Pharmacokinetics of l-Citrulline in Neonates at Risk of Developing Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

Background: Options to treat pulmonary hypertension (PH) in neonates with bronchopulmonary dysplasia (BPD) are few and largely ineffective. Improving the bioavailability of nitric oxide (NO) might be an efficacious treatment for BPD-PH. When administered orally, the NO-l-arginine precursor, l-citrulline, increases NO production in children and adults, however, pharmacokinetic (PK) studies of oral l-citrulline have not been performed in infants and children. Objectives: This study characterized the PK of enterally administered l-citrulline in neonates at risk of developing BPD-PH to devise a model-informed dosing strategy. Methods and results: Ten premature neonates (≤ 28 weeks gestation) were administered a single dose of 150 mg/kg (powder form solubilized in sterile water) oral l-citrulline at 32 ± 1 weeks postmenstrual age. Due to the need to limit blood draws, time windows were used to maximize the sampling over the dosing interval by assigning neonates to one of two groups (ii) samples collected pre-dose and at 1- and 2.5-h post-dose, and (ii) pre-dose and 0.25- and 3-h post-dose. The l-arginine concentrations (µmol/L) and the l-citrulline (µmol/L) plasma concentration-time data were evaluated using non-compartmental analysis (Phoenix WinNonlin version 8.1). Optimal dosage strategies were derived using a simulation-based methodology. Simulated doses of 51.5 mg or 37.5 mg/kg given four times a day produced steady-state concentrations close to a target of 50 µmol/L. The volumeof distribution (V/F) and clearance (CL/F) were 302.89 ml and 774.96 ml/h, respectively, with the drug exhibitinga half-life of 16 minutes. The AUC from the time of dosing to the time of last concentration was 1473.3 h*μmol/L,with C_max and T_max of 799 μmol/L and 1.55 h, respectively. Conclusion: This is the first PK study in neonates presenting data that can be used to inform dosing strategies in future randomized controlled trials evaluating enteral l-citrulline as a potential treatment to reduce PH associated with BPD in premature neonates. Registration: Clinical trials.gov Identifier: NCT03542812.