Model‐Informed Dose Optimization of Anakinra in Preterm Neonates Implications for Safe and Effective Dosing

Anakinra, an interleukin‐1 receptor antagonist, shows promise for reducing inflammatory complications of premature birth. However, the pharmacokinetics (PK) of anakinra in neonates has not been characterized, limiting evidence‐based dosing. This study aimed to develop a population PK model for anakinra to guide dosing in preterm neonates. Data from 25 preterm neonates (median gestational age: 26.3 weeks) from a Phase I/IIa trial of intravenous anakinra (Anakinra Pilot, NCT05280340) were analyzed, with 4–8 samples collected per neonate across 0–20 days postnatal age (PNA). A population PK model was developed and dosing simulations were performed incorporating a pharmacodynamic (PD) direct effect model (I _max , IC ₅₀ ) and target exposure (AUC _0‐24h ). The data were best described by a one‐compartment model with linear elimination and a baseline component for endogenous IL‐1Ra. Allometric scaling was applied to clearance (CL) and volume of distribution (V), with a maturation function using PNA on CL to account for early age‐related pharmacokinetic changes. Estimated CL and V were 3.97 L/h/70 kg (0.15 L/h/0.9 kg) and 28.9 L/70 kg (0.37 L/h/0.9 kg). At birth, CL was ~45% of the maximal early postnatal value, achieving ~100% by day 10 PNA. Simulations suggest that an optimal intravenous dosing regimen of 0.6 mg/kg 12 hourly at birth, 0.8 mg/kg 12 hourly on PNA day 1, 1.0 mg/kg 12 hourly from PNA days 2–3 and 1.15 mg/kg 12 hourly day 4 onward. This model delivers the first critical understanding of small protein PK in premature neonates, establishing a foundation for evidence‐based dosing strategies to guide future prospective clinical trials.