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 (Imax, IC50) and target exposure (AUC0-24h). 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.