are sparse, limiting definitive age-based comparisons. Existing PK models of anakinra lacked incorporation of endogenous IL-1Ra kinetics, and do not currently describe diverse patient populations, with only one population PK/PD model identified. Furthermore, currently available data are insufficient to validate the target exposure of anakinra across the full continuum spanning PK, PD, clinical outcomes, and safety.

Overall, this review highlights substantial gaps in the clinical PK/PD knowledge on anakinra, and model robustness. Future studies, integrating physiologically informed covariates, improved biomarker strategies, and comprehensive ER data, are essential to support model-informed dosing for anakinra repurposing across populations and administration routes. These would facilitate the safety and efficacy of anakinra therapy across diverse populations.