Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia.

Objective: Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline as a therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Our goal was to evaluate the tolerability and ability to achieve a target steady-state L-citrulline plasma concentration in prematures treated enterally with a multi-dose L-citrulline strategy based on our single-dose pharmacokinetic study. Study Design: Six prematures received 60 mg/kg of L-citrulline every 6 hours for 72 hours. Plasma L-citrulline concentrations were measured before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study. Results: Plasma L-citrulline concentrations agreed with the simulated concentration-time profiles. No serious adverse events occurred. Conclusions: Simulations based on single-doses can be used to predict target multi-dose plasma L-citrulline concentrations. These results assist the design of RCTs evaluating the safety and effectiveness of L-citrulline therapy for BPD-PH. Clinical trials.gov ID: NCT03542812.